SCORECARD - Scientific American Worldview

Transcription

worldView
a global biotechnology perspective
Featuring the
Worldview
Scorecard
A country-by-country
assessment of innovation
climates across the globe
5 WorldView 09
International Strategies in
Challenging Times
Cutting-Edge Science &
Technology
Social & Political Dimensions
of Life Science Progress
Fostering a Worldwide
“Innovation Climate”—with Clarity, not Clichés
By Steven Yee
I
Illustration by Aaron McKinney
n science, transformative
ideas are rarely hatched
in a vacuum. Despite the
romantic notion of the lone
researcher toiling toward a
moment of solitary genius,
the optimum conditions for ingenuity and the delivery of its attendant
societal benefits are best created in a
hospitable climate for innovation.
An innovation climate is very
much like that of any other climate,
be it political, economic, social or
even meteorological. When the
various conditions and influences
are favorably aligned, this can set the
stage for truly transformative events
and ideas. This is particularly true
in the life sciences, where ideas have
the potential to bring about dramatic
improvements in healthcare, energy,
global food demand and industrial
processes—but only if circumstances
allow these ideas to be properly nurtured and developed.
Creating the necessary conditions
for successful biotechnology development is uniquely challenging. Patent
a widget, and you can sell it tomorrow. Patent a biological molecule and
the timeframe for clinical trials and
regulatory approval can span 12 or
more years. Though such scientific
advancements carry enormous potential, the sheer cost in time, effort
and financial resources necessary
for the idea-to-product process is
staggering. This is where policy takes
center stage. For governments across
the world, fostering an environment that offers sound educational
opportunities, rewards ingenuity,
encourages investment, protects
intellectual property and ensures the
safety and benefits of new products
is a Herculean task—a task infinitely
compounded by the current global
economic crisis, where credit and
cash are scarce and promising innovative ideas face an uncertain future.
To elucidate the subject of international life science support and its
many challenges, we proudly offer
this special annual report, Scientific
American Worldview: A Global
Biotechnology Perspective,
covering the most-relevant advancements in biotechnology in the context
of international progress.
Our annual Worldview Scorecard
headlines this report with a countryby-country assessment of the best
national innovation climates in the
world today. We hope this ranking
will inspire dialogue, comments, feedback and reflection among a broad
audience of world leaders in science,
policy, government and business. We
also hope that both emerging and mature markets will gain valuable insight
from the issues and stories we cover.
In addition to quantitative analyses
of various nations, we also provide
unique country spotlights that illustrate significant biotechnical developments poised to make an impact.
This exciting project from
Scientific American—led by an
independent team of editors and
experts—is intended to offer an objective and comprehensive roadmap to
understanding genuine innovation,
a term that must remain meaningful and be ever-scrutinized, lest it
become a cliché devoid of substance.
As a global publisher, our role is to
clarify, not complicate issues. Through
our Worldview report, we hope to go
beyond innovation as a buzzword or
marketing concept, and explore its
true scientific, societal, economic and
political dimensions.
We are enormously grateful for
the support of the forward-thinking
companies and organizations that
have made this project possible:
Amgen, our Marquee Sponsor; the
Biotechnology Industry Organization;
Merck; and Pfizer.
We welcome your comments
and feedback as we span the globe
in search of the best biotechnology
has to offer, and as we address today’s
economic challenges by demanding a
renewed commitment to innovative
thinking and strategies worldwide.
Steven Yee is the president of Scientific
American, Inc.
introduction
i
worldView
a global biotechnology perspective
Scientific American Worldview is published by Scientific American, Inc.
with project management by
Publication Director:
Jeremy Abbate
Editorial Director:
Mike May
Art Director:
Joelle Bolt
Lead Editorial Consultant:
Yali Friedman
Board of Advisers
Andrew Powell:
CEO of Asia BioBusiness
Bruce Jennet:
Co-Chair, Global Life Science Sector,
DLA Piper
David Beier:
Senior Vice President, Global Government and Corporate Affairs, Amgen
Sean Darragh:
Executive Vice President,
International Affairs, BIO
Steven Casper:
Associate Professor and Director of
Masters of Bioscience Program at
Keck Graduate Institute
Tomasz Mroczkowski:
Willy De Greef:
Professor and Chair of the International Business Department,
Kogod School of Business, American
University
Secretary General of EuropaBio
On The Cover:
adapted from original art:
© digital art/corbis
Editor in Chief:
John Rennie
Executive Editor:
Mariette DiChristina
Managing Editor:
Ricki L. Rusting
Chief News Editor:
Editors:
Philip M. Yam
Peter Brown
Davide Castelvecchi
Graham P. Collins
Mark Fischetti
Steve Mirsky
Michael Moyer
George Musser
Christine Soares
Kate Wong
Associate Publisher, Production:
William Sherman
Production Manager:
Christina Hippeli
Prepress and Quality Manager:
President:
Vice President and Publisher:
Silvia De Santis
Steven Yee
Bruce Brandfon
Director, Global Media:
Jeremy Abbate
Vice President, Finance and
General Manager:
Michael Florek
Managing Director, International:
Vice President:
Managing Director, Online:
Kevin Hause
Frances Newburg
Michael Harbolt
The publisher would like to thank Joseph M. Damond and Sean Darragh
for their steadfast championing of this project.
Scientific American Worldview is published by Scientific American, Inc., 415 Madison
Avenue, New York, NY 10017. Copyright © 2009 by Scientific American, Inc. All rights
reserved. No part of this issue may be reproduced by any mechanical, photographic
or electronic process, or in the form of an audio recording, nor may it be stored in a
retrieval system, transmitted or otherwise copied for public or private use without
written permission of the publisher.
Contact us at [email protected]
2
Scientific American | WorldView
CONTENTS
Scientific American Editorial and Publishing Staff
5
Why Take a Worldview?
Looking far and wide to see our
innovation future
By Yali Friedman and Mike May
POLICY &
ECONOMICS
6
Fighting in the Face
of Distress
Undervalued and cash-strapped, a
global industry wrestles with its future
By Mike May
20
Turf Battles:
Politics Interfere with
Species Identification
As nations view their flora and
fauna as commodities, science
suffers
By Linda Baker
22
The Next Generation
of Biofuels
Algae and engineered
microorganisms—the oil of
tomorrow
By Melinda Wenner
10
26
The increasingly global nature
of the pharmaceutical supply
chain presents opportunities, but
requires panoramic vigilance
What makes follow-on biologics
a thousand times messier than
typical generic drugs?
Overseeing Outsourcing
The Regulatory Battle
over Biosimilars
By Cormac Sheridan
By Jared Feldman
14
28
Protecting IP:
Anything but Simple
Countries that once ignored
intellectual property now embrace
it to protect their own inventions
By Peter Gwynne
Rescues around
the World
From cash infusions to tax
incentives, countries are seeking
ways to boost biotech
By Ted Agres
THE SCIENTIFIC AMERICAN
WORLDVIEW
SCORECARD
A biotechnology survey
assessing innovation
capacities across the globe,
with a quantitative, countryby-country analysis.
SCIENCE &
TECHNOLOGY
60
32
Introduction and
Data Summary
by Yali Friedman
42
Case Studies in
Innovation:
County Spotlights
Life science stories from around
the world: Singapore, Israel,
China, Brazil, Canada, Australia,
Spain, Hungary, Scotland,
Mexico, South Africa and India
What Biotech Needs
from Technology
Polling a panel of experts reveals
a range of wish lists as broad as
the field itself
By Jeffrey M. Perkel
62
Is It Time to Give Up on
Therapeutic Cloning?
A Q&A with Ian Wilmut
Dolly’s creator turns to a new
approach for creating stem cells
By Sally Lehrman
66
Biotech’s U.S. Birth
Connections and
Computation
By Yali Friedman
By Mike May
54
Why, exactly, did the industry
originate and thrive in America?
Electronic devices transform all
areas of biotechnology
table of contents
3
Why Take a
Looking far and wide to see our innovation future
T
…CONTENTS
By Yali Friedman and Mike May
70
Biomedical Information
—A Matter of Trust.
A Q&A with Howard R. Asher
Can a new kind of ATM change
global healthcare?
By worldview staff
74
Magic Nano-Bullets
Advances in nanotechnology
could make drug delivery far more
accurate and effective
By Charles Choi
76
P is the New D
Peptide nucleic acids are poised for
a world of applications
By Melissa Lee Phillips
SOCIETY &
CULTURE
84
Simple Solutions for
Global Health
Across the world, the least expected
changes help deliver better care
By Dawn Stover
88
Sharing the Wealth
of Data
Combining knowledge can drive
innovation, if everyone can agree
on how to do it
by Mike May
94
Hungry for GM Crops
78
High Content is King
Robotic handlers and automated
imaging are revolutionizing drug
discovery
Feeding the world takes genetic
modifications—sometimes
opposed by sociopolitical
constraints
By Emily Waltz
By Charles Choi
96
80
Silent Green
Industrial enzymes protect the
environment, while enhancing a
range of products
By Alan Dove
4
The Beauty of Biomass
Plant material—often wasted—
could fuel 8 percent of the world’s
energy needs by 2020
By Bill Caesar, Nicolas Denis, Jens
Riese and Alexander Schwartz
98
Big Ideas from
Small Places
A fly—plus animal behavior and
nanotechnology—teaches us how
to hear the world around us
By Ronald R. Hoy
100
An Innovation
Call to Arms:
Brazil’s Option for
Science Education
A nationwide plan to enfranchise
all citizens promises a high-tech
future
By Luiz Inácio Lula da Silva,
Fernando Haddad and
Miguel A. L. Nicolelis
he breadth of biot e c h n o l o g y— f r o m
advanced farm crops
and novel pharmaceuticals to forests
that hold the raw
materials for biofuels—takes us
around the world. Every country benefits from biotechnology in some way,
more likely many ways. In addition,
a wide range of thinking—scientific,
political, financial, regulatory, social—determines what biotech can
and cannot do. To assess this jumble
of interacting objectives and controlling forces, one must take a worldview.
Innovation is a key element of
biotechnology. In most cases the important discussions of innovative capacity and output take place primarily among government economists
and academic researchers. It is our
intention to bring this discussion to
a larger audience in a meaningful,
independent forum; too often a region or country’s climate for scientific
growth and development is masked
by marketing messages. As taxpayers, innovators, commercial partners
and consumers, it is important to understand why innovation matters and
how best to measure and support it.
Before descending into any details, we must ask the fundamental
question: Why do governments invest
in biotechnology? First, global economies desire the economic and social
benefits that biotech brings, such as
creating high-value products, which
can be sold in international markets.
Thus, policies that foster the creation
of these products expand domestic
economies through revenues from
foreign sales. Second, biotechnology
generates high-paying jobs, which can
increase both a nation’s prosperity and
the quality of life of its citizens. Third,
biotechnology impacts health, nutrition and the environment. The ability to produce drugs domestically, for
example, can reduce healthcare costs
and improve overall care in small or
poor economies. And the ability to
improve crop yields addresses the
pressing need faced by many nations
to feed increasing populations with a
diminishing amount of arable land.
For these nations, biotechnology can
help avoid otherwise inevitable mass
starvation. And, of course, biotechnology can reduce the financial cost
and environmental impact of industrial processes, helping corporations
profit and governments attain their
“green” goals of the future.
This project—the assessment of
innovation in international biotechnology—was conceived prior to the
current global economic crisis, at a
time when the funding environment
for biotechnology was very different
than it is now. Our initial goal was
to inventory global activities that
support the development of domestic biotechnology industries, and to
rank the performance of the various
initiatives. Since we started, the environment has changed and the stakes
are now much higher. Biotechnology requires great up-front capital
investments—often well in advance
of revenues—that make biotechnology companies especially sensitive to
poor capital-raising environments.
In a sense, the current economic
climate serves as a test of resolve. It
is easy to pledge large investments
to support biotechnology companies
when cash is plentiful, but in a financial crisis, supporters must carefully
assess their priorities. The influence
of the economic crisis will undoubtedly transform the global biotechnology industry and separate the
weak from the strong—distinguishing policies that enable growth from
ones that do not. Still, choices will be
complex. Legislators will make policy
decisions with future elections at risk.
Moreover, tax subsidies to biotechnology could create higher taxes for
other industries or taxpayers in general. It will be interesting to follow the
choices that leaders make.
To explore this variety of topics,
we have gathered a unique mix of editorial perspectives from overviews,
such as our data-driven scorecard
of global biotechnology innovation,
to more-focused pieces, including a
dozen country-specific vignettes, and
traditional feature articles. We welcome your comments and feedback
and look forward to continuing this
important conversation.
Yali Friedman is Lead Editorial Consultant
and Mike May is Editorial Director for
Scientific American Worldview.
introduction
5
Fighting in the Face
of Distress
Undervalued and cash-strapped, a global industry wrestles with its future
By Mike May Illustration by Curtis Parker
A
long the Mediterranean coast of France,
people are concerned with more than
films. Just 20 minutes to the north of
Cannes lies Sophia Antipolis—a technology park with clients ranging from
Agilent Technologies to W3C, the World
Wide Web Consortium. This is also
home to NicOx, a company focused on producing drugs
from compounds that release the well-known signaling
molecule nitric oxide. NicOx is alive today only because of
its failures in the past.
In short, NicOx once focused on ideas more than products. “That was almost killing us,” says Michele Garufi,
chairman and chief executive officer of NicOx. Like many
small companies in biotech, NicOx once operated as if it
existed in an academic environment rather than a commercial one. “In 2003, we said: ‘It’s time to be concrete,
because we have no money, and we must invest every penny in a product that becomes a reality, rather than merely
a hope.’” That transition turned NicOx toward pushing
ahead naproxcinod, its anti-inflammatory compound under development for treating the signs and symptoms of
osteoarthritis.
By concentrating on producing a product it took just
five years for NicOx to get naproxcinod through Phase III
trials, which showed that this drug is effective and safe.
Consequently NicOx expects to file a new drug application
in 2009. As Garufi points out: “It’s very important for a
biotech company to get something on the market even if
it is a niche indication in a small market.” If naproxcinod
does get to market, though, it will be far beyond a niche. It
will be gigantic. Garufi estimates the market as a “possible
billion dollars a year in the U.S.”
So it is possible to face failure and then fight back
toward success. While today’s economic environment
makes many biotechnology companies around the world
struggle, a range of experts envision success even during
a down economy.
6
Assessing the Environment
“Our companies take 10 to 15 years to take a product from
bench to bedside,” notes Alan Eisenberg, executive vice
president for the Biotechnology Industry Organization’s
emerging company section. “During that time there is preclinical testing and testing that goes on in humans—first
for safety, then efficacy and finally larger-scale population
testing. That length of time and complexity represents
high levels of risk from a financial standpoint.”
That risk, though, is not entirely new. In fact, biotechnology in the United States started feeling the crunch
in 2007. “We entered a credit crisis beginning in August
2007,” Eisenberg says, “and that became a capital crisis.”
As a result, investors started looking for lower-risk opportunities in 2008. That creates problems for companies
developing new therapeutics, a high-cost enterprise. As
Eisenberg explains: “Projects get delayed, and some get
shelved, because companies can’t raise capital.”
A similar divide exists in Europe. “Most companies in
Europe with products on the market are selling medical
products that are not immediately affected by the economic
downturn,” says Willy De Greef, secretary general for EuropaBio, “but start-ups or companies working on their pipeline that don’t have a current cash flow are in for some very
difficult times.” (See sidebar “Europe’s No Silicon Valley.”)
For a brand new start-up in Europe, De Greef declares,
“I wouldn’t want to be the manager looking for money this
year.” On the other hand, if a company finished a round
of raising capital in 2008, De Greef thinks that it should
survive, as long as the company has enough money for a
couple of years. “CFOs who have turned down all of the
unneccessaries and use their money sparingly will probably do okay-ish,” De Greef says.
Beyond the challenges faced by start-ups, some experts
see today’s financial trouble crippling mid-stage companies. “A company that is just getting back Phase II data
or starting a Phase III trial often need tens of millions
of dollars,” according to Spencer Feldman, an attorney
policy & economics
7
Europe’s No Silicon Valley
B
y “Silicon Valley” people do
not always mean the home
of chip makers south of San
Francisco Bay. “The idea of ‘Silicon
Valley’ has become a model,”
explains Steven Casper, associate professor and director of the
Master of Bioscience program at
the Keck Graduate Institute in Claremont, Calif. That model is: Start
a company with venture capital in
exchange for equity and then grow
the company until it is ready to go
public or be sold. But that’s not
how things usually go for European
biotechs. “Financing in Germany,
Uncertainty in India
France and many other European
countries is not geared toward
VC,” Casper says. “It’s more credit
based, depending on secure collateral, like land or a factory.” Moreover European biotech companies
are much less likely to aim at going
public. Among all of the European
countries, Casper says that the
United Kingdom is the most like
the United States in terms of its
approach to creating and funding
biotechs. If European countries
want to emulate the U.S. model,
Casper points out, “they have a lot
of work to do.”
with Greenberg Traurig in New York city and an expert
on providing counsel to emerging biotechnology companies. “That is difficult to get right now.” Feldman adds that
large pharmaceutical companies often use this situation to
their advantage. He continues: “These mid-size companies
are left abandoned, giving big pharma the opportunity to
come in and buy the valuable IP in bankruptcy or in a distressed selling situation.”
Financial issues also extend beyond the size or stage
of a company. For instance, the health of biotechnology in
one country often depends on the industry’s wellbeing in
other countries. As an example, about 80 percent of Ca-
In addition, many biotechnology companies across
Europe depend on scientists
for management. “Looking at
senior management in German
biotechs in 2003 to 2004, only
11 out of 300 had any industry experience,” Casper says.
“By comparison, 85 percent of
senior managers in San Diego
had a background in industry.”
He adds, “You need to match
scientists with people who know
what to do next.” So success in
biotechnology requires more
than good science.
nadian biotechs are privately owned and always searching
for investors, according to Peter Brenders, president and
chief executive officer of BIOTECanada. “Since we have a
small investor market,” Brenders explains, “our companies
pursue multinational connections for licensing or cash or
even co-investors.”
Brenders says the real investor crisis for Canadian
companies came as a “massive meltdown late in 2008.” The
last big deal that he saw was when Oncolytics Biotech in
Calgary closed on a $4 million investment late in December 2008. In describing investments in the first quarter of
2009, Brenders merely says, “Very quiet.” Nonetheless, he
adds that half of the Canadian biotech companies have
enough money to get through 2009 and into 2010. That
also means that half of them don’t, and the half that do
have enough money for another dozen months must be
worried about what they’ll do after burning that capital.
In fact, no one knows just how the current financial
challenges will affect the future of biotechnology. (See sidebar “Uncertainty in India.”) As Eisenberg explains: “People
that I’ve talked to say that they haven’t seen anything like
this in the entire 30 years of the biotechnology industry.”
Reaching Out for Repairs
Money can push biotechnology back into a moving-ahead
strategy. “We need policies that reignite a functioning capital market,” Eisenberg says.
In addition, Eisenberg points out that government
policies in the United States could stimulate biotechnology. Nonetheless biotech companies might need a different sort of government assistance than is usually required
for other industries to regain their footing. “Things that
might help ordinary small businesses may not necessarily
be helpful for us,” reveals Eisenberg. “BIO’s companies are
in long-term research-and-development projects, and one
8
T
here’s a mixed opinion about how the Indian biotech industry will do ahead,” says
Viren Konde, biotechnology analyst, consultant and writer from Pune, India. “Some say
biotech will grow despite the global meltdown,
and some say it won’t.” The answer probably
depends on the kind of company under consideration. For contract manufacturers in India,
an economic turndown in other countries could
enhance India’s business. “Clinical research
and manufacturing companies will find it easier
to get funding, because of the low-cost ways in
India,” Konde says. Still if large pharmaceutical
companies in other countries slow down their
clinical trials, contract companies in India would
slow down, too.
an entirely new compound could be regulated more strictly at first and less so over time, if it is not causing any problems. He adds, “There’s nothing like a crisis to really shake
the foundation of our beliefs.”
The Power of Products
If anyone knows the value of getting a product to market, it’s
Stan Yakatan, chairman and chief executive officer at Katan
Associates in Hermosa Beach, Calif. Yakatan played a founding or co-founding role in nine companies and was a top administrator in seven. From 2003 to 2005, for example, Yakatan was the chairman and chief executive officer at Grant
Life Sciences, which focuses on diagnostic kits. To get ahead,
Yakatan believes that companies must focus on products.
“There are people who believed that the biotech business was driven by innovation,” Yakatan explains. “That
meant that it consisted of people thinking all day and coming up with new ideas.” This current economy, though,
of the key ways to help these companies is to monetize net leaves little room for innovation without results. “The
operating losses that only become useful when cash flow is business is now moving from innovation to commercialpositive. For example, the government could accelerate the ization,” Yakatan says. “We can’t afford geniuses thinking
all day. We need people really developing products.”
use of these deferred tax assets.”
As a result, the industry—biotech and pharma—has let
In Europe De Greef also sees a need for more money.
As an example, he points to Europe’s less-developed ven- go of some people, and more cuts could continue. Those
cuts, though, could make companies
stronger. “I would absolutely think
that a decreased head count is not
bad,” adds Yakatan.
Beyond cuts, where should biotech look for stability? Yakatan’s immediate answer: “Chronic disease.”
–Stan Yakatan
As examples of success there, he
points out Lipitor and Crestor—two
ture-capital (VC) community—in comparison to VC in lipid-lowering blockbusters. “If I’m developing something
the United States—and he adds, “Therefore, support from and I want to have long-term sustainability, chronic disgovernments is essential, but 90 percent of the money to ease is where I’d go,” Yakatan says.
continue to fund biotechnology innovation in the European Union must come from the member states, not from Experience Counts
the European institutions.”
Despite the troubles around the world, many experts see
On the other hand De Greef thinks that some of the today as a good for biotech. “Now is a great time to start
costs of biotechnology should be reduced. “Why is biotech a biotech company that has an early stage product and is
innovation so expensive?” he asks. His answer: Regulatory at least partly founder-financed,” according to Feldman.
costs. “At least half of the cost is regulatory, whether in So if the founders can take on some of the financial risk,
medicines or genetically modified crops,” he says. “Euro- venture capital can be found.
pean regulatory systems are out of control.”
Beyond the founders paying some of their own way,
And it’s not that De Greef wants to bypass safety. In Feldman finds that it takes an experienced management
fact, he comes from the biosafety field. “In terms of regu- team to get today’s VC dollars. “You need the science and
lating clinical trials,” he explains, “only a minority of the technology,” Feldman says, “but venture capitalists are
cost is really biosafety, the rest is procedural—paperwork.” looking for management that understands business.” In
De Greef thinks that the money that does not improve bio- fact, today’s economic hurdles could force everyone in
safety must somehow get funneled back into creating new biotech to get back to the basics of business. The results
life-saving drugs. He suggests that some of the regulatory could improve the world’s biofuels, foods, pharmaceutirules should be tuned in case-by-case ways. For example cals and more.
“We can’t afford geniuses thinking
all day. We need people really
developing products.”
policy & economics
9
The increasingly global
nature of the pharmaceutical supply chain
presents opportunities,
but requires panoramic
vigilance
B
By Cormac Sheridan
radmer Pharmaceuticals lost more than
one-third of its value
in February. This
small, Toronto-based
biotechnology firm’s
losses arose from stopping a Phase III
trial for its lead product, Neuradiab,
an antibody in development for glioblastoma, a form of advanced brain
cancer. Bradmer had outsourced the
760-patient study to Icon Clinical Research—a Dublin, Ireland-based clinical research organization (CRO)—
but delays in recruitment pushed
Bradmer beyond its financial ability
to continue to fund the study. This
episode illustrates the perils attached
to outsourcing. Regardless of the vendor involved or its location, outsourcing necessarily implies a certain loss
of control and a certain degree of risk.
Managing that risk successfully is
now a key function for most pharmaceutical firms.
Outsourcing benefits pharmaceutical and biotechnology companies
in many ways: saving on operational
costs and capital expenditures, as well
as providing access to expertise, facilities and technology. Over the past
decade the practice has become deeply embedded in the business models
of life sciences companies, large and
small. Whether the function is in
general administrative areas—such
as payroll, information technology
10
Outsourcing
or human resources—or in core operations—such as drug discovery,
clinical-trial management, manufacturing or drug sales—a growing
roster of external specialists will take
on the task. Business models range
from the rare companies that use no
outsourcing to virtual organizations,
in which everything is outsourced.
“There’s no inherent reason why one
model is better than another,” says
Kim Wagner, senior partner at The
Boston Consulting Group of Boston,
Mass. “I personally believe any model
can be made to work.”
Variation in Application
Many biotechnology firms are happy
to outsource most, if not all, of their
manufacturing requirements. On the
other hand, Tengion—a tissue-regeneration specialist headquartered in
East Norriton, Penn.—does the exact
opposite. This company is developing
bladder-replacement therapies, and
Companies with more-standard
production processes, however, can
take advantage of the expertise and
the facilities of contract manufacturing organizations (CMOs). According
to Bruce Carlson, publisher at New
York-based market research firm Kalorama Information, revenues from
contract manufacturing of biologic
drugs are growing at about 13 percent
annually and will reach an estimated
$5.2 billion in 2013. For CMOs making biologic drugs, 55 percent of them
are in North American, and 24 percent are in the European Union.
Asia accounts for only three percent of biologic CMOs, according to
Kalorama data, but Asia has obviously come under sharp scrutiny following the heparin-contamination
crisis of last year, in which an estimated 200 people died. The deaths
were caused by an apparently deliberate adulteration of raw material in
China with over-sulfated chondroi-
“Most biotechnology companies see
manufacturing as a burden. It’s not
something they want to invest in.
For us, this is all about manufacturing.”
its manufacturing process, which involves the cultivation of autologous
cells on biocompatable scaffolds, has
to be tailored for each individual patient. Moreover, this has to be done at
scale. “Most biotechnology companies see manufacturing as a burden.
It’s not something they want to invest
in. For us, this is all about manufacturing,” says Tengion chief financial
officer Gary Sender.
—Gary Sender
tin sulfate, a substance with heparin-like activity, which can trigger
fatal immune reactions. It was not
detectable in the quality-control
tests then in use. Although Baxter of
Deerfield, Ill., was most prominently
associated with the incident—given
its 50 percent share of the U.S. market for the blood thinner—more
than a dozen companies around the
world were affected.
{© michael austin}
Overseeing
The whole incident highlighted—
for the public and politicians alike—
the increasingly global nature of the
pharmaceutical supply chain, and it
has put pressure on both companies
and the U.S. Food & Drug Administration (FDA) to ensure that the quality
standards implicit in an FDA approval
are upheld, regardless of the origin of a
product or its constituents. “I think the
phrase ‘made in China’ has taken on a
whole new meaning, not only for the
pharmaceutical products and drugs
that are manufactured there,” observes
Mike Keech, director of pharmaceutical industry advisory services at PricewaterhouseCoopers, noting problems
in other areas of Chinese manufacturing, such as food and toys.
The Price of Vigilance
Additional vigilance, of course,
will erode some of the savings that
companies achieve by outsourcing.
“Companies are doing those calculations,” says Carlson. But no pharmaceutical company wants to save money by endangering patients, Wagner
points out. “There’s no desire to do
things cheaply and introduce more
risk into the system. There is a desire
to do things more flexibly.” Companies are tightening up their supply
chains by reducing the number of
vendors they work with and by working more closely with those that they
do select. “People are more rigorous
in how they oversee the vendors,”
Wagner says. This can include plac-
ing company employees on site and
conducting more inspections. Testing, of course, remains a key guarantor of the quality of a manufactured
product. “The importance of testing
cannot be over-emphasized: test,
test, test,” Keech says.
There is no immediate equivalent
for companies that outsource the
management of their clinical trials,
Wagner says. “When the thing that
you’re buying is clinical data, how do
you know it’s clean?” she asks. Developing a close relationship with a
CRO is the best solution. This can extend to providing training to its staff
and accompanying them to clinicaltrial sites. “By being there with them
you will observe practice and be able
to train them further,” she adds.
In parallel with the efforts of
companies to effectively manage outsourcing, FDA is increasing its focus
on the area. For example, it recently
established three offices in China
and two in India to support these activities, and further expansions are
planned for the Middle East, South
America and Europe.
The heparin incident notwithstanding, a PricewaterhouseCoopers
report published in October 2008
ranked China ahead of India as
Asia’s most attractive outsourcing
destination, based on a combination
of cost, risk and market opportunity.
Companies that can successfully
manage partnerships with China’s
CMOs and CROs are also expected
to be best positioned to tap into the
country’s significant potential for innovation. But successfully managing
the resulting matrix of relationships
will be the ultimate determinant of
their success.
policy & economics
11
Sponsor Profile
Amgen:
pioneering science
delivers vital medicines
cientists at Amgen pursue fundamental cellular signaling pathways. Following these uncharted molecular trails can lead to
important discoveries about the root causes of grievous illnesses –
and to new targets for drug development. Amgen researchers have
found pathways that play a role in various types of cancer, bone
loss, and immune system and inflammatory disorders. The result
is a robust pipeline that currently contains more than 50 molecules from late
discovery research through Phase 3 clinical trials.
The principled pursuit of
innovation
Amgen’s Research and Development teams follow four
guiding principles:
1 Focus on grievous illness
Patients suffering from the greatest unmet medical needs are Amgen’s first
priority. Approximately 90 percent of the new molecules that Amgen is bringing into the clinic target pathways that have never previously been addressed
in humans. Many of these are aimed at cancer, an area in which Amgen is
conducting clinical trials in more than a dozen different tumor types.
2 Be modality independent
In other words, choose the right tool for the task. Amgen scientists look first at
the disease process, then seek to determine the most advantageous therapeutic
approach, be it large-molecule biologic, antibody, peptibody or small molecule
(oral) therapy.
3 Study disease in people
Studying disease in people is the best way to develop medicines for people.
Experimental models often have little predictive value, and promising preclinical
studies too often lead to high-cost clinical failures. Amgen seeks to identify
safe and effective disease interdiction methods as early as possible in the development process, using biomarkers and other tools.
4 Seamless integration
Amgen is structured to incorporate perspectives from health economics, regulatory and government affairs, clinical development and basic research into all
development programs. Being rigorous in our prioritization, clear in our focus,
and attentive to all aspects of therapeutic intervention enables us to develop
medicines that address important unmet medical needs while also presenting
a compelling value proposition for society.
12
Pathways in cancer
research
Amgen oncology researchers are
fighting cancer on multiple fronts,
including:
Growth regulation:
Identifying and blocking the pathways that regulate cancer cells’
ability to proliferate, migrate, invade,
and survive
Angiogenesis:
Preventing tumors from stimulating
the formation of new blood vessels
to feed them
Amgen: Bringing the promise
of biotechnology to life
At Amgen, we use innovative research to improve the
health of patients.
As pioneers in biotechnology, we apply our expertise to discover, create and
deliver vital medicines that so far, have helped more than 15 million people
in their fight against cancer, kidney disease, rheumatoid arthritis, and other
serious illnesses. With a deep and broad pipeline of potential new medicines,
we’re working to continue to bring the promise of biotechnology to life – to
help many more.
Apoptosis:
Enabling programmed cell death,
or “cancer cell suicide”
Bone metabolism and
metastases:
Controlling the signals that trigger
bone buildup and breakdown, in
an effort to treat and prevent the
spread of cancer to the bone
“Our goal
is simple:
to advance
innovative
new therapies
that improve
the lives
of patients
around the
world.”
—Roger M. Perlmutter, Amgen executive vice
president, Research & Development
In the United States, one out of every two
women over age 50 will suffer an osteoporotic
fracture. Bone biology is an important area of
exploration where Amgen scientists work to
address unmet needs
sponsor profile 13
Protecting
IP
Anything but Simple
By Peter Gwynne
Illustrations by Greg Betza
14
Countries that once ignored
intellectual property now embrace
it—hoping to protect their own
inventions in biomedicine and
biotechnology
F
or many years Jordan had a healthy pharmaceutical business. Firms staffed largely
by local scientists with European doctorates manufactured popular medications
and sold them in Arab countries in the
Middle East and North Africa. The firms
routinely ignored multinational companies’ patents on those drugs. But when
Jordan joined the World Trade Organization (WTO) early
this decade, it signed onto the organization’s requirements
for protecting intellectual property (IP). Business models
immediately changed for local pharmas. Some Jordanian
firms began to focus on incremental research and development for niche markets—creating injected rather than oral
biopharmaceuticals, for example—and licensing out the results. Other firms are licensing in biopharmaceuticals that
they sell in the Arab world, the Balkans, the central Asian
republics and other markets too small or complicated for
Western pharmas to enter.
“Several Jordanian companies said that they know the
drug marketplace and could identify incremental or alternative drugs with small niche markets,” says Michael Ryan,
director of the creative and innovative economy center at
the George Washington University School of Law. “Firms
that used to manufacture generics have started to focus on
incremental R&D. Two start-up companies in Jordan focus on injectable versions of oral drugs.”
The change of direction quickly produced results. “A
couple of years ago, Jordanian pharmas became number one
in the Arab world, over the Egyptians,” Ryan says. “They
have even moved into the West.” For example, Hikma Pharmaceuticals—founded in Amman, Jordan, in 1978—began
manufacturing injectable powdered cephalosporin, an antibiotic, in Portugal in 2001, the same year that it received
approval to sell some products in the United Kingdom. In
2007 Hikma acquired two German companies making
injectable oncology products, and it had already acquired
West-ward, a New Jersey pharmaceutical company.
policy & economics
15
Enforcing
IP Protection
C
ountries who are
members of the World
Trade Organization can
still exclude a number
of categories of invention from
patentable matter,” says Matthew
Rimmer of the Australian National
University College of Law as he
explains the reach of the World
Trade Organization’s Agreement
on Trade Related Aspects of Intellectual Property (TRIPS). “These
include methods of human treatment; diagnostic devices; animal
patents; and, potentially, patents
on human genes and stem cells.”
First-world nations have moved to
exploit those loopholes. Rimmer
says, “New Zealand continues to
have a prohibition on patenting
methods of human treatment. And
Canada prohibits the patenting of
‘higher life forms.’”
Regarding developing nations,
Jill Hobbs and William Kerr of the
University of Saskatchewan write
in the Canadian journal Bioscienceworld: “Enforcement, however,
has been problematic. This has
been particularly the case in the
areas where biotechnology figures
prominently, agriculture and phar-
Changing Attitudes, Growing Complexity
Attitudes toward protection of biomedical IP have begun
to change. Biotechnology and biopharmaceutical firms in
developing countries that once disregarded patents held
by overseas companies now find themselves obliged to follow the rules set by the WTO. These companies also want
patent protection for the results of their own research and
development.
The issue, therefore, has gone beyond the desire of
multinational biotech and biopharma companies to protect their IP against companies in developing countries that ignore patent
rights. It also focuses on the increasing need of third-world firms to protect their IP from potential assaults by
multinationals.
One further complication: Biotechnology IP isn’t limited to biomedical advances. “There has been
a massive growth in applications for
patents in the field of biotechnology,
covering microorganisms, plants,
animals, human genes and stem cells,
bioinformatics, nanotechnology, proteomics and synthetic
biology,” says Matthew Rimmer, of the Australian National University School of Law, author of Intellectual Property
and Biotechnology: Biological Inventions.
maceuticals.” For example, some
developing countries routinely
break Western companies’ patents
to produce locally affordable treatments for HIV/AIDS.
In theory, developed nations
can dispute that behavior in the
World Trade Organization and
apply trade sanctions against
countries that do not protect the
IP of overseas firms effectively.
But in practice, Hobbs and Kerr
have found, few governments
have used those sticks to protect
their firms’ biotechnology IP. Nor
has any effective carrot emerged
to persuade developing nations to
respect the IP.
erty. Known as TRIPS, it went into force in 1995. It requires that “patents shall be available for any inventions,
whether products or processes, in all fields of technology,
provided that they are new, involve an inventive step and
are capable of industrial applications.”
The agreement has some loopholes. (See sidebar “Enforcing IP Protection.”) For example, it gives the leastdeveloped countries that join the WTO extended lead
times to follow its precepts. It also allows states to exclude
certain plants, animals and biological processes for pro-
“The flood of applications has
placed a great strain on patent
offices around the world.”
The Impact of TRIPS
The guarantor of global protection of intellectual property,
in biotechnology and other technical fields, is the WTO’s
Agreement on Trade Related Aspects of Intellectual Prop-
16
—Matthew Rimmer
ducing them from patentability. But it gives biotechnology
firms in both developed and developing nations the ability
to patent their processes and products and to protect those
patents in a way that was impossible before TRIPS.
What distinguishes a product patent from a process
patent, and why does TRIPS require both? The names tell
the difference. A process patent relates only to the means
of producing a biotechnological entity or other product.
A product patent, by contrast, allows rights—for exclu-
A Message from India
T
he Indian authorities have
sent a message to the rest
of the world: Despite past
history, they now welcome
applications for biotechnology
patents. That communication has
significant implications for local
and multinational biotechnology
and biopharmaceutical companies
that look to market their products
in this teeming South Asian nation.
But overseas firms remain somewhat skeptical about their ability
to obtain Indian patents on certain
biomolecules and their ability to
prevail in court cases related to
their patenting activity.
The change in India’s view of
patents began in 2002. For the first
time, an Indian court overturned
the Indian Patent Office’s rejec-
tion of patent claims for processes
that created live products. In the
same year, an amendment to the
country’s patent laws enabled applicants to patent “biochemical,
biotechnological, and microbiological processes.” A more-important
change occurred later, on January
1, 2005, when the patent office incorporated the requirements of the
World Trade Organization’s Agreement on Trade Related Aspects of
Intellectual Property (TRIPS) in the
country’s Patent Act. The change
permitted the first filing of product
patents on compounds for use as
drugs and other medications.
“These paradigm shifts away
from India’s earlier anti-patent culture, coupled with a rapidly expanding biotechnology industry fueled by
The new patent laws haven’t satisfied everyone.
Overseas biotechs and biopharmas have
already complained about the Indian courts’
administration of the laws.
investments from both the private
and public sectors, portend a surge
in biotechnology patenting in India,”
says Julie Mueller of the University
of Pittsburgh Law School.
The new patent laws haven’t
satisfied everyone. Overseas
biotechs and biopharmas have
already complained about the
Indian courts’ administration of the
laws. In particular, the courts seem
unwilling to grant multinationals’ requests for patent protection
on products that represent small
improvements to existing goods
rather than de novo advances. When
the Indian Patent Office refused to
allow Novartis to patent its chronic
myeloid leukemia drug Gleevec for
that reason, the Swiss company
challenged it in court—only to have
the court reject its claim.
policy & economics
17
Denmark: Small Country,
Large Portfolio
W
sive manufacturing and marketing, for example—that
relate directly to the product. Product patents also confer
more benefits on their holders than process patents. The
importance of the inclusion of both in the TRIPS agreement stems from the fact that, in the effort to protect local
companies that make generic drugs and other items, thirdworld countries frequently denied product patents.
Flood of Applications
The decision by several developing nations to join developed countries in TRIPS protection of IP doesn’t mean the
end of patenting controversies. For example, the numerical and geographic advances of biotechnology and related
fields have created problems. “The flood of applications has
placed a great strain on patent offices around the world,”
Rimmer says.
Equally important and hardly surprising, patent authorities in different countries have interpreted the global
patent law differently. The European Union has equivocated on the patentability of stem cells. New Zealand prohibits patent methods for human treatments. And Canada
refuses to allow ‘higher life forms.’
Developing nations also have unique approaches to
upholding the TRIPS agreement. In India courts have
agreed with the patent office’s refusal to grant patents on
certain biomedical products that represent only incremen-
18
ith just 5 million inhabitants, Denmark
ranks as one of the world’s smaller
nations. But it acts as an 800-pound
gorilla in global biotechnology. This
Scandinavian nation leads the world in both the
number of biotechnology patents per member of the
population and the ratio of biotech patents to total
patents. It has Europe’s highest ratio of biotech venture capital investments to gross domestic product.
And it takes third place in Europe in terms of the
absolute number of projects in clinical investigation.
What accounts for Danish domination of biotech
IP? In part it’s tradition. In the mid-1800s, Carlsberg’s brewery created a microbiology research
enterprise that has continued ever since. And the
country’s cheese industry stimulated research in
enzymes. In recent years Denmark’s government,
academic and industrial sectors have built on those
capabilities through education and innovation.
“Denmark is not a country that is rich in natural
resources,” explains Søren Carlsen, a managing
partner at Novo A/S who chairs the Danish Association of Biotechnology Industries. “However, it has
one of the most well-educated populations in the
world. Over the last few decades, Denmark has
changed from an agricultural nation to a one built
on a sophisticated and flexible workforce and the
intellectual capital of this workforce.”
The growth of the corporate world exemplifies
that change, and its transition into biotech activity.
In the past half-decade the growth of the ‘Medicon
Valley’—a cluster of biomedical companies and universities that spans the Øresund between Denmark’s
capital of Copenhagen and the southern Swedish city
of Malmö—has encouraged the emergence of several
small firms that contribute significantly to patenting
in biotech. Today, the country has more than 180 dedicated biotechnology companies and over 300 biotech
service providers. In addition large public and private
companies such as Genmab, Leo Pharma, Lundbeck,
Neurosearch, Novo Nordisk and Novozymes have
their own focus on biotechnology research and development. “There is a strong tradition for patenting
in companies such as Novo Nordisk and Novozymes,
due to fierce competition,” Carlsen says.
That activity does more than defend corporate
innovation. “Patents protect Denmark’s intellectual property, which is the one thing that can
ensure continued growth and prosperity for a
small nation,” Carlsen says. “Biotech patents are
part of the notion that Denmark’s future rests on
its know-how and intellectual property.”
tal changes to entities about to lose their patent protection.
(See sidebar “A Message from India.”) “The courts have interpreted the changes as not sufficient to patent,” Ryan explains. In other countries, Western corporations complain
that ministries of health, rather than the patent office, decide which products and processes should receive patents.
In nations with emerging biotech and biopharma industries, such ministries have obvious conflicts of interest.
One area of biotechnology and biopharmaceuticals that
is growing at a rapid rate and drawing escalating controversy involves biodiversity. Organizations in developing
countries increasingly set out to identify and isolate the active ingredients of plants traditionally used for healing and,
once they prove their medicinal value, put the ingredients
into clinical trials. Since multinational companies sponsor their own efforts to detect, identify and use medicinal
plants, Ryan says, “biodiversity-based local developers are
looking for patent protection.” (See “Turf Battles: Politics
Interfere with Species Identification,” page 20.)
Brazilian companies have taken the lead in developing
and patenting biodiversity compounds, benefiting from
the huge resources available in the Amazon rainforest.
They took a cautious approach, waiting until 1996, when
Brazil reformed its patent law, before showing their hands.
Take Acheflan, an anti-inflammatory cream based on the
traditional maria-milagrosa plant and traditional medical
knowledge. “Ache, a company wholly owned by Brazilians,
of its biotech and biomedical firms that had lived off patent-infringing generic drugs began to develop their own
products. “As multiple Indian companies compete to sell
the same biotechnology product, each firm’s need to distinguish itself by process development increases,” says Janice Mueller, professor of law at the University of Pittsburgh
School of Law. “Strong process patent protection will facilitate competitive advantage among Indian biotechnology companies.”
The exemplar of developing countries in terms of patent protection is Singapore. The government of the nation city first sought advice on the promise of biotechnology a quarter of a century ago. It has the financial and
academic resources to attract scientists from China, India and even Europe and North America. And according
to Ryan, “Singapore is quite the leader in the developing
world with respect to IP diplomacy. Its content is similar
to America’s.”
Other Asian nations have had less success in developing commercial biotechnology. Thailand, for example,
proves that productive patenting does not guarantee
market success. Thai universities have developed and
patented plenty of biotechnology. But the country’s private sector has lacked the resources to exploit the licenseready IP.
That’s unlikely to happen in China. Not only does the
Middle Kingdom have a strong academic base in biotechnology and a well-funded and growing private sector, but as a member
of the WTO it is bound to abide by
the TRIPS agreement on patenting.
However, last year’s extended episode of melamine-tainted milk casts
doubts on its reliability whatever its
patent positions.
Despite the successes stimulated
by TRIPS, patenting controversies
continue to divide developed and
developing nations. “There has been
conflict over countries such as South
Africa, Brazil, India and Thailand that have made use of
the flexibilities under the TRIPS agreement to deal with
public-health epidemics and national emergencies. There
has been controversy over patents in respect of research
concerning the SARS virus and avian influenza,” Rimmer
says. “There has been a great deal of conflict over access to
essential medicines in respect to HIV/AIDS, tuberculosis,
malaria and certain neglected diseases.”
Overall, protecting IP depends on attitude. (See sidebar
“Denmark: Small Country, Large Portfolio.”) Any country
in the world can chose to be a safe home for patenting and
IP. In fact, a country’s success in international biotechnology could well depend on such an IP-safe reputation.
Despite the successes stimulated
by TRIPS, patenting controversies
continue to divide developed and
developing nations.
knew about the product in the early 1980s,” Ryan recalls.
“But it didn’t launch the R&D on it until after the patent
protection became available.” The company released the
cream in 2005, making it the first pharmaceutical product fully innovated in Brazil. Since then, Ryan says, “Ache
has achieved a 40 percent market share with it in Brazil,
because of the patent protection. The company is beating
Novartis and Pfizer in Brazil. Now, they’re doing R&D in
the United States and Europe to get it approved there.”
Competitive Advantage
A similar situation is now playing out in India. Once the
country joined WTO and enhanced its patent laws, many
policy & economics
19
Turf Battles: Politics Interfere
with Species Identification
of the Indian Ayurvedic tradition for
centuries. “It was the most ridiculous
patent I’ve ever seen,” exclaims David
Gang, a professor of plant sciences at
the University of Arizona.
After protests erupted in India,
the patent was revoked. But so were
opportunities for research—and the
public benefits that go along with it.
Gang says he would like to see a glob-
By Linda Baker
F
or the past three years,
botanist Vicki Funk of
the Smithsonian Institution has been trying,
unsuccessfully, to transfer select leaf specimens
from Brazil to the U.S. National Herbarium for identification. Comparing
closely related plants “is the bread and
butter of systematics,” she explains.
“We need stuff from other places.”
But as biodiversity becomes a valuable commodity, developing countries
have complicated efforts to collect and
analyze biological samples. Funk says:
“It doesn’t matter if you’re an academic, not a drug company. You’re treated
the same.”
In 1992, the twin goals of the United Nations Convention on Biological
Diversity—signed by more than 150
countries—were to preserve biodiversity and to ensure tropical nations
were compensated for any “genetic
resources” leading to drug discoveries for developed nations. But even as
those goals were reaffirmed at a conference held in the spring of 2008 in
Bonn, Germany, scientists continue
to criticize policies stemming from
the convention. The claim is that the
international agreement, which gave
countries ownership of plants and
animals inside their borders, is hindering tropical research and conservation, not facilitating them.
“The biodiversity convention
made the argument that plants and
other microorganisms were sovereign
entities that needed to be treated with
commercial transaction approval,”
remarks Josh Rosenthal, a deputy director at the Fogarty International
Center at the U.S. National Institutes
of Health. As a result, “the ethos of
global scientific collaboration has
20
changed,” and the conditions for research have become more challenging.
Western scientists are not alone in
their analysis. The January 2008 Current Science, a journal published by
the Indian Academy of Sciences,
included an article decrying the
“shackles” Indian biodiversity law
imposes on native scientists—such as
prohibiting them from placing specimens in international repositories.
“We need to highlight the importance of sharing biological resources
among nations,” says co-author K.
Divakaran Prathapan, an entomologist at the University of Kerala. The
article was entitled “Death Sentence
on Taxonomy.”
Of course, a history of abuses
means poorer countries have every
reason to question scientific work
conducted on behalf of industrial
countries. In 1995, for example, the
United States granted a patent for turmeric to two doctors at the University of Mississippi—even though the
anti-inflammatory properties of the
herb had been documented as part
{ © altrendo travel}
As nations view their flora and fauna as commodities, science suffers.
al consortium of labs to sequence the
genome for turmeric—modeled after
the successful International Rice Genome Sequencing Project, which was
completed in 2004. “But there is no
possibility of collaboration with anyone in India,” he laments.
Designed to prevent exploitation,
proprietary botany laws block opportunities for developing countries
Designed to prevent exploitation,
proprietary botany laws block
opportunities for developing
countries to form their
own scientific infrastructure.
to form their own scientific infrastructure, argues Art Edison of the
University of Florida, who is forming
a project to analyze soil activity in a
Peruvian reserve. “The problem is,
people are so focused on the remote
possibility of a major drug discovery
that they don’t deal with the practical benefits of attracting U.S. research
dollars, such as helping train [native]
students and set up labs,” he says.
These jobs in turn help supplant logging and other destructive practices.
Peru and its neighbors have some
of the strictest rules in the world
against collecting and transferring
biological material. “When I first entered into the project, I was focused
on the science,” Edison recalls. “The
great fear of ‘biopiracy’ was a complete eye-opener.”
There are some positive developments. Prodded by its own scientists,
the Brazilian government implemented a system last year expediting
licenses to collect biological material
for scientific research—although applications involving conservation areas or the export of biological samples
were excluded from the new rules.
Some Western research institutions,
such as the New York Botanical Garden, have put together detailed protocols outlining benefit-sharing opportunities for host countries that have
helped facilitate scientific research
and exchanges.
But as nations renew their commitments to the biodiversity convention, “many are tightening up regulations,” says Phyllis Coley, a plant
sciences professor at the University
of Utah. Panama, for example, used
to have one of the most liberal attitudes toward foreign scientists but is
now drafting more restrictive legislation, she states. Framing biodiversity
in terms of political boundaries and
sovereign intellectual property was
supposed to encourage preservation,
the Smithsonian’s Funk says. “It’s
backfired,” she declares. “We have to
conserve life on its own terms.”
policy & economics
21
Next
By Melinda Wenner
Algae and engineered microorganisms—the oil of tomorrow
A
mericans burn through 140 billion gallons of gasoline a year. And even if drivers switch to more fuel-efficient cars
and trucks, the nation’s fuel needs are
expected to increase by a fifth over the
next 20 years, thanks to dramatic increases in car and airplane use. Which is why—in addition
to developing solar, wind and geothermal energy—policy
makers, including President Barack Obama, are advocating biofuels to transform the transportation culture.
Among some of the most radical—and promising—
ideas stirring within the biotechnology community today
is the idea of making the equivalent of gasoline and diesel
from the lowest life-forms on the totem pole: yeast, algae
and bacteria. Such microorganisms could revolutionize
our fuel infrastructure. One day you could swing by the
local energy station and fill up on a microbe-made liquid
from U.S. companies, not shipped from the Middle East.
And even though biofuels release carbon dioxide when
they are burned, the organisms they are made from draw
an equivalent amount of carbon dioxide from the air—
making biofuels essentially carbon neutral. The challenge
is to make enough of these fuels economically and in a
form compatible with today’s vehicles.
{© ashley cooper/corbis}
Pushing Pond Scum
22
{
Algae and more:
Tomorrow’s cars and trucks could
completely bypass petroleum.
}
J. Craig Venter, the entrepreneur and biologist whose Institute for Genomic Research in Rockville, Md., played a
key role in mapping the human genome, argues strongly
for this approach. He believes that the best biofuels will
rely on algae and a few microorganisms that have a plantlike knack for directly and efficiently turning sunlight
into energy through photosynthesis. The “most exciting”
biofuel, he says, will be made from microbes that, when
exposed to sunlight, consume carbon dioxide and turn it
into energy directly—the equivalent of upgrading to a direct airline flight from one that had a long stopover. The
idea might sound too good to be true, but Venter, who is
known for his restless ambition, says it is possible.
policy & economics
23
The earth’s energy comes from the sun. An hour’s worth
of sunlight holds enough power to meet a year’s worth of
human energy needs. But less than a tenth of 1 percent of
that energy is captured by plants. Venter and other scientists are experimenting with photosynthetic microbes such
as algae and cyanobacteria (sometimes referred to as bluegreen algae). Not only do these microbes remove carbon
dioxide from the air, they also grow quickly—some forms
double in just 12 hours, whereas grasses and other large
plants can take weeks or months to do so. Photosynthetic
microbes also store plenty of fat, which forms the basis
for fuel. Biologist
Willem Vermaas of
Arizona State University recently engineered cyanobacteria to accumulate
up to half their dry
weight in fat. Just
by opening up the
cells, he can harvest
the stored fats and
convert them, in a
few simple steps,
into biofuel. Some
plants, such as soybeans, also store fats
and can be used as
fuel sources, but Bruce Rittmann, Vermaas’s colleague at
Arizona State, argues that photosynthetic microbes produce nearly 250 times more fat per acre.
The concept of algae-based fuel is not exactly new, and
it’s fraught with problems. In 1978 the U.S. Department
of Energy began trying to make biodiesel from algae, but
the program ended 18 years later after the government
concluded the concept wasn’t economically feasible. Algae and cyanobacteria are complicated critters. Although
they can grow in open ponds, unwanted microbial strains
can easily contaminate the water and interfere with the
growth of the fuel-making strains. Venter’s alternative is
to grow algae in transparent, outdoor vessels called photobioreactors, but these containers are expensive to build
and maintain. They must also be constructed so that the
right amount of sunlight hits them—too much or too little
slows growth. What is more, harvesting the microbes and
sucking out the stored fats requires environmentally unfriendly solvents, and new organisms have to be grown to
replace the harvested ones.
Venter says that his newest company, Synthetic Genomics in La Jolla, Calif., is well on its way to overcoming
one of the hurdles: His microbes can be reused multiple
times because he has engineered them to release fat rather
than store it. In addition, he has found a way to prevent
the unwanted spread of these organisms should they ever
be accidentally released from a facility; they can survive
only if they are fed a chemical they cannot produce on
their own. Synthetic Genomics will soon be testing the
approach on a commercial level. “We’ve had some really
major breakthroughs,” Venter says.
Hedged Bets in a High-Stakes Game
Other companies are well on their way, too. San Diego
biotech firm Sapphire Energy claims it could be selling
gasoline made from algae by 2011. Solix Biofuels, a start-
24
up based in Fort Collins, Colo., plans to have its first pilot facility running by this summer. “A lot of people said
we’d never fly, we’d never walk on the moon, the light bulb
would never work. What it takes is a lot of discipline and
diligence to move forward,” says Rich Schoonover, Solix’s
chief operating officer.
According to Samir Kaul, a partner at Khosla Ventures, a San Francisco Bay Area venture-capital firm, the
companies that survive will be the ones whose fuels can
compete with oil at $40 a barrel. Venter agrees: “I think
that’s going to end up being the biggest challenge: Can
we build these really large facilities and do it in a costeffective, environmentally friendly way?” It’s a highstakes game, and even the scientists are hedging their
bets; some of Venter’s projects involve producing fuels
from plants instead.
Ultimately, whoever produces abundant biofuels could
end up making more than just big bucks—they will make
history. “The companies, the countries, that succeed in
this will be the economic winners of the next age to the
same extent that the oil-rich nations are today,” Venter
says. He even suggests, in his characteristically unabashed
way, that those companies and nations could end up igniting a second industrial revolution—one fueled by the need
to undo the environmental consequences of the first.
{© Thor Swift/New York Times/ Redux Pictures}
The most exciting biofuel will be made
from microbes that, when exposed to
sunlight, consume carbon dioxide and
turn it into energy directly—the equivalent of upgrading to a direct airline flight
from one that had a long stopover.
{
J. Craig Venter:
A genomics pioneer
turns to pond scum.
policy & economics
}
25
Seeking Stem-Cell Therapies
What makes follow-on
biologics a thousand
times messier than
typical generic drugs?
By Jared Feldman
F
or over a year the U.S.
Food & Drug Administration (FDA) held up
approval of Massachusetts-based Genzyme’s
new plant for Myozyme,
a treatment already produced and
marketed by the company for a rare
Assessing Similarity
Regardless of the impetus behind
the regulations, or the lack of them,
there is a scientific debate. It revolves around: How similar is sim-
26
I
n the middle of January this year two remarkable, but supposedly unrelated things happened.
Barack Obama was inaugurated as the United
States’ 44th president, and FDA released a draft
guideline governing the manufacture of cell- and
tissue-based products, so-called “advanced therapies.”
These events might have led to a third event: The
first-ever clinical trials with an embryonic stem cell–
based therapy—in this case for spinal-cord injury—
conducted by the California-based company Geron. Is
this a coincidence? Anyone who knows for sure isn’t
saying. What is known for sure is that the European
Medicines Agency (EMEA) beat FDA to the draw.
The EMEA is very proactive, notes Marisa
Papaluca-Amati, deputy head of the sector on clinical safety and efficacy at EMEA. The agency, she
points out, already had guidelines on gene therapy
in 1995, and the office “tracks innovation so that
in 2001—the year specific requirements governing
gene-based products was addressed legislatively—
we were already poised to consider advanced therapies.” The latest regulation [(EC) No1394/2007] on
advanced-medicinal products, which also includes
cell-and tissue-based products, came in effect in
the European Union in January 2009, around the
same time FDA issued its draft. In addition, the
EMEA just created the Committee for Advanced
Therapies (CAT). Composed of health professionals
and patient representatives, CAT performs scientific
evaluations of novel gene- and cell-based therapeutics and then suggests to EMEA guidelines to keep
pace with the innovations.
Nonetheless, neither EMEA nor FDA guidelines on
advanced cell and tissue therapies make any specific
mention of embryonic stem cells. It is now clear—
through the Geron decision—that the FDA guidelines
pertain to embryonic stem cells. The EMEA guidelines
do as well, says Papaluca-Amati, but the decision
to move forward on those therapies is left up to the
member states. “The legislation does not exclude
embryonic stem cells,” she says. “But member states
may choose out of ethical considerations not to accept
them or use any product derived from embryonic
stem cells. Science should respect ethics.”
How similar is
similar enough?
{
{© michael austin}
The Regulatory Battle
over Biosimilars
neurological disorder called Pompe
disease. Genzyme built its Framingham facility to handle increased
demand. While neither Genzyme
nor FDA would comment on the
nature or cause of the delay, industry
insiders—including Scott Gottlieb,
resident fellow at the American
Enterprise Institute in Washington,
DC, and former Deputy Commissioner for Medical and Scientific Affairs, FDA—believe that at issue is
whether the drug manufactured in
the new plant is sufficiently similar
to the product already on the market.
That’s just one example among
many of the challenges companies
and countries face in regulating biosimilars, also known as biogenerics
or follow-on biologics. By any name,
they are just generic versions of biological drugs.
On the legislative front, Europe
took the lead by setting out a regulatory framework in 2003 and issuing its first guidelines in 2005. In
contrast, it took until March 2008
for the U.S. Congress to develop a
pathway toward regulating biosimilars. To some—notably groups that
stand to gain from legislation that
lets biosimilars move ahead—the
U.S. delay is purely political, the
result of a campaign by pharmaceutical companies to protect what
William Haddad, president of New
York-based Biogenerics, calls “perpetual patents.” Likewise, in a statement about the action of the U.S.
Congress, Kathleen Jaeger, chief executive officer of the Generic Pharmaceuticals Association, said, “At
worst, it’s a step backwards that puts
brand-company profits before patient needs.” Nonetheless, the pharmaceutical issues go beyond corporate and political battles.
Sizing up complexity: Small molecules—like the 21-atom aspirin (left)
—are far easier to make as generics than biological molecules, such as the
1,297-atom erythropoietin (right).
ilar enough? In order to qualify as a
follow-on and not an entirely novel
product, the follow-on must be similar in composition and in biological
effect to the branded molecule. For a
traditional small-molecule pharmaceutical, demonstrating both qualities
is a relatively simple matter. Biosimilars, however, are exponentially more
complex. A biotherapeutic may be a
large, complex string of amino acids—
a thousand or more times the size of a
traditional drug—and the exact composition of these molecules is difficult
to analyze and control. Moreover,
small changes in processing could alter the basic amino-acid composition
of the molecule, or it could alter the
}
way the basic molecule is modified.
The placement of sugar molecules, for
example, can differ markedly from
molecule to molecule—even for molecules made in the same facility under
the same conditions.
How does the European Medicines Agency (EMEA) assess similarity? Well, it doesn’t exactly. To date
the molecules approved by EMEA
for follow-on status have been small,
well-characterized drugs, such as
recombinant human insulin. More
complex molecules are currently under review, says Monika Betstetter,
EMEA spokesperson. “It is true,” she
says “that we started off with relatively easy biologicals—definitely no
antibody yet. Further guidelines will
be developed as needed.” She would
not say which medicines are currently
under review or how bioequivalence
will be determined.
Observers expect that once FDA
grapples with establishing criteria
for equivalence between a branded
and follow-on biological product, it
will be “extremely conservative,” says
Gottlieb. He adds that the only possible exception will be the smaller,
simpler molecules, like the ones already approved by EMEA. (For an
even more complex issue, see sidebar
“Seeking Stem-Cell Therapies.”)
For both Europe and the United
States, we can only wait to see how
anything beyond a relatively easy biosimilar will be handled. It appears
that the regulatory processes around
the world will continue to evolve. Indeed, the complexity of biosimilars
seems to create as much trouble for
regulators as it does for manufacturers. In the meantime, those waiting to
realize the cost benefits of biosimilars
might be waiting a long, long time.
policy & economics
27
one-time credit for tax losses if the
money is re-invested in research and
development; create a capital-gains
exemption for new science and technology research investments; and
make more companies eligible for
refundable scientific-research and
experimental-development tax credits. Nonetheless, Canada’s $30 billion
(U.S.$24.2 billion) stimulus budget
for Fiscal 2009, released January 27,
did not address those issues.
In the United States, where 30 percent of the biotech companies have
less than six months cash on hand,
the Biotechnology Industry Organization (BIO) lobbied—unsuccessfully—for Congress to include biotech tax credits and incentives in the
Rescues around
the World
From cash infusions to tax incentives,
countries are seeking ways to boost biotech
B
by Ted Agres illustration by tomasz walenta
y most accounts the
countdown clock to
biotech bankruptcy
keeps ticking, drawing companies worldwide closer to the day
when they run out of cash and shut
down or become acquired at liquidation rates. Depending on the country,
a critical mass of meltdowns might be
only a few months away.
Some favor the Darwinian approach. “The economic crisis will help
to make the biotech industry more
sustainable and more robust longterm because the weak companies
won’t survive,” says Jürg Zürcher, a
biotech expert at Ernst & Young in
Switzerland. On the other hand, many
governments, industry executives and
private investors are not as sanguine
and are crafting plans to keep companies afloat long enough to survive.
“You are trying to a get a greater
number of good companies through
this period, so they come out the
other side of the recession viable and
able to flourish in the new market,”
says Roger Wyse, managing director
of Burrill & Co., the San Franciscobased venture-capital and merchantbanking firm.
Government Giving
This past January the government
of Norway submitted to Parliament
28
a £2 billion ($2.9 billion) economicstimulus package, about £302 million
($432 million) of which would be earmarked for biotech companies. Many
of Norway’s biotechs need that help,
because half of them are projected to
run out of cash in nine to 16 months.
This investment in biotech would allow Innovation Norway, the country’s
main industrial development agency,
to sponsor a range of biotech benefits,
such as tripling the loans available to
biotech and information-technology
companies, providing £7 million ($10
million) in research-and-development contracts and allowing up to
£580,000 ($830,000) in tax breaks.
“At this point, these seem to be the
necessary measures to bring the Norwegian biotech companies through
the financial crisis,” says Bjarte Reve,
chief executive of the Oslo Cancer
Cluster, an industry research association representing 25 biotech companies focusing on oncology products.
India also plans to buy new hope
for its biotechs. In November 2008,
India’s government approved a 3.5
billion rupee ($72 million) Biotechnology Industry Partnership Program to fund projects in a range of areas, including biomarkers, stem cells
and others. This program will also
provide 100 percent grant-in-aid support to clinical trials involving biotech-based products—if they include
some innovation from India. Once
commercialized, 3 to 7 percent of net
product sales would be returned to
the government as royalties.
Government giving has also
been proposed—although not acted
on—in the United Kingdom, where
one-quarter of the biotech companies could go bankrupt by year’s end.
One U.K. proposal, endorsed last year
by 22 biotech-industry executives
and submitted to the government in
December 2008, seeks at least £1 billion ($1.4 billion) in new government
spending through the creation of two
public–private biomedical funds.
One is a £500 million ($715 million)
National Biomedical Consolidation
Fund that, with matching private
money, would encourage less-successful companies to consolidate into
higher-quality biotechs. A second,
£500 million National Super Growth
Biomedical Fund with matching
private funds would provide loans
to a select handful of high growth–
potential companies. “The logic is that
government should put back some of
the money it has taken from taxpayers to where there is both a need and
good grounds for spending, such as in
healthcare, which is important to the
nation’s health,” says Chris Collins,
chief executive of Nomura Code Securities investment bank in London
who endorsed the proposals.
“... it’s not only the lives of the
companies that are on the line, it’s
the lives of patients.” –Jim Greenwood
Cranking Up Tax Cuts
Other countries want to nurture the
biotech industry, rather than simply
buying it out of trouble, even when the
trouble is severe. In Canada, for example, more than 25 percent of its biotech
companies had less than six months
cash remaining at the end of last year.
“These firms are not suffering from
structural problems or bad business
decisions, they simply need investments,” says Peter Brenders, president
and chief executive of BIOTECanada,
the country’s trade association.
BIOTECanada asked the government to take the following measures:
allow small companies to receive a
$787 billion stimulus package, which
passed in February.
“We’re going to continue to pursue
it,” says Jim Greenwood, BIO president and chief executive. “We will be
looking for other legislative vehicles
to get it enacted into law, which might
be subsequent stimulus bills or a future comprehensive tax package.”
Like Canada, the U.S. industry is
not looking for a bailout. Rather, BIO
seeks legislation to allow companies
to accelerate net operating losses and
to take research and development
tax credits as a deduction against future earnings, but at a discount from
what they would otherwise have
been. BIO also wants Congress to
at least suspend rules that limit the
amount of net operating losses that
may be taken in successive rounds of
equity financings or following company mergers. And BIO would like
capital-gains taxes on invested funds
to be reduced or even eliminated to
encourage investments in biotechrelated funds.
“It’s sad, that for any company
that has to go out of business or shelve
their research because of all this, we
may or may not see those projects
continue in the future,” Greenwood
says. “So it’s not only the lives of the
companies that are on the line, it’s the
lives of patients.”
Similar to stimulus packages in
place for other industries, all the
above biotech initiatives aim to prime
the pump. The question is: Can it be
done in time?
policy & economics
29
Sponsor Profile
Pfizer: uniquely
changing discovery
ood health is vital to all of us, and finding sustainable solutions
to the health care challenges of our changing world cannot wait.
That’s why Pfizer is committed to being a global leader in health
care. At Pfizer, we help change millions of lives by discovering,
developing, and delivering innovative treatments that society values to prevent and cure diseases.
To achieve these goals, Pfizer is committed to fostering innovation across
all facets of the research and development continuum. Innovation at Pfizer begins with the discovery of novel disease targets, and includes how discoveries
are translated into new medicines. These Pfizer innovations improve current
treatments or provide medical solutions for diseases where treatments are not
available. Through technology and business model innovation, Pfizer strives to
improve productivity, accelerate the delivery of medicines to patients, increase
pipeline transparency and clinical trial practices, improve drug safety monitoring, and work with stakeholders in new ways to ensure that effective new
medicines reach patients.
As advances in medical care help more and more people live longer lives,
the need for new medicines to keep people healthy continues to grow.
Pfizer researchers and scientists are working to discover and develop new
ways to treat and prevent life-threatening and debilitating illnesses—such as
Alzheimer’s disease and cancer—as well as to improve wellness and quality of
life across a range of therapeutic areas.
How Pfizer is uniquely changing the way new medicines
are discovered and developed
Establishing an Innovation
Engine for Discovery
A human stem cell culture
30
In October 2007, Pfizer launched the
Biotherapeutics and Bioinnovation
Center (BBC) to propel Pfizer to the
forefront of bioinnovation and into
the top tier of biotherapeutics companies. The BBC represents an innovative
model for Pfizer and the pharmaceutical industry, as it brings the best features of science, venture capital, entrepreneurship, and pharmaceutical scale
together in one place for the first time.
The BBC is a federation of dynamic, entrepreneurial, biotech-like
units each focusing on the innovation
of key biotherapeutic technology platforms—antibodies, peptides, nucleic
acids, stem cells—to deliver best-inclass and first-in-class medicines
through clinical proof of concept.
These biotech-like units are located in the major academic and bio-
technology hubs of the world. They
are encouraged to preserve their identity and culture, to develop their own
cutting-edge technology while bringing forward new drugs, and to remain
largely independent in their decisionmaking. Each unit in the BBC federation has no more than 150 scientists
and is run by a Chief Scientific Officer. The units interact with each other
to access talent and technologies and
have the added benefit of working collaboratively with the resources and
expertise of Pfizer’s Global Research
and Development organization.
With the broad therapeutic area
knowledge and experience of Pfizer’s
global business units behind it, the
BBC has site-based business, legal,
and financial resources to ensure that
its scientists and collaborators have
close local support to deliver immediate and innovative business solutions.
Pfizer scientists collaborate in the lab
The BBC has emerged as an engine of
discovery with tempo. This same innovative thinking is being applied to
the complexity of pharmaceutical discovery and development to position
Pfizer at the forefront of emerging
technologies. In fact, Pfizer restructured both its research and commercial organizations into business units
last year to help spur new ideas, making the enterprise more efficient and
more entrepreneurial. Smaller operating units will enhance innovation and
accountability, while benefiting from
the scale and resources of the world’s
largest pharmaceutical company.
Forming Partnerships with
the Best External Science
In addition to the significant technical
innovation accomplished internally,
Pfizer aggressively pursues bioinnovation through collaborations with
world-class academic, public-sector,
and private-sector institutions in areas of emerging science. By acquiring high-value targets, cutting-edge
technologies, and the latest scientific
knowledge, the company can accelerate research and develop medicines
across a wide range of therapeutic
areas to focus on satisfying unmet
medical needs. The BBC is supported
by senior business development col-
leagues, most with academic and
pharmaceutical credentials, and well
connected to Pfizer’s broader Worldwide Strategy and Business Development team.
Tackling a Major Industry
Challenge to Lower Clinical
Attrition
Generation of novel, validated, targets is so fundamental to Pfizer’s ability to succeed that it has established
a stand-alone research unit called the
Target Generation Unit (TGU). The
TGU combines human genetics and
systems biology approaches to identify and validate novel targets that are
proven relevant in human disease.
Led by Dr. David Cox, a worldrenowned geneticist, the TGU team
applies knowledge of human genetics
and systems biology to improve preclinical validation and inform clinical
trial design. This approach serves to
reduce clinical attrition and to deliver
safer, more effective medicines to patients—doing so more quickly and at
lower cost.
The TGU combines resources
across Pfizer with a rich set of collaborators from biotech and academia,
to identify new biochemical pathways
that provide opportunities for therapeutic intervention. A series of ge-
netic research projects are underway
in which gene sequencing technologies are being used to identify rare
genetic changes that protect individuals from disease. Through these
approaches, the TGU then develops
therapeutic interventions, which are
tested in human cell-based assays
and through systems biology models.
The use of human genetics to identify relevant disease targets and the
avoidance of animal models that are
poorly predictive of human disease is
the cornerstone of Pfizer’s strategy to
generate novel, high-quality targets.
Establishment of the TGU is a bold
move that Pfizer believes will provide
valuable target substrate for its drugdiscovery programs.
Investing in Emerging Areas
of Science: Nucleic Acids and
Stem Cell Research
Last year, Pfizer took a meaningful
position in nucleic acids and stem cell
research—two new, highly promising, and transformative areas of science capable of delivering novel clinical therapies across all disease areas.
Because nucleic acids have the
potential to expand therapeutic intervention and treat diseases that are not
successfully addressed using today’s
traditional approaches, Pfizer has put
together a team of experts who are
securing the company’s foothold in
this area. Pfizer also entered the field
of regenerative medicine; and in 2008
launched the Pfizer Regenerative Medicine Unit, positioning Pfizer as the
first pharmaceutical company to have
a dedicated effort in stem cell–based
therapeutics. This unit extends Pfizer’s
commitment to stem cell research,
takes advantage of the scientific advances in understanding stem cells,
and explores the opportunities they
provide to supporting better therapies.
Pfizer believes this area of research
holds considerable promise for biomedical science and for the treatment
of many debilitating conditions.
sponsor profile 31
C
A global biotechnology survey
[ worldview
scorecard ]
WV
Sc
32
ountries around the
world bolster biotechnology programs
in hopes of raising
their economic success and to
enhance the quality of life and
health of their people. With so
many earnest efforts dedicated
to growing domestic biotechnology industries, the central
question remains: Who is doing
what, and how well are they
doing it? To shed light on this
issue, I, along with a team of
advisors working with Scientific
American, sought to identify the
global leaders in biotechnology
and to provide a framework that
could measure the progress and
potential of countries—especially ones that are not currently
regarded as world leaders. This
was our guiding objective in
creating the Scientific American
Worldview Scorecard.
Although numerous broad
regional rankings exist, often
comparing the United States,
Europe and Asia, this project’s
goal was to dig deeper into the
innovation potential of individual
nations and the multiple factors
that should be taken into consideration. For example, size must
be considered and contextualized (especially as the United
States is larger than any single
European nation). Moreover,
regions such as Europe and Asia
consist of numerous politically and economically distinct
countries. So rather than simply
comparing gross productivity—
the population and economic
differences among countries
limit the relevance of such a
crude measure—this report
investigates and enumerates
the factors promoting and impeding biotechnology innovation.
Furthermore, biotechnology
activities are not restricted to the
manufacture of products; many
companies are active in services such as contract research,
clinical-trial management,
consulting and other activities
with nontangible outputs. As a
result, the data in this report
come from diverse measures—
including educational attainment
of a nation’s population and
research and development (R&D)
funding and activity—to capture
the broad array of biotechnology
activities and factors supporting
innovation.
In the following pages we
assess the biotechnology innovation strength in various countries. The results are not a mere
ranking of the countries—a basic
comparison of national revenues
would have accomplished that
task. Instead, these results dig
more deeply into the elements
that impact overall biotech innovation. When examining these
data, it is important to consider
that a high innovation score
does not necessarily mean that
a country is producing a lot of
biotechnology products. These
measures indicate the capacity
for biotechnology innovation.
This analysis also includes innovation-output measures, which
were not used in determining the
innovation score. Nonetheless,
these outputs—such as publiccompany performance and
market-size measurements—
help frame the innovation score.
We believe most readers will find
some surprises in the results.
Illustrations by Joelle Bolt
By Yali Friedman
WorldView scorecard
33
Intensity
3
Basic Data
Methodology
A key challenge was deciding
what to measure, and how to
gauge performance. Poor selection of metrics can yield outputs
that are difficult to interpret and
lack utility. For example, focusing on gross revenues correctly
identifies the global biotechnology leaders, but diminishes
the important contributions by
smaller nations or those with
rapidly growing biotechnology industries. Dividing gross
numbers by a country’s population or gross domestic product
(GDP) can identify nations with
relatively strong biotechnology
industries, but might underrepresent the activities of larger
nations. To resolve this conflict,
these data include both gross
and relative metrics to provide
a balanced viewpoint. Desiring
to also identify countries with
strong opportunities for biotechnology growth, we looked at
several fundamental measurements such as the strength of
intellectual-property protection,
government support of R&D,
educational attainment and
others. To collect the data and
compile the final list of countries, we relied on an objective
approach. Rather than focusing on surveys, polls or existing lists of leading nations, we
decided to let the data guide the
way. We started with lists that
2
1
34
ranked all the world’s countries
in broad topics, such as ease
of doing business and capital
availability, and these were
combined with numerous biotechnology-specific data sets.
Counting the data gaps for each
country, and eliminating those
with the most gaps, made it
possible to cull the list to arrive
at a set of global biotechnology–
innovation leaders. Excluding
countries for which data were
unavailable (because of a lack of
transparency, or a general lack
of biotechnology activity) was
necessary, as these deficiencies
would have made it impossible
to fairly compare them against
the others.
Adding it all up
Compiling all the individual
metrics into the overall innovation score created another
dilemma. What is the relative
importance of each factor? Is
the number of patents granted
more or less important than
the availability of funding or
workers? Is patent enforcement
more important than having a
business-friendly environment?
If so, by how much? The weighting of these factors is dynamic
and hard to objectively measure;
the relative weight of factors is
also subject to change based on
context. Rather than assigning a
weighting to each of the factors,
which would imply that the relative importance is measureable
and known, we decided to put
all the measures into discrete
categories and compare them
on par. Examining the individual
category scores makes it possible to independently evaluate
the rationale for a country’s
innovation score.
Two factors that were not
directly measured are market
access and regulatory burdens.
These factors are difficult to
objectively measure, but their
impact can be assessed by
evaluating market data. The
measurement of therapeutics market size, for example,
reflects the revenues from drug
sales in a given country. This
value is influenced both by the
size of the patient population
in a country as well as pricing
influences. Likewise, measuring
the hectares of biotechnology
crops planted reflects the ability
to grow and sell biotechnology
crops in a given market. These
are important measurements
of innovation capacity, because
companies will often locate
their R&D and other operations
in proximity to the most lucrative markets.
As described in the Methods (page 55) at the end of
Measuring the intensity—public
companies per capita, portion of
overall R&D spending used for
biotech, and so on—of a country’s
biotechnology activities balances some of the size-related
differences between countries.
Simply counting the gross sum of
companies, patents or revenues
generally favors the largest
countries, which win largely
because of their size. Comparing
the intensity of biotechnology activities, on the other hand, makes
it possible to fairly compare large
countries with each other, and
to identify small countries with
strong biotechnology activities.
Enterprise
Support
this section, each country’s
performance in the individual
metrics was ranked on a scale
from 0 to 5, with the lowestranked country scored as 0 and
the highest-ranked country
scored as 5. Next, the individual
category means were calculated
and then averaged to derive the
overall innovation score. The
purpose of this normalization
and two-step averaging was to
consider the measurements on
equal weighting and to isolate
any biases due to data gaps in
individual categories.
I ntellectual
Property
Intellectual-property (IP)
protection is very important in
biotechnology. The great time
requirements, financial costs,
developmental-failure risks of
innovative R&D and the relative
ease of reverse-engineering
make the scope and strength
of IP protection strong determinants of biotechnology
innovation. Nonetheless, some
countries maintain weak IP
protection to promote growth of
domestic industries. This strategy, however, often discourages domestic investments by
foreign firms.
Enterprise support promotes
growth of domestic biotechnology start-ups and encourages
foreign companies to establish
facilities domestically. To assess
enterprise support, this report
looks at factors such as how
“business friendly” a country
was perceived to be and the
availability of various forms of
capital, which are essential to
support the growth of emerging
biotechnology firms.
Education /
Workforce
Biotechnology is a technically
complex field, requiring skilled
scientists and other workers
for R&D and supportive activities. Moreover, many managers
at biotechnology companies
have advanced degrees, making
education an important measure
of a country’s capacity for biotechnology innovation. The data
used here examine educational
attainment at undergraduate
and doctorate levels, and also
enumerate the number of R&D
personnel and biotechnology
workers in addition to publication of scientific papers. Together, these measurements provide
a robust assay of a country’s
scientific potential and output.
Foundations
Beyond general national statistics, this study includes some
broad measurements of the
foundations for biotechnology
innovation. So this category focuses on more-general factors
that can support activities at
biotechnology companies.
orldview in
W
context
In general, an objective comparison of statistical indicators
should not be expected to provide a complete picture of any
one country’s innovation. Subtle
differences in political environments, economic strength,
social influences and technological capacities have profound
impacts on biotechnology innovation. The individual country
reports throughout Worldview
are important complements to
this global ranking, and provide
additional context and details.
WorldView scorecard
35
2.68
0.05
1.42
1.7
Ireland
4.78
1.68
3.46
1.78
2.17
2.8
Israel
4.23
0.89
4.30
1.73
4.44
3.1
Italy
4.78
0.31
2.26
1.23
1.59
2.0
Japan
4.78
0.61
4.04
1.45
3.01
2.8
Mexico
3.97
1.13
3.01
0.29
0.68
1.8
Netherlands
4.78
0.95
3.32
1.84
2.07
2.6
New Zealand
4.10
2.66
4.43
2.35
1.45
3.0
Norway
4.27
1.07
3.55
1.65
2.72
2.7
Poland
4.31
1.08
2.24
0.74
1.52
2.0
Portugal
4.48
0.16
2.70
1.55
1.21
2.0
Russia
3.77
1.48
2.27
1.30
1.95
2.2
Singapore
4.31
1.54
4.69
3.16
3.71
3.5
Slovak Republic
4.31
0.00
2.65
1.01
0.74
1.7
South Africa
4.35
0.51
3.81
0.29
1.62
2.1
South Korea
4.43
0.93
4.20
1.10
3.00
2.7
Spain
4.43
1.05
2.59
1.20
1.59
2.2
Sweden
4.65
1.36
3.54
2.24
3.92
3.1
Switzerland
4.43
1.61
3.24
2.55
3.31
3.0
Turkey
4.10
0.89
2.81
0.37
1.01
1.8
United Kingdom
4.65
1.21
3.69
2.03
2.70
2.9
5.00
2.83
4.87
2.50
3.64
3.8
United States
See Methods (p.55-57) for details.
36
What could my
country do to
stimulate its
innovation in
biotechnology?
4.24
4.65
4.78
4.78
4.78
4.78
4.78
5.00
2.83
0.68
us
3.85
2.50
India
us
3.0
1.54
Iceland
switzerland 1.61
2.0
3.11
singapore
1.32
1.02
2.55
0.67
2.89
2.03
2.51
4.24
uk
0.92
3.59
switzerland
4.61
2.66
Hungary
1.48
1.7
russia
0.71
new zealnd
1.40
2.24
2.05
sweden
0.00
3.16
4.40
singapore
Greece
1.68
2.7
ireland
3.51
2.35
1.68
new zealand
3.16
2.46
0.64
iceland
4.61
denmark
Germany
2.41
2.6
finland
France
netherlands 1.84
3.0
2.87
1.80
3.74
1.72
canada
2.41
3.01
1.89
3.48
0.85
1.64
0.51
4.78
brazil
4.78
2.39
Finland
denmark
3.2
australia
3.23
intensity
1.89
education/
workforce
3.46
us
2.46
4.87
4.78
us
Denmark
3.64
2.1
us
2.03
4.78
1.29
uk
2.19
4.20
0.76
3.69
4.43
uk
Czech Republic
south korea
2.1
3.31
2.59
switzerland
0.21
4.78
2.85
netherlands
0.62
japan
4.18
3.81
China
T
south africa
2.9
3.92
2.79
3.71
1.64
sweden
3.52
singapore
1.80
italy
4.78
4.44
Canada
4.69
1.8
singapore
1.40
israel
0.27
ireland
2.13
france
1.64
4.43
3.67
3.55
Brazil
norway
2.6
new zealand
2.07
3.11
1.58
iceland
3.12
germany
1.38
3.51
4.78
denmark
Belgium
canada
2.6
4.30
3.13
4.04
1.82
japan
2.98
israel
0.52
3.74
4.43
3.23
Austria
hese figures portray
the capacity for biotech
innovation in nations
around the world. Taken
together, the presentations in this section
reveal a collection of fundamental
capabilities that a country needs to
excel in this industry. The category
rankings (left, blues), for instance,
provide a rapid means to assess the
balance of IP protection and activity,
biotechnology-innovation intensity,
enterprise support, educational and
workforce strength, and general
foundations in each country. The
overall innovation score (left,
magenta) is the simple average of
these category rankings.
Exploring the results in this table
reveals that a country that did not
achieve a high overall score might
still perform well in some categories. Additionally, the countries that
scored highest overall have areas of
innovation potential that could use
improvement. Like any rich dataset,
this one offers plenty of information
to ponder. As you tour these data,
ask yourself:
finland
3.0
denmark
2.74
ip
2.39
belguim
4.54
4.54
0.86
australia
4.27
3.13
Australia
foundations
/
ise
s
ionce
pr
t
r
ion
te ort uca for
at final
d
n
e pp
ed ork
un
score
su
fo
w
enterprise
support
nsi
te
in
IP
ty
austria
Innovation Capacity Scores
4.78
The Category Leaders: 5 Key Benchmarks
The Overall Leaders:
H
ere are the top-10 countries—
listed alphabetically—in each of the
individual five categories. In assessing the innovation strength of each
country, it is important to look at the
measurements that comprise the
overall innovation score. Because the innovation
score is the simple average of the five category
measurements, examining the strength in each
category can indicate areas for improvement or
rationalize why dissimilar countries might have
similar innovation scores.
WorldView scorecard
37
THE TOP
a
li
a
tr
rk
a
nm
s
The Shape
of Innovation
Au
De
3.0
3.2
1
2
3
4
5
d
nd
an
l
in
IP
a
el
ic
f
intensity
3.0
enterprise
support
3.0
education/
workforce
foundations
l
ae
ne
si
3.1
en
ed
T
38
3.0
3.5
d
an
3.1
l
er
z
it
sw
sw
he spider charts for the countries with the top-10 overall innovation scores (right) display the relative
strength—rated on a scale of 0 to 5—of each country in each of the category areas: intellectual property (IP), intensity, enterprise support, education/workforce and foundations. Points further from the
center indicate a higher score in a category, and points closer to the center indicate a lower score in a
category. A ‘big’ web indicates high results in all categories, whereas a smaller web indicates weaker
measurements. The numbers inside the webs give the overall innovation scores for each country.
e
or
ap
ng
z
w
r
is
d
an
l
ea
us
3.0
3.8
WorldView scorecard
39
asia
.6
canada-7
fr
a
ge nce
rm
an
y
o
st
re th
u
so rea
ko
-2
d
1
-1
an
us -2 erl
z
UK t
swi
any-5
Germ
-3
nce
Fra
n
japa
europe
US & Canada
($Millions)
7
us
87
90
,5
1.
8
43
Denmark-47
1
2
a-
therapeutics
market
.4
86
hectares of
biotech crops
planted
tin
en 5
g
ar -62.
us
m
ca exic
na o
da
industrialenzyme
production
(Millions)
(tons)
5
3 19
45 ,
no. of
public
Biotechnology
companies
11
public
Biotechnology
company
revenues
10
($millions)
market
capitalization
6,564 824
($Millions)
allocations of firms by activity areas (Selected Countries)
australia
47
33
1
97
belgium
31
23
54
28
3448.33
301
249.94
iceland
17
218.98
1557.05
31
27
23
49
16
53
19
15
29
34
48
uk
31
15
21
17
41 5
8
452
switzerland
6
53
9
25
25
30
sweden
11
20
19 3
53
38
14
17
south africa
south korea
21
14
10
46
5
41
25
norway
us
17.1
87.5
uk
switzerland
31
poland
45.75
156.87
sweden
0.01
75.5
norway
new zealand
25
65
israel
1116
netherlands
japan
italy
ireland
india
israel
0.05
67.25
6.8
136.5
2.4
40.4
78
iceland
hong kong
germany
144.56
555.75
50.66
france
finland
denmark
64.83
449.33
24.73
521.37
12.2
106
china
10.77
99.15
canada
belgium
7.85
74.9
31.12
256.71
59.95
1002.5
1210
($Millions)/company
41
4
35
18
52
ireland
1412.66
153.98
revenue
Austria
198.96
203.5
Market capitalization
15
58 4 3
germany
267.7
What these companies
are worth on the market
and the funds that they
generate.
($Millions)/ company
denmark
france
Agri-food
12
28
6
39
7
10
Industrial/ enviromental
11
8
17
63
finland
Health
6
52
canada
Public
Biotechnology
company
efficiencies:
24
15
china
australia
70,078.7 7,248.
ch
ina
- 3.
pa
8
ra
gu
ay
-2
.7
australia
a
si
fa
pan
6-Ja ds
lan
er
ra
ze n lia
al ew
an
d
8
1.
aic
r
7
af -0.0
th uay .06
u
0
so rag viau li
o
b
th
Ne
18-
st
ndia
7.6-i zil
a
-br
au
italy
in
spa
T
he category scores reflect a country’s capacity for biotechnology
innovation, but intentionally sidestep output. Measuring output
would be too polarizing, yielding insufficient information on the
prospects for future innovation. The United States’ biotechnology output is far higher than other countries—due to its size,
economic strength and other factors—and comparing other
countries to the U.S.’s output would diminish the important differences
among them. Although measurements of output and company performance
were not included in the innovation score, they are still important to develop
a perspective of global biotechnology innovation. So here are selected
measurements that serve as accessories to the innovation score.
market size
of
st pe
reuro
e
public
Biotechnology
companies
1 5 .8
The Outputs:
I
other
nnovation capacity depends on
context. Furthermore, different countries might elect to
focus on different areas. R&D
activities in some countries,
for example, might eschew the
popular quest for therapeutics in
favor of agricultural or industrial
applications. The measurements
on this page provide perspective on
these trends.
Issues such as regulatory
transparency, ease of regulatory
approval, bans on specific applications and control of drug pricing
can also influence the capacity for
innovation. Such factors also influence decisions by multinational
firms to place facilities in certain
countries. In fact, companies often
locate R&D and other operations
in proximity to the largest, mostaccessible markets. Accordingly,
the market-size measurements
(above) are included here as indicators of commercial opportunities.
30
us
65
12
12
11
WorldView scorecard
41
Country spotlight: Singapore
Country spotlight: israel
Beefing Up
Biotech
with
Biopolis
Despite autocratic
expectations, Singapore
built a free-thinking
environment for innovation
By Mara Hvistendahl
W
hen Singapore unveiled
a 46-acre bioscience
complex in 2003, it
met with a few raised
eyebrows. How can an autocratic citystate that meddles in everything from
bungee-jumping to gum-chewing
stimulate free-wheeling innovation?
But with research at Biopolis, as
the complex is called, now hurtling
Genome
Proteos
ahead, the naysayers are being proven
wrong. The seven buildings in the
$500 million (U.S.$328 million) development—which sport names like
Genome, Matrix and Nanos—now
house 2,000 scientists from around
the world, along with a collection of
new state research agencies. The two
buildings in Phase II, completed in
2006, are fully booked. “The take-up
has exceeded our timeline,” says Keat
Chuan Yeoh, executive director for
biomedical sciences at Singapore’s
Economic Development Board, which
spearheaded the project along with
the Agency for Science Technology
and Research (A*STAR). “We brought
[the timeline] forward at least a year
because of stronger than anticipated
demand.” While many spots in the
world show biotechnology slowdowns
because of the global economic crash,
Biopolis keeps moving forward.
In 2000 Singaporean leaders
debated how best to diversify the
small state’s economy, which at the
time depended on manufacturing.
“We wanted to move up the chain to
knowledge creation and inventions,”
explains Andre Wan, deputy executive director of A*STAR’s Biomedical
Research Council. Bioscience made
sense: “We already had a pharmaceutical manufacturing presence and a
good healthcare system.”
Biopolis is part of a larger area
intended to showcase the country’s
Matrix
Centros
Chromos
Nanos
Helios
42
new strength. The neighborhood also
holds the National University of Singapore, an outpost of Duke Graduate
Medical School and the early research
hub Singapore Science Park II—along
with Fusionopolis, a new complex
devoted to technology and information science.
That concentration of resources—
along with $1.5 billion (U.S.$1 billion)
in funding for translational research—
has helped Singapore recruit major
pharmaceutical companies and
big-name Western scientists. In 2003,
for example, Alex Matter stepped
down as Novartis’s head of oncology
research in Basel, Switzerland, where
he led development of the cancer
drug Gleevec, to take over the company’s Institute for Tropical Diseases
in Biopolis. Today, Matter says he
doesn’t have any regrets: “It’s all fresh
and new here, but there is a huge
amount of energy and drive.”
Another big recruit is Jackie Ying, a
young hotshot from the Massachusetts
Institute of Technology who now heads
A*STAR’S Institute of Bioengineering
and Nanotechnology. Ying says she’s
had the freedom to structure problemoriented projects, hire scientists from
a variety of disciplines and even tweak
the focus of the institute—A*STAR
leaders originally envisioned it as the
Institute of Bioengineering, without
the nanotech. The government “gave
me a lot of flexibility and resources so
we could do cutting-edge research in
Singapore,” she says.
Ultimately, Singapore’s government hopes Biopolis will spark interaction between research institutes and
the private sector, leading to a proliferation of small spin-off companies.
But now that scientists have moved in,
the state doesn’t meddle in their work,
Matter says: “The government doesn’t
tell researchers what to research. It’s
a very enlightened form of top-down
administration.” The government is,
perhaps, too busy forging ahead with
its bioscience vision. “We’re looking at
Phases IV and V,” Yeoh says.
®
Israel’s Pharma-Patent Killer
Teva, the world’s largest maker of chemical generic drugs, is moving in
on biogenerics By Shailaja Neelakantan
I
n 1984 Orrin Hatch and Henry
Waxman unknowingly created
a giant killer when they pushed
through an amendment to the U.S.
Federal Food, Drug and Cosmetics
Act, which allowed drug manufacturers to challenge the validity of patents.
Israel’s Teva was already making
many patented drugs for local use
through licensing agreements, so
all the company needed to reap the
benefits of the new legislation was to
put in place a crack legal team to bust
existing patents. “The core of Teva’s
business model is challenging existing
patents of innovative drugs,” says Yoav
Burgan, an analyst at Leader Capital
Markets in Tel Aviv, Israel. “It has been
long-acting biopharmaceuticals for
therapeutic uses, including preventing infections in cancer patients
undergoing chemotherapy. Then
in January 2009 Teva signed a joint
venture agreement with Swiss biologic
contract manufacturer Lonza Group
to develop biogenerics.
A spokesperson from Teva
would only say, “Teva and Lonza will
cooperate to develop, manufacture
and market a number of affordable,
efficacious and safe generic equivalents of a selected portfolio.”
While most analysts are bullish about Teva’s biotech buys, some
doubt it will turn them into earners
as quickly as did its chemical-drug
Starting in January 2008 …
Teva’s acquisitions signaled a move
into biotechnology.
very successful at this.” That skill, as
well as a knack for acquiring competitors—including Sicor, Ivax and Barr
Pharmaceuticals—has made Teva the
world’s biggest generic-drug company.
Starting in January 2008, however,
Teva’s acquisitions signaled a move
into biotechnology. For example, Teva
bought CoGenesys for $400 million.
CoGenesys is developing improved,
acquisitions. “CoGenesys was a waste
of money,” says Ori Hershkovits of Tel
Aviv’s Sphera Fund, because there is
no way of competing with proprietary
companies in biotech. The products
aren’t substitutable, which means the
generic versions are never an exact
match and require expensive clinical
trials. Moreover, they aren’t AB-rated,
so they must be marketed directly
to doctors, which Hershkovits says
would require Teva to develop a more
extensive sales network.
In addition Hershkovits dislikes
the joint venture with Lonza, since its
monoclonal antibody is less efficient
than the antibodies of other companies. “Lonza manufactures a monoclonal antibody that is 1.5 grams per
liter, and there are companies out
there that are manufacturing such
antibodies at 20 grams per liter,” he
says, explaining that the higher the
number of grams per liter, the lower
the manufacturing costs.
Others, including Ronny Gal an
analyst at New York-based Bernstein
Research, are more optimistic. As Gal
points out, the sales force already in
place for Teva’s proprietary multiplesclerosis drug Copaxone will be useful
when its biogenerics come to market.
Moreover, Teva spent about $150
million on scientific research and
development in 2007, so its biotech
acquisitions could work.
Nonetheless making biotech drugs
is very difficult, and Teva still spends
less than half the amount that typical
proprietary-drug companies invest in
research and development. It’s probably time for Teva to complement
its crack legal-research team with
a stellar group of scientists in drug
discovery and development.
WorldView scorecard
43
®
Country spotlight: china
Country spotlight: brazil
The Future of
Ancient Cures
Turning traditional
Chinese medicine
modern and leading
the way for new drugs
By Mara Hvistendahl
W
olfberry, licorice and
caterpillar fungus. Such
substances don’t sound
like the makings of
modern medicine, but they might
soon be just that. China’s current
five-year plan lists the “modernization” of traditional Chinese
medicine (TCM) as one of 12 focal
points, allotting 1 billion yuan ($146
million) for the task. The goal is to
move away from philosophies like
44
yin–yang and meridian theory and
toward science—by introducing
randomized, double-blind, placebocontrolled trials.
“We find the pure compound
first, then evaluate the efficacy of that
compound,” explains Wu Jun, vice
president of Xiangxue Pharmaceutical
Company, which tests and develops
herbal medicines in the southern city
of Guangzhou. “Let’s just call it Chinese medicine. It’s not traditional.”
The epicenter of the drive is
Shanghai’s Zhangjiang High Technology Park, a sprawling complex at the
city’s futuristic edge. There the gleaming Research Center for Modernization of Traditional Chinese Medicine
holds court before a scattering of
biotech start-ups, along with the
research arms of almost every major
pharmaceutical company. The area is
brimming with returnees—bilingual,
bicultural scientists educated overseas—intent on proving and improving China’s worth. “The talent pool
is huge,” says Mirielle Gingras, chief
executive officer of Huya Bioscience
International, a U.S. company that
in-licenses drug compounds from its
office in Zhangjiang.
One early Chinese success is artemisinin, an extract of sweet worm-
wood determined in the 1970s to
be effective in fighting malaria. The
World Health Organization approved
artemisinin in 2001, recommending that tropical countries adopt a
combination therapy that includes
the Chinese drug—sparking a boom
in sweet-wormwood production in
the Chinese heartland.
The Holy Grail for Chinese biotech companies is approval by the
U.S. Food and Drug Administration.
But adapting Chinese medicines
to western medical standards is far
from easy. Many modern disorders
are not described in centuries-old
Chinese materia medica. And herbal
medicines often have a strong smell
that can be difficult to emulate in
a placebo.
Some companies spend years
isolating a compound, only to learn it
has been patented. “A lot of times you
find a compound that is connected [to
a treatment], but it’s already known,”
says Wang Ming-Wei, director of the
National Center for Drug Screening
in Shanghai. “It’s a good academic
story, but it’s not a passage to [intellectual property].”
But with problems surrounding
overall drug development in China—
the head of China’s State Food and
Drug Administration was executed in
2007 for taking bribes, leaving thousands of licenses under review—some
say TCM is a bright spot. Recently
the central government unveiled
Herbalome, a 15-year project with the
goal of isolating active compounds in
thousands of ancient medicines. For
companies like Huya, the investment
in research translates into licenses,
and Gingras estimates that 10 percent
of the company’s compounds are
derived from TCM.
Wang is optimistic that Chinese
companies will succeed at updating
an ancient practice. “Not only are
traditional doctors studying [TCM],
but other scientists in China and the
world are as well,” says Wang. “More
and more good stories will come up.”
Cellulose in Campinas
A Brazilian pilot plant fuels the country’s changing direction in ethanol By Emily Waltz
A
t a press conference in February in Campinas, Brazil,
molecular physicist Marco
A. P. Lima presented plans
for the country’s third cellulosicethanol pilot plant. This plant would
make biofuel from next-generation
feedstocks, such as grasses, wood
chips and agricultural waste. He envisioned a facility where any qualified
scientist with the goal of converting agricultural waste to ethanol
could conduct experiments with the
facility’s equipment, lab space and
personnel. Lima hoped that an open
collaboration might hasten development of this technology.
The Campinas pilot plant, a federally sponsored project, might indicate
a shift in Brazil’s plans for its ethanol
industry. Until a recent surge in funding, the country has devoted few resources to technologies for cellulosic
ethanol—even though Brazilian government officials have said that they
want Brazil to lead the international
biofuel market. To do that sustainably,
however, the country must make the
switch to cellulosic feedstocks.
Brazil has already built what is
arguably the most-developed ethanol
market in the world. The country
meets more than half of its gasoline needs with ethanol and in 2008
exported a record 5.16 billion liters—
up 46 percent over 2007. In addition
more than 33,000 filling stations
pump pure ethanol fuel, called E100.
Nearly all of this fuel comes from
sugarcane, a first-generation crop.
Only about a third of the sugarcane
plant—the sucrose part—is used to
make ethanol. The rest—the leaves
and residue, called bagasse—is
tough to break down, so it is usually
converted inefficiently for power, or
wasted. Figuring out a way to break
down this cellulosic biomass is the
key to producing more ethanol without planting more sugarcane.
The technology to make cellulosic ethanol in an economic way
doesn’t exist, but scientists worldwide
are working on it. The U.S. Depart-
largely on enzymatic hydrolysis of
bagasse. “I have accepted the invitation to direct the project because it
seems to be a very serious proposition with important consequences to
Brazil and to the planet,” Lima says.
Brazil has already built what
is arguably the most-developed
ethanol market in the world.
ment of Energy in 2007 committed
$1 billion to next-generation biofuel
projects, and in February 2009 the
U.S. stimulus bill promised the field
up to $1.3 billion in research grants
and loan guarantees. The Chinese
central government in 2007 committed $5 billion over 10 years to
ethanol development with a focus on
cellulosic technologies.
Brazil’s recent interest in the
technology is starting to show. Dedini
S/A and the Centro de Tecnologia
Canavieira in Piracicaba, São Paolo,
built a 5,000 liter-per-day pilot plant
producing cellulosic ethanol with an
acid-hydrolysis technology. Petrobras,
an oil refiner, built a small reactor
for enzymatic hydrolysis of cellulosic
feedstocks. And two years ago Embrapa, a research corporation, created
a division focused on finding enzymes
and microorganisms involved in
converting such feedstocks. The group
is planning to build a pilot plant by
July 2010.
The Campinas project is part of
the Centro de Ciência e Tecnologia do
Bioetanol, and will receive $25 million
per year in government funding. Lima
expects construction to be completed
by early 2011. By then, he will have
hired 160 employees and will focus
WorldView scorecard
45
Country spotlight: canada
Country spotlight: australia
Making
Apples
Edible
Longer
Genetic engineering bears
non-browning fruit
By Meredith Small
A
n apple a day might be the
easiest way to keep the doctor away, but if you don’t eat
that apple quickly it’s bound
to turn brown, unappetizing and be
thrown in the trash. To fight that
problem, Okanagan Specialty Fruits
of Summerland, British Columbia,
Canada, reinvented the apple so that
it keeps its fresh color while sitting
in a lunchbox or gracing a cheese
platter. In short, Okanagan’s scientists
block the gene for polyphenol oxidase
(PPO), which causes browning, the
first stage of spoilage. Neal Carter,
Okanagan’s president, explains that
the when the enzyme is inhibited,
the apple doesn’t go through the
usual oxidizing process, and it takes
much longer—up to 16 days—before
secondary spoilage sets in.
“People identify with this benefit,” Carter says. “Everybody is an
apple expert. They know what they
like and don’t like, and browning
comes up high on the list of what
they don’t like.” People not only
wrinkle their noses at the brown
scuff marks, bruises and discoloration of apples, they also know the
brown parts simply don’t taste all
… the non-browning apples are
simply new,improved breeds of
the same apples we know and
love. They just look better
and last longer.
that good. That’s especially true for
kids who wrinkle their noses and
say “ewww” at the merest hint of
apply browning. And since children
and their busy parents represent a
significant slice of the market for
cut-up, convenient fruits and vegetables, this innovation might have a
big commercial impact.
According to Carter, the apple
industry took notice when cut baby
carrots entered the consumer market
in 1988, followed by cut salad greens
and fruits, such as peaches and melons. By 1995 the cut-fruit and -veggie
market had doubled, but apples and
pears were left behind, hampered by
that pesky browning issue.
46
Figuring out how to preserve
apples without dousing them with
chemicals or changing their genetic
structure took some time. Traditionally, sliced apples are dipped in an anti-oxidant, such as calcium ascorbate,
a process that stops the browning but
is also very expensive. These are the
apples that show up in McDonalds
salads, school lunch trays and on tiny
plastic airplane platters.
Although Okanagan Specialty
Fruits is a small company with only
six employees, they are moving
forward with their blocked-PPO
apple. The Okanagan non-browning
apples are currently in development
in both the greenhouse and in field
trials. The company has had test fruit
since 2002 and plans to have them on
the market by 2012. Best of all, the
new-age apples probably won’t cost
much more than apples with bruises
and brown spots. “Apple breeders receive a royalty from growers for new
varieties,” Carter explains, and the
non-browning apples are simply new,
improved breeds of the same apples
we know and love. They just look better and last longer.
Imagine not having to pick
through all the Golden Delicious
apples at the store to find the ones
without spots. You could even take a
bite of your favorite Gala, leave it sitting for hours, and still find the next
bite white inside. Even better, imagine
a lunchbox that comes home with
sliced apples that can be packed again
the next day.
Plowing under A
GM Draught
Upcoming field trials
with genetically modified
canola could clear room
for more growth
By Mara Hvistendahl
W
hen the Western
Australian government
changed hands last
September and ushered
in trials on genetically modified (GM)
canola, it should have been a joyous
moment for the biotech researchers
who have been struggling to adapt
crops to the country’s arid heartland.
But a sudden erosion of funding has
agricultural scientists withholding
their cheers.
Capital raised by listed biotech
companies plunged from $609 million
in 2007 to a meager $118 million in
2008. The Australian government
withdrew key funding just as the
economic downturn hit, the two
unrelated events conspiring to crush
biotech companies. “We have a perfect storm in the biotech space,” says
Anna Lavelle, chief executive officer
of AusBiotech, a national biotech
industry association.
In its May 2008 budget the Australian government axed a dollar-matching grant program that had been a
lifeline for small biotech start-ups. “It
was a complete and absolute shock,”
Lavelle says. “Nobody saw it coming.
Following that we had the impact of
the global financial crisis. Biotech
companies have been hit very hard.”
This is hardly the beginning of
trouble for Australian agricultural
scientists. In 2003 national food and
drug regulators approved GM canola
for consumption. The next year
four agricultural states banned the
modified crop, fearing it would be
outsold in the export market. Then
in 2007 Bill Crabtree, a GM advocate
in Western Australia, tried to start a
company developing frost-tolerant
wheat in collaboration with the
Molecular Plant Breeding Cooperative Research Center in Victoria.
He aborted his plans after only a
few months because of inadequate
capital. “The moratorium had a
devastating effect on Australian agriculture,” he says. “It killed research
in Western Australia.”
After the Liberal and National
parties ousted the ruling Labor
party last fall, they reversed Western
Australia’s policy on GM crops. In
inaugural trials this summer 20 farmers will grow 2,500 acres of Monsanto’s GM Roundup Ready canola,
which has a resistance to herbicides
that proponents say will boost yield
by up to 20 percent. If the trials are
successful the government will lift
the moratorium in late 2009. In fact
New South Wales and Victoria lifted
their bans last year. But whether that
will be a boon for research is unclear.
Australia’s 130 listed biotech companies are concentrated in medical and
industrial research, in part because
the agricultural sector languished
under the bans. Although some fear
that new companies might not have
a chance to get off the ground, there
are a few success stories. In Western
Australia, for example, NemGenix is
developing wheat and sugarcane resistant to round worms.
Scientists remain cautious, but
optimistic. “Hopefully [GM canola
trials] will kick start GM in Western
Australia, and we can move forward
after 15 years of stalemate,” says
Mike Jones, director of the Western
Australian State Agricultural Biotechnology Center in Perth. If that doesn’t
happen, movement in other parts of
the region might help. “We’ll see a big
increase [in GM adoption] in China
and India. And that will drag others
along with it.”
WorldView scorecard
47
Country spotlight: spain
Country spotlight: hungary
Overcoming Hurdles in Hungary
For years, this country shied away from biotech, but that is changing By Emily Waltz
all located in the Barcelona Science
Park—rose out of this research sector
of the city.
Other regions in Spain haven’t
had the luxury of clinical-research
programs or existing pharmaceutical
industries to attract biotech startups. Instead, some adjusted their
traditional industries to bring in
life-science clients. Basque Country,
for instance, has strong manufactur-
Spanish
SpinOffs
Focusing on a specialty—
such as human-tissue
samples—creates a
source of new companies
By Emily Waltz
O
f all the things that a city
could be known for, a solid
supply of human-tissue
samples is one of the least
sexy. But it is this feature—combined
with a strong medicinal-chemistry
sector—that helped make Barcelona
a hub for biotech spin-outs focused
on oncology.
Take, for example, Oryzon, a
nine-year-old biotech company
housed in the Barcelona Science Park.
Its founder, Carlos Buesa, originally
envisioned a microarray services–
based company. But as he developed
his business plan, he realized that
a business model better suited to
Barcelona was one that focused on
biomarker discovery and cancer
therapies. The company now has six
diagnostic projects and four therapies
in its cancer pipeline. “Cancer is the
main topic here because of the very
strong medicinal chemistry and access to tissue samples,” he says.
Oryzon’s researchers need several
hundred tumor samples every year to
conduct their experiments. To ensure
a consistent supply, they developed
48
strong ties with surgeons at nearby
research hospitals. “Physicians and
hospital ethics committees have close
relationships with small communities,” Buesa says. “We have one-on-one
relationships with them.” Buesa says a
location in proximity to the hospitals
is important not only for the ease of
transporting the tumor samples, but
also for increasing the possibility for
scientific collaborations with clinical
researchers at such hospitals.
For instance, Barcelona’s Vall
d’Hebron Hospital sees 40 percent of
all breast-cancer patients in the Catalonia region. José Baselga, a clinical
researcher, helped transform the oncology department at Vall d’Hebron
from a few shabby consulting rooms
in the mid-1990s to running more
than 55 clinical and pre-clinical trials
of cancer therapies.
A number of spin-outs have been
inspired by Barcelona’s academic medicinal-chemistry programs as well.
“It’s had quite an impact,” says Montserrat Vendrell, director of BioCat, a
biotech industry organization for the
Catalonia region. Some strong influences include the chemistry programs
at the University of Barcelona and the
Institut d’Investigacions Químiques i
Ambientals de Barcelona within the
Spanish Higher Council of Research,
known as CSIC. Moreover, biotech
start-ups such as Crystax Pharmaceuticals, Palau Pharma and GP Pharm—
“Cancer is the
main topic here
because of the
very strong
medicinal
chemistry and
access to tissue
samples.”
—Carlos Buesa
ing and engineering sectors, and some
companies in these industries have
begun making detection systems and
machines for personalized medicine.
In addition, Basque Country’s Biobide, created in 2003, integrates expertise from the region’s robotics and
manufacturing industries to conduct
automated high-throughput screening
of potential drugs. “We found it difficult to see development of biotech in
Basque Country,” says María Aguirre,
who runs the region’s biotech industry
organization, BioBasque. “So our idea
was to build on our relative strengths.”
Now medically oriented biotech companies are popping up in the region,
most of which focus on regenerative
and personalized medicine, she says.
H
ungarian university scientist György Kéri begrudgingly founded one of his
country’s first biotech companies. “I didn’t have a choice,” he
says. It was 1991, and Kéri was a biochemist at Semmelweis University
in Budapest. In those days, Hungary
was still transitioning from socialism
to a free-market economy, and most
Hungarian universities didn’t have
the money to protect their scientists’
intellectual property. Even if Kéri’s
university could pay the international patent fees, it didn’t have the
capacity to license those technologies to the private sector. Financiers
outside the university weren’t much
help. When Kéri sought funding
from Hungary’s Innovation Bank to
patent and sell a hormone technology that he had developed, the bank
handled it badly, Kéri says. As a
result, he lost his patents.
So when Kéri developed a series
of promising anti-cancer compounds,
there was only one way to protect
them: He had to set up a private entity
to commercialize his own work. He
mortgaged his home and borrowed
money from his best friend to cover
the patent fees and start-up costs.
Kéri’s company, Biosignal, is a
typical Hungarian biotech story—
born out of dramatic political changes
and homegrown money. “At the end
of the socialistic era and beginning
of the new system, lots of researchers
had similar problems regarding patent
financing and technology transfer,”
says Kéri. “But actually the system
helped these scientists to establish
biotech companies.” The path for
these forced entrepreneurs wasn’t
easy. They had little biotech experience and no venture capital. Most
young businesses survived on service
work, not innovation.
Making matters worse, many
scientists considered the move to the
private sector as a conflict of interest.
University scientists weren’t supposed
to be involved with companies. That
sentiment still lingers, says Erno
Duda, head of the Hungarian Biotechnology Association. Until recently,
the Hungarian Academy of Sciences
curbed its researchers’ private-sector
work. Recent economic changes in
Hungary, however, have encouraged
the birth of new biotech companies.
Hungary’s Research and Technological Innovation Act of 2004 required
public research institutes to develop
and protect intellectual property.
The law also encouraged university
employees to spin-off companies. “Six
biotech companies started up right
after that,” Duda says.
In addition, Hungary’s 2004 accession to the European Union put
its biotech companies on improved
international footing. For instance
Budapest-based ThalesNano Nanotechnology immediately lured three
high-level employees from abroad,
says Laszlo Urge, the company’s
chief executive officer. Industry
wide, contracts with international
clients increased.
Through all of Hungary’s changes
and funding barriers, Kéri continued
working at Semmelweiss University.
In 1999 he started Vichem Chemie,
a new company where he developed
Biosignal’s kinase-inhibitor library
and drug-discovery technologies.
The profits from Vichem support 41
employees and much of the company’s innovative drug-development
projects in HIV, tuberculosis and
cancer—not bad for a guy who didn’t
want to be in the business. “Maybe
he didn’t want to be an entrepreneur
at first,” Duda says, “but I think he
would have eventually.”
WorldView scorecard
49
Country spotlight: Scotland
Country spotlight: mexico
The Fish
Injectors
To keep aquaculture
healthy, a Scottish
company employs some
of the world’s fastest
vaccinators
By Meredith Small
I
n addition to its world-famous
music festival where people enjoy
folk melodies while munching on
wild-boar burgers, Scotland’s Isle
of Sky is also home to a crack crew
of, let’s call them, fish-medics. This
isle’s Aqualife Services is the world’s
largest fish-vaccination company—
and also one of the fastest. With 50
trained employees in Scotland and
Norway, Aqualife Services purports
that one of its employees can vaccinate up to 25,000 fish per day. So a
four-person team can vaccinate half
a million fish a week. “Most of what
we do in Scotland and Norway are
salmon,” explains technical manager
Phillip Brown. “The salmon begin life
in freshwater hatcheries, where they
are vaccinated and then are moved
to net enclosures in the sea. The risks
don’t always work, and they are very
expensive. Still fish farming keeps
growing. In the 1950s, fish farmers
raised about one million tons of marketable fish, but in 2004, that production rose to 59.4 million tons.
Today fish farmers prefer vaccination to keep fish healthy. At first,
the vaccine was simply poured in the
water, and fish would literally swim in
it, but that is clearly an inefficient use
of the medication. In the 1990s injectable vaccines for fish became widely
available. Today there are vaccines for
many species—salmon, trout, carp,
Atlantic cod, catfish, seabream and
other varieties—to stave off infectious
disease and make aquaculture a more
viable business.
But still, the mind boggles with
the thought of picking up fish, one by
one, and giving them a shot. It takes
skill to hold a sedated fish and inject
the vaccine in the underbelly, being
careful to miss the swim bladder and
vital organs. Many fish vaccines are
also delivered with an adjuvant that
kick starts the fish’s immune system.
If the vaccinator gets stuck, though,
the adjuvant can cause the loss of
tissue, fingers and even dangerous
allergic reactions.
That’s why many fish farmers
turn to the pros at Aqualife. They can
poke thousands of fish efficiently.
It takes skill to hold a sedated fish
and inject the vaccine ...
of infectious disease are higher in the
sea, as sea water is a better medium
for bacteria and viruses to thrive.”
Such aquatic afflictions can
devastate the industry. In the past,
half of farmed fish contracted infectious diseases and died before being
turned into a healthy dinner. In 1980
for instance, bacterial disease almost
destroyed salmon farming in Norway,
and it took buckets of antibiotics to
save the fish. Even worse, antibiotics
50
Furthermore Brown says that fish vaccinated by Aqualife have lower rates
of abdominal inflammation on what
is known in the fish business as the
Speilberg scale.
Since 1996, the company claims
to have vaccinated 466,526,551 fish,
which means there is a strong possibility that one of those fish has been
poached, filleted or fried and ended
up on a table near you as a healthy—
and disease-free—meal.
A Manufacturing
Move
By changing a law,
Mexico could bring in
more pharmaceuticals
By Emily Waltz
F
or as long as the biotechnology
industry has been around, Mexico has required international
drug makers who want to sell
their products there to conduct at least
part of their manufacturing operations
on Mexican soil. The rule forces such
companies to either build facilities in
Mexico or partner with Mexican drug
makers—barriers that have locked out
some biotechs from this market. But in
August 2008, the Mexican government
lifted those barriers. “Clearly this is an
example of Mexico opening its market
in another area,” says James Jones, former U.S. Ambassador to Mexico.
Now international biotech
companies are eyeing the nation as
a new market opportunity. Amgen
has been active in Mexico for some
time—starting clinical trials there
in 2003 and opening a clinicaldevelopment office in Mexico City in
2006 to oversee the company’s clinical
trials in Mexico and Latin America. A
company spokesperson says that the
company plans to expand its presence
in Mexico to include commercial operations, now that the manufacturing
requirement has been lifted.
The new rule reforms part of Mexico’s Ley General de Salud, or general
health law, enacted in 1984. According
to the new regulations, therapies for
HIV, vaccines, serums and biological
hormones are among the first products
to be accepted for importation without
a Mexico-based facility. Biotech drug
imports will be accepted starting in
August 2009 and other types of imports will be permitted in 2010.
Mexican government officials
hope the amended regulations will
introduce new competition and bring
down prices. The rule should also
give the people of Mexico treatment
options they wouldn’t have otherwise
had. But not everyone is convinced
that the rule will achieve those goals.
“This policy was decided without
any information about the changes
Mexico might see in drug prices,” says
Jorge Espinosa, an attorney and the
director of consulting firm Grupo de
Asesoría Estratégica in Mexico City.
“There were no studies,” he says.
Another concern is that international companies already selling drugs
in Mexico—which includes
most big pharmas—will
close their manufacturing
facilities there or discontinue partnerships with
Mexican-based companies,
taking away skilled jobs. “If
all relevant manufacturing
and developing activities are
done abroad, then only low
added-value activities will
be done in Mexico, such as
storage and distribution,” says
Tonatiuh Ramirez, a professor at the
biotechnology institute at the National
Autonomous University of Mexico.
“I’m concerned we’ll end up being a
country of warehouses.”
Since 2003 Massachusetts-based
Genzyme has partnered with host labs
in Mexico, but is re-evaluating that now.
Because of this law, “we will no longer
need these host labs,” says Bernardo
Tinajero, a government affairs director
for Genzyme Mexico. “We’ll be able to
directly export to Mexico,” he says.
Proponents of the law, however,
counter that biotech companies lured
to Mexico by the new law might find
that they like the market there and
decide to expand operations. Says
Ambassador Jones: “If you invite
world-class companies to come in
… there’s a real possibility that the
companies will see opportunities for
manufacturing.” If that comes about,
this changed law could bring Mexico
a broader selection of pharmaceuticals and an economic boost.
WorldView scorecard
51
Country spotlight: south africa
Country spotlight: india
Sorghum
in South
Africa
This grass can survive
in most any climate, but
people cannot live well
on it, unless genetic
improvements make it
more nutritious
By Meredith Small
S
orghum is a grass that prospers in the worst conditions.
It loves high temperatures,
and even drought doesn’t
impede its growth. Moreover it
thrives in nutrient-poor land that has
been planted over and over. In other
words it can gown anywhere. Consequently it’s the fifth–most planted cereal in the world. But toughness isn’t
sorghum’s only virtue. It can be eaten,
made into sweet syrup, turned into
beer, fed to livestock and transformed
into bioplastics or biofuel. Despite
that wide array of uses, sorghum
needs some improvements.
Although in the United States it is
grown for livestock feed, most of the
sorghum grown in Africa and Asia is
involved. It makes sense that South
Africa is part of this initiative since
sorghum is the third most–used grain
there, after maize and wheat. Also,
because sorghum is used primarily for
human consumption in South Africa,
it’s a critical crop.
Luke Mehlo of the South Africa
Council for Science and Industrial
Research (CSIR) explains why a genetically engineered, more-nutritious
sorghum is important for South
Africa: “In the case of crop failure due
to drought or excessive rain, we can
have confidence that at least one crop
can sustain our communities.”
So far, there has been little genetic research on sorghum in Africa
but in September, 2008, the South
It can be eaten, made into
sweet syrup, turned into beer,
fed to livestock and transformed
into bioplastics or biofuel.
used as human food, which is a nutritional risk. It is low in Vitamins A and
E and deficient in minerals, such as
iron and zinc. And although the grass
is full of healthy fiber, the protein in
sorghum is hard to digest. As a result,
relying too heavily on sorghum as a
food can cause malnutrition, an impaired immune system and blindness.
A sorghum-heavy diet can even lead
to low birth weight and stunt a child’s
growth. And yet, while not commercially grown, it remains one of the
staple crops of Sub-Saharan Africa.
A variety of groups hope to
improve sorghum’s nutrition. For example, The Gates Foundation’s Grand
Challenge in Global Health provided
$18.6 million to establish the Africa
Biofortified Sorghum project, initiated to make a better sorghum though
genetic engineering. Seven African
organizations, including the University of Pretoria in South Africa, are
52
African government gave CSIR
permission for the Africa Biofortified
Sorghum project to start greenhouse
trials on genetically modified sorghum. With that green light, explains
Mehlo, researchers in South Africa
can begin genetically engineering
sorghum by employing the better
understood sequences of maize and
rice, as well as what is currently
known about sorghum’s genome. The
goals are more nutritious and more
easily digestible versions.
“This project could not have
come at a better time,” Mehlo says.
“Climate change is an undeniable
reality. Africa is increasingly becoming prone to droughts and famine. The population is also increasing and there is an overwhelming
need to diversify our food sources
through harnessing crop genetic
diversity, even amongst neglected
crops like sorghum.”
Indian Brewer Turned
Biotech Queen
Biocon, Kiran Mazumdar-Shaw’s creation, hopes to
improve the odds of drug discovery By Shailaja Neelakantan
I
ndian liquor manufacturers who
scorned Kiran Mazumdar-Shaw’s
skills as a brew master never expected her to become one of India’s
richest women with a net worth
of some $350 million. In 1978 she
had just $200 to start Biocon in her
garage in the southern Indian city of
Bangalore. Now Biocon has a market
capitalization of $500 to $700 million
on the Bombay Stock Exchange.
After a chance encounter with an
Irish entrepreneur, Mazumdar-Shaw
formed Biocon India as a joint venture
with the intial goal of developing
enzymes for the beer industry, an
industry that Mazumdar-Shaw—the
daughter of the creator of India’s flagship Kingfisher beer—already understood. Starting with an enzyme from
papaya that prevented chilled beer
from turning cloudy, Biocon was soon
developing enzymes for industries
ranging from fruit juices to textiles.
Even with her enzyme business
booming, Mazumdar-Shaw decided to
expand. Through 2000 and into 2001,
she started making active ingredients
for bulk-drug manufacturers, such as
the statins used in cholesterol busters.
Biocon’s patented process produces
statins that are less expensive than
chemical versions, making them an
attractive buy for many generic-drug
manufacturers in the United States
and Europe.
In 2002 Biocon began using a yeast
expression system called Pichia, which
it had licensed to develop an alternative
process for making insulin. The result
was Insugen—Biocon’s first foray into
branded biotech formulations—which
it launched in 2004. This product made
Biocon the first Indian company to
make insulin using its own proprietary
technology, and now this insulin is the
world’s fourth-best seller.
That same year Biocon went public,
becoming only the second Indian company to exceed a market capitalization
of $1 billion on the first day of its listing.
Dubbed India’s “Biotech Queen”
by the local press, Mazumdar-Shaw
has also turned out to be the queen of
reinvention. In 2006 Biocon acquired
a proprietary technology platform
for oral peptides from Nobex in
North Carolina. This acquisition
marked the initiation of Biocon’s oral
insulin program. Then in a surprise
move, Mazumdar-Shaw sold Biocon’s
enzymes business to Novozymes for
$115 million in June 2007. The reason:
She wanted to focus on research and
development of “novel and affordable”
biopharmaceuticals, as well as biogenerics, the latter being harder to make
than chemical generics. “We knew that
going forward, [biopharmaceuticals]
would contribute more to us. It was
an emotional decision to let go of
enzymes,” says Mazumdar-Shaw.
Although drug discovery is
a costly and uncertain business,
Mazumdar-Shaw believes that by carrying out most of the early development work in India and taking on
only the most-promising candidates
for further research, the company
substantially reduces its risk. “We have
a strategy and a model for affordable
drug development that allows us to
take calculated risks,” she says. And
she’s confident that her model will
reduce the costs associated with those
risks. That could mean the fulfillment
of her cherished dream—developing a
proprietary oral form of insulin.
WorldView scorecard
53
x
Start Here
nological foundation for the biotechnology industry it
is readily apparent that many of them were produced by
Americans. For example, Brooklyn-born Arthur Kornberg
earned a share of the 1959 Nobel Prize in Physiology or
Medicine for his work on the synthesis of DNA and RNA.
And Americans continue to push ahead biotech tools, as
shown by the 2006 Nobel Prize in Physiology or Medicine
going to Americans Andrew Fire and Craig Mello for work
on RNA interference. The common national origin of these
scientific leaders suggests that the United States likely had
many other prolific scientists, and that there were ample
opportunities for local collaboration, facilitating spill-over
from the laboratories of these Nobel laureates and other
productive scientists.
To answer the question of how the United States was
able to cultivate this group of outstanding scientists, one
can look at research-and-development (R&D) funding.
According to figures from the Organisation for Economic Co-operation and Development (OECD), in 2006 the
United States accounted for 42 percent of R&D funding by
OECD member nations. This leadership has persisted for
decades. In 1973 when Stanley Cohen and Herbert Boyer
developed methods for gene splicing, the United States’
share of OECD R&D funding was 55 percent, meaning
that the United States spent more on R&D than all other
OECD members combined.
Although the United States currently has many supportive regulatory policies and opportunities for funding, this was not always the case. Shortly after Cohen and
Boyer’s demonstration of gene splicing, for example, the
technology was banned by an international moratorium.
Moreover, the popular Bayh-Dole Act (which encourages biotechnology by giving inventors the right to patent
discoveries made when using Federal funding) and the
Small Business Innovation Research (SBIR) funding program were not implemented until the first biotechnology
companies were well on their way to commercialization.
This indicates that other elements—beyond supportive
policies and funding opportunities—must play an important role in the development and growth of the biotechnology industry.
Building U.S. Hubs
Creating hubs for the biotechnology industry makes up
one of those other elements. In 1978, for example, Ivor
Royston (an untenured professor at the University of California at San Diego) and his research assistant Howard
Birndorf formed Hybritech with the objective of commercializing monoclonal antibodies. Hybritech was one of the
first biotechnology firms, and it is credited with helping to
lay the foundation for San Diego’s biotechnology cluster.
Why did Hybritech form in San Diego? The simplest
explanation is that Royston was a UCSD professor and
started his company close to home. With $300,000 in seed
funding, Hybritech set its focus on diagnostic tests and
went public in 1981. As the company grew, it started to attract attention from large pharmaceutical companies. Following the 1985 development of a test for prostate cancer,
Eli Lilly purchased Hybritech for nearly $500 million. A
collision of cultures quickly ensued between Hybritech,
whose managers and scientists were accustomed to a very
casual corporate structure, and Eli Lilly, where policies ex-
methods
Biotech’s U.S. Birth
Why, exactly, did the
industry originate and
thrive in America?
By Yali Friedman
54
I
t is often taken for granted that the United States is where
biotechnology was born and where most of the industry’s
successful companies are located. This success was obviously not preordained and raises the question: Why the
U.S.? Examining the factors contributing to the early development of biotechnology, and to the continued success
in its commercialization, yields insights on how a nation
can enable innovation and make it flourish.
Biotechnology is based in innovative science and when
examining the key scientific discoveries that laid the tech-
T
hat none of the existing biotechnology datasets are ideal presented a central
challenge in this project. Definitions of biotechnology vary between studies and
many datasets focus on specific regions, excluding countries outside of their
scope. Complicating matters further, individual countries vary in the rigor of their statistical measures and in their transparency. We found that countries that are not part
of the European Union (EU), Organisation for Economic Co-operation and Development (OECD) or the Group of Twenty Finance Ministers and Central Bank Governors
(G-20) tend to be excluded from global comparative surveys. To overcome these issues, we employed a careful selection of broad data sets to avoid bias from any single
source and to ensure global coverage. In certain limited cases, selected measurements
for individual countries were added to ensure their representation. China was counted
as three independent entities: Mainland China (measured only as Shanghai in some
cases), Taiwan and Hong Kong.
Metrics
The following is an inventory and description of the metrics used in this survey.
Public Biotechnology Company Data (not used to calculate the Innovation Score)
Public biotechnology company revenues and Number of public biotechnology companies were
derived from: Lawrence, S., Lähteenmäki, R. 2008. Public biotech 2007—the numbers. Nature Biotechnology 26(7):753–762. In selecting public companies, the authors selectively
included “companies whose primary commercial activity depends on the application of
biological organisms, systems or processes, or on the provision of specialist services to
facilitate the understanding thereof.” They also excluded pharmaceutical companies, medical-device companies and contract-research organizations. The increased transparency
of public companies, relative to private companies, enables a more objective comparison
of biotechnology activities. Market capitalization was derived from company disclosures.
Efficiency (not used to calculate the Innovation Score)
The public-company efficiencies were calculated using company data acquired as described above.
Intellectual Property
Patent strength was derived from: Park, W.G. 2008. International patent protection:
1960–2005. Research Policy 37(4):761–766. This index is the unweighted sum of five separate measures: patentable inventions, membership in international treaties, duration
of protection, enforcement mechanisms and restrictions (e.g., compulsory licensing).
Intensity
Public biotechnology companies per capita was derived by dividing the public-company count, as described above, by the 2007 mid-year population as sourced from the
U.S. Census Bureau International Database. Public biotechnology company employees
per capita was derived by dividing the public-company employee count, as described
above, by the 2007 mid-year population as sourced from the U.S. Census Bureau International Database. Public biotechnology company revenues per GDP was derived by
dividing the public biotechnology company employee count, as described above, by
the 2007 GDP as sourced from the IMF World Economic Outlook Database. Biotech
patents / total patents filed with PCT (Patent Cooperation Treaty), Biotechnology VC per
GDP and Biotechnology R&D per total R&D were derived from the OECD. The measure
of Biotechnology R&D per total R&D for Singapore was derived from the Singapore
Economic Development Board (SEDB).
Enterprise Support
The Business Friendly Environment metric was derived from: The World Bank Group.
2008. Doing Business 2009: Measuring Business Regulations (www.doingbusiness.org).
WorldView scorecard
55
ist for seemingly everything. Within a year of the acquisition, most of Hybritech’s key talent had left the firm. Many
of these individuals, rich in experience and cash, went on
to start new biotechnology ventures or became venture
capitalists, funding other interesting opportunities themselves. With the support of community organizations and
an entrepreneurial environment, San Diego has grown
to become the third-largest biotechnology cluster in the
United States, after the San Francisco Bay area and Boston. More than 100 San Diego companies can trace their
history to Hybritech.
While biotechnology clusters may form organically in
the vicinity of strong research bases, government actions
can also facilitate their development. A prime example of
a planned biotechnology cluster is Research Triangle Park,
N.C. In the 1950s North Carolina suffered from a brain
drain and a declining economy. Markets for the state’s primary industries—textiles, furniture and tobacco—were
declining and college graduates typically left the state to
find career opportunities elsewhere. Seeking to capitalize on the three nearby universities—Duke, North Carolina State and the University of North Carolina at Chapel
Hill—local politicians and businesspeople sought to create
homegrown opportunities to stem the mass exodus of talent. Research Triangle Park was founded in 1959 on 4,400
acres of worn-out farmland.
Following a slow start, years of lobbying government
and private institutions began to pay off in the late 1960s
Building New Benchmarks
>300
200 - 300
50 -100
<50
Source: Beyond Borders: The Global Biotechnology
Report 2006. Ernst & Young. 2006
Education / Workforce
Post-secondary science graduates per capita were derived from UNESCO figures, divided by 2007 mid-year population as sourced from the U.S. Census Bureau International
Database. PhD graduates per capita, R&D personnel per total employment, Biotechnology
workers, and Scientific papers per capita were derived from the OECD.
Singapore figures for Post-secondary science graduates per capita, PhD graduates per
capita, R&D personnel per total employment, and Biotechnology workers are from the
SEDB. The Biotechnology workers figure for China measures Shanghai only. Post-secondary science graduates per capita, PhD graduates per capita, R&D personnel per total
employment and Biotechnology workers serve to provide as comprehensive a picture
as reasonably possible of the biotechnology workforce. Measuring Ph.D. graduation
alone would exclude individuals who obtain education at foreign schools and repatriate, and those who emigrate following doctoral research (although it is important to
56
note that knowledge spillovers from doctoral research are captured by the country of
education). Furthermore, Ph.D. graduates are not the only employees of biotechnology
companies. Post-secondary science graduation was included as a crude measure of science literacy among post-secondary graduates who might obtain subsequent Masters
degrees in science or degrees in fields such as law, business and medicine. More direct
measures of biotechnology workforce were also available for many countries and are
counted by measuring R&D personnel per total employment and Biotechnology workers.
Measuring Biotechnology workers in absolute numbers also provides a strong measure
of actual biotechnology-workforce strength to complement the relative measures of
worker availability.
Foundations
Business R&D expenditures per GDP and Government R&D support per GDP were derived from the OECD. For Singapore these measures were derived from the SEDB.
Infrastructure quality was derived from: Porter, M., Schwab, K. 2008. The Global Competitiveness Report, 2008-2009. World Economic Forum. This utilizes an international
survey to produce its index.
Activity Areas (not used to calculate the Innovation Score)
The Allocation of firms by activity areas was derived from the OECD. The figures for
China measure Shanghai only.
Market Size (not used to calculate the Innovation Score)
Hectares of biotech crops planted were derived from: James, C. 2007. Global Status of
Commercialized Biotech/GM Crops: 2007. ISAAA Briefs No. 37-2007. Therapeutics
market were derived from OECD Health Data pharmaceutical sales per capita, multiplied by the mid-year population as sourced from the U.S. Census Bureau International
stage investments, mergers and acquisitions and market
access. Multinational companies also tend to locate their
operations closest to their largest markets, which is a
strong continuing driver for U.S. growth. Consequently,
it’s unfair to expect a country with a smaller economy to
have a biotechnology industry that is
comparable in size to that of the U.S.
And not all of the United States is
necessarily conducive to thriving biotechnology, as evidenced by the uneven
distribution of the U.S. biotechnology industry. While there are several very successful regional concentrations, such as
San Diego and Research Triangle Park,
a majority of U.S. states are struggling
to build their local biotechnology industries—a challenge
shared by many countries. Given that all states adhere to
the same basic federal laws supporting biotechnology but
differ in the size of their biotechnology industries, the solution to developing a local biotechnology industry cannot simply be to adopt U.S. federal laws and incentives. In
short, local conditions play a significant role in the health
of biotech. Additionally, the current set of U.S. federal regulations and incentives helped the biotechnology industry grow to its current state, but that does not necessarily
mean that the same conditions would work as well in different political systems and economies. In the end, every
company and each country must find their own systems of
success in biotech.
Multinational companies also tend to
locate their operations closest to their
largest markets, which is a strong
continuing driver for U.S. growth.
host to more than 150 organizations and its 39,000 employees draw more than $2.7 billion in salaries, making it
the largest planned research center in the world. Roughly
one-third of the resident firms and organizations are biotechnology and pharmaceutical companies.
distribution of
U.S. biotechology
companies
This index is constructed by surveying local experts on a synthetic business case. Potential limitations of this index are that it is based on a specific business form of a specified
size, and refers to conducting business in a country’s largest city (with the exception of
certain countries such as China). Biotechnology venture capital was derived from the
OECD measures of venture capital activity from 2001–2003. Venture capital availability was derived from: Porter, M., Schwab, K. 2008. The Global Competitiveness Report,
2008-2009. World Economic Forum. This source employs an international survey to
produce its index. Capital availability was derived from: Milken Institute Capital Access
Index, 2007. This data set is an important complement to Biotechnology venture capital
and Biotechnology venture capital availability because venture capital is neither necessary nor generally independently sufficient to support nascent biotechnology ventures
to financial independence; other forms of capital can play important roles.
and 1970s as industry leaders and government agencies
decided to establish laboratories and offices in Research
Triangle Park. Common draws to locate in Research Triangle Park were the quality of life and modest costs. Today
Research Triangle Park encompasses nearly 7,000 acres, is
Many countries benchmark their local biotechnology industry against the United States. Some even recommend
domestic innovation reforms to match current U.S. laws
and incentives. But such comparisons and development
plans need to be viewed with respect to the size of the U.S.
economy, and the distribution and history of the U.S. biotechnology industry.
First, the U.S. is home to the world’s largest economy
and the world’s largest pharmaceutical market—one without price controls. In addition, the relatively consistent legal and political frameworks across states facilitate early
Database. Industrial-enzyme production was derived from Zika, E., Papatryfon, I., Wolf,
O., Gómez-Barbero, M., Stein, A.J., Bock, A-K. 2007. Consequences, Opportunities and
Challenges of Modern Biotechnology for Europe. European Commission Joint Research
Center, Institute for Prospective Technological Studies.
Scoring Methodology
There are two basic types of metrics in the Worldview Scorecard: Those which were
used to compute the innovation score, and those which were not. Public Company data
were not used to calculate the innovation score because they are too polarizing. They
clearly show that the United States is the leader in biotechnology, with the most public
companies and greatest revenues, but they are largely—and unfairly—uninformative
of countries with few or no public companies. The Efficiency data, which were derived
from the Public Company data, were likewise not used to calculate the innovation score.
The Allocation of Firms by Activity Area and Market Size were also included as an accessory; they provide information on biotechnology activities, market size and market
access in various countries. Because regulatory burdens, price controls and bans on
products directly affect sales and the capacity to produce biotechnology products, their
impact is reflected in the Market Size data. To calculate the final innovation score, we
first ranked the individual metrics on a scale from 0-5, with the most-favored country
(e.g., most patents, greatest capital availability, highest rank in Business Friendly Environment, etcetera) receiving a score of 5 and the least-favored country receiving a score
of 0. Countries for which no data were available received no score, which enabled the
averaging process to not penalize them for not being included in the data sources used.
The average score of each country in each category was calculated, and the average of
these category scores was used to determine the overall innovation score. Averaging the
scores within each category was necessary to resolve data gaps. Summing the scores in
each category would have unfairly penalized countries that are not included in specific
The material in this article is derived from: Friedman, Y. 2008. Building Biotechnology: Business, Regulations, Patents, Laws, Politics,
Science. Washington, DC: Logos Press.
measures, and employing a single average across all categories would bias the results
in cases where some countries were included in more measures of one category than
another (e.g., if a country was poorly represented in the education metrics, but well
represented in the education/workforce metrics, the overall innovation score would be
biased by this altered representation).
Example
1) Get raw numbers
Country 1
Country 2
Country 3
Category 1
Metric 1
Metric 2
0
200
60
40
150
Metric 3
40
10
50
Category 2
Metric A
Metric B
.5
.3
.9
0
.45
Metric C
0
25
15
Category 2
Metric A
Metric B
5
3
5
0
2.5
Metric C
0
5
3
2) Rank each metric on a scale from 0-5
Country 1
Country 2
Country 3
Category 1
Metric 1
Metric 2
0
5
2
1
5
Metric 3
4
1
5
3) C
onsolidate category averages, and combine these averages to derive the
innovation score
Country 1
Country 2
Country 3
Category 1 Avg
3
1.33
5
Category 2 Avg
2.5
4.33
1.83
Innovation Score
2.75
2.83
3.42
WorldView scorecard
57
Sponsor Profile
Merck & co Inc:
BUILDING ON A HISTORY
OF BIOLOGICS EXPERTISE
t Merck, our primary corporate responsibility is discovering,
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of a new division at Merck, Merck BioVentures.
Access and Innovation
A Merck bioprocess development
laboratory
58
Vaccines are one of the public health
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In December 2008, Merck introduced a new division, Merck BioVentures. This built on Merck’s acquisition
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Merck recognizes the significance
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all biosimilars and allow for the molecules to be fully characterized. Further, we support efforts by regional
health authorities to harmonize such
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A bioprocess development laboratory
showing cell culture
This fact sheet release contains “forward-looking
statements” as that term is defined in the Private
Securities Litigation Reform Act of 1995. These
statements are based on management’s current
expectations and involve risks and uncertainties,
which may cause results to differ materially from
those set forth in the statements. The forwardlooking statements may include statements
regarding product development, product potential
or financial performance. No forward-looking
statement can be guaranteed and actual results
may differ materially from those projected. Merck
undertakes no obligation to publicly update any
forward-looking statement, whether as a result
of new information, future events, or otherwise.
Forward-looking statements in this press
release should be evaluated together with the
many uncertainties that affect Merck’s business,
particularly those mentioned in the risk factors and
cautionary statements in Item 1A of Merck’s Form
10-K for the year ended Dec. 31, 2008, and in any
risk factors or cautionary statements contained in
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An image of a human papillomavirus
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sponsor profile 59
What Biotech Needs from
Technology
a patient’s genotype through DNA
sequencing, along with various clinical phenotypes and symptoms. These
data get projected onto the pathway
model, resulting in a detailed diagnosis of the illness and a personalized
treatment plan.”
By Jeffrey M. Perkel
I
Polling a panel of experts reveals a range of wish lists as broad as the field itself
Today’s Technology Helpers
To get a feel for the mix of existing
technologies that make a difference,
consider these replies. Harvard University geneticist George Church, for
example, says that advances in computing power, oligonucleotide microarrays, microfluidics and next-generation DNA sequencing technologies
all propel his research. Brainbow developer and neurobiologist Jeff Lichtman, also of Harvard, credits advances in optical and electron microscopy.
60
He says, “We are using both to probe
the three-dimensional structure of
the nervous system at higher resolution than previously possible.”
By contrast, systems biologist Trey
Ideker of the University of California
at San Diego, tips his hat to technologies for high-throughput protein–protein interaction mapping and genotyping. The “grand opportunity for the
next decade of research,” Ideker says,
is “to understand the complex relationships connecting the vast number
of uncharacterized single-nucleotide
polymorphisms to human pathology.”
Without such a map of these singlebase variations in DNA, he says, making sense of the data would be “like
trying to decipher how your computer
works without the wiring diagram.”
In short, new technologies push
biotechnology forward. Genotyping and interaction mapping help
researchers identify novel therapeutic targets, for instance, and microfluidics-driven miniaturization and
automation make once-intractable
processes robust.
replacement at nearly 100 percent
efficiency without selection.” That,
plus easily created patient-specific
induced pluripotent stem cells would
enable researchers to “change the genome to be exactly what you want for
gene therapy or for testing hypotheses,” he says. Suppose, for instance,
a researcher finds several potentially
causative alleles for some phenotype in a cell line; by making those
changes one at a time or in combination in mammalian cells, it becomes
possible to pin down the critical variants. “You can go from association to
causation,” he says.
Lichtman says his research would
benefit from “tools that monitor the
function—activity—of the nervous
system at millisecond time scales
and micrometer length scales.” He
explains: “Ultimately the structure
of [the] nervous system needs to be
linked to the function, so [having]
functional assays that match the
resolution of the structural probes
would be highly useful. I assume
new ways of looking at things may
Funding the Future
“The grand opportunity for the next decade
of research is to understand the complex
relationships connecting the vast number
of uncharacterized single-nucleotide polymorphisms to human pathology.” —Trey Ideker
Tomorrow’s Technology Desires
Technology, though, isn’t static, and
there’s still much that researchers
cannot do. For example, Church says
that he would like to have the ability
to do “automated homologous allele
ultimately provide assays for poorly
understood diseases, such as of the
nervous system.”
Also hoping to “see” more, James
Mansfield, director of multispectral
imaging systems at Cambridge Re-
{© daniel bejar}
nnovation, at least in biotechnology, stands at the intersection of technology and science. Where would biotech
be without the polymerase
chain reaction, liquid-handling robots and automated DNA
sequencers? For that matter, where
would biotech be without advanced
imaging systems, detection reagents
and bioinformatics? From microtiter
plates to microarrays, technology development has changed the way biotechnology is done, raising the bar
on scientific progress and forcing researchers to reassess their limitations.
To get a sense of just what is possible, I surveyed thought leaders in academia and biotech, asking them how
innovation has shaped their present,
and will continue to mold their future. The mix of experts polled here
includes pioneers of DNA sequencing
and microfluidics, the cell biologist
behind the Brainbow “glowing brain”
mouse, an imaging-platform developer, a molecular diagnostician and a
systems biologist. As you will see, the
technologies that these experts find
important—and their visions of the
future—are as varied as their respective fields.
search & Instrumentation, says that
his firm could use access to new and
simpler multiplex histological and
fluorescent labeling methods—not to
mention more and better-annotated
clinical histology samples. “These will
greatly enhance the ability to interrogate tumors for a wide range of cellsignaling pathways,” he explains, thus
accelerating personalized medicine.
At Genomic Health, which is a
molecular diagnostics firm, chief scientific officer Joffre Baker says that
internal research and development
efforts would benefit from integrating
ever-greater numbers of sequenced
human genomes into a functional ge-
nomics database that links sequence
to biology and to disease. Such a database “will immeasurably accelerate
the discovery of optimal new drug
targets and diagnostic biomarkers,”
he says.
Ideker’s wish list also includes
more and cheaper sequencing, as well
as “more, better, faster and cheaper
tools for measuring different types of
protein interactions,” both in model
organisms and in humans, as well as
more of the complete network maps
that such tools will yield. “Imagine
computer models of these pathways
being available in the clinic,” he
says. “Enter the nurse, who collects
Beyond wanting new tools and techniques, some scientists also want
to change the system. For instance,
Harvard microfluidics expert George
Whitesides hopes for—among other
things—“a system for support of fundamental research that was not captured by advocacy groups and riskaverse peer review and distributed
funds in a way that was more to the
benefit of ultimate users.” That might
be some of the most wishful thinking of all.
We do know, however, that technology advances will rewrite what
researchers can and cannot accomplish, continuing the cycle of innovation and discovery that drives both
academic and industrial progress.
Funding agencies, therefore, must
adjust to recognize technology development as a worthy research goal in
its own right, says Lichtman. “Technology, in my view, drives progress
in scientific research, not the other
way round, so we need to invest in
efforts to improve tool building in
scientific research.”
Yet, not everyone sees technology development as a make-or-break
for biotech. “That isn’t what is holding us back right now,” says Gajus
Worthington, president and chief executive officer of Fluidigm. “Instead,
it is the efficient application of current
technologies and on areas that will
turn out to have an impact.”
In the end, advances in biotech
will surely depend on wise use of today’s tools, and clever development of
tomorrow’s new ones.
science & technology
61
Is It Time to Give Up on
Therapeutic Cloning?
A Q&A with Ian Wilmut
I
By Sally Lehrman
an Wilmut, famed for creating Dolly
the cloned sheep, abandoned that
technique to concentrate on a popular new approach: making induced
pluripotent stem (iPS) cells. Starting with adult cells, Wilmut uses
viruses to deliver genes that revert the
differentiated cells to an unspecialized
state. Such cells get around the ethical
and legal issues surrounding embryonic stem cell work, of which cloning, or
somatic-cell nuclear transfer, has been
an integral part. Sally Lehrman asked
Wilmut about his change in focus. Here is
an edited excerpt of that interview.
The creator of Dolly the sheep has
ended his focus on somatic-cell nuclear
transfer, or cloning, in favor of another
approach to create stem cells
You are now director of the Scottish Center for
Regenerative Medicine in Edinburgh, where you oversee
20 principal investigators, including a team that hopes
to use iPS cells to observe the progression of the disease
amyotrophic lateral sclerosis (ALS) and to develop
treatments. What are some of the questions related to the
iPS system that must be worked out?
» The limiting factor is not literally getting cell
lines anymore; it’s going to be studying them. The first
thing you’ll have to do is to look at the cells for the usual
quality-control things to see that they’re expressing the
right markers. And for quite a number of years, until you
get confidence in the procedure, you’ll have to at least
form embryo bodies and differentiate them into different
lineages. You’ll then have to do quality controls to be confident that you’ve got what you want.
{ © ralf hiemisch}
What are some aspects of your studies with somatic-cell
nuclear transfer that will carry over into the iPS work?
62
»
We’ve been trying, without any success at all so
far, to understand how reprogramming works in nuclear
transfer. The strategy that we adopted was to use frog egg
and oocyte extracts and to expose the nuclei from alien
cells to those extracts and look for reprogramming. That
seemed a very reasonable approach, because John Gurdon
[a renowned British developmental biologist] showed 30
years ago that if you put mammalian nuclei into frog eggs,
some of the mammalian nuclei are switched on. I mean,
this was done by very, very simple techniques 30 years ago.
But I still find it puzzling. We failed. We worked for two
years to try to make this system work before we gave up, because we couldn’t get consistent effects. So we changed over
to using mouse embryo stem cell extracts to reprogram human cells, and that works. So that’s put us into a position
where we can now begin to think of using that as an assay
system and begin to try and identify active factors in the
embryonic stem cells. So, obviously what we’ll do is complement the iPS technology with other things, just to see.
For example if you treat cells with the extracts first and then
use the iPS system, is there an enhanced reprogramming?
In your scientific career you’ve shifted almost entirely from
animal science to a focus on treating human disease.
Why did you choose ALS as a target?
» It’s a nasty disease, and there isn’t an effective
treatment. But you could say that about a lot of things. I
guess I’m surprised that more people haven’t recognized
the way in which the iPS system, presuming it works, will
revolutionize the study of inherited diseases.
The idea that things which we collectively do might
contribute to treatments for ALS, for example, I find really
exciting. One of the best known ALS sufferers in Britain
was a soccer player called Jimmy Johnstone. He played for
Glasgow Celtic when they were the first British team to
win the European Cup in 1967. And here you had a man
who was extraordinarily gifted in this sports activity. He
was known as “Jinky” because he was so fast and light on
his feet. And he was struck down so that, by the time I
met him, he was on a sort of an eye-level bed, not able to
move anything. You know, I think that’s hellish; I don’t
know how people cope with that illness. And to be able to
contribute to development of a treatment for a disease like
that is fantastic.
63
»
“My own view has not
changed at all that there
are other reasons why
reproductive cloning
should be prohibited,
which are essentially because of the psychological
effects of being a clone.”
No, no, no. I mean, there is a
very difficult balance, isn’t there?
We should be ambitious to try to
see what we can achieve using these
cells. But you do have to consider
the risks carefully and see that the
patients are informed of the risks.
The people who were involved in the
development of revolutionary treatments in the past, like, for example, organ transplantation, will tell you that you do not make progress unless
you are prepared to, with the patient’s consent, take risks.
And if you think of things like spinal-cord injury, there is a
huge potential benefit there. So it seems appropriate to me
that those are the sorts of things that you would try first.
Are patients eager to participate in trials?
» Most of my conversations have been with pa-
tients with ALS and other neurodegenerative diseases. I
can tell you that they are very positive about taking part
in trials like this, even though they know that the probability of a benefit to them may be very small. But they
feel they’re contributing something to the next generation of people that will suffer from these conditions.
Can any of these patients expect to benefit personally from
the treatments?
» For some of them, at least, I think treatments
will arise from research with stem cells at some time in
the future. You can get a perspective on this sort of thing
if you look back to the development of new approaches
to therapy in the past. So if you were to look back at, for
example, the use of antibiotics, the first really powerful
one was penicillin, which emerged during the Second
World War. And I think probably soldiers and other war
victims were among the first to be treated. You can see a
continuing process that’s still developing in antibiotics
now, 60 years later. The same sort of thing would apply if
you think of vaccination. It’s centuries since approaches
to immunization were first being developed. But even
64
within my lifetime, the person who was my best man, he
suffered from polio as a boy, just before the Salk vaccines
first came through. Over a very long period, treatments
develop. And I think we should expect the same thing
to apply to stem cell–devised treatments, that some will
come through in the next few years, but 50 and 100 years
from now, people will still be developing new therapies.
Are there things that you learned from your experience
with Dolly that now shape your thinking in this area?
» Well, I guess maybe it made the world seem a bit
grayer, if you like. You would think that there are merely
positive benefits to come from something new like this,
but you also see that there are problems as well. And so
there is a sort of gray area in the middle, where things
are not just as rosy and as satisfactory as you might like.
For you, what were the hardest parts of the whole process?
» It would be the media side of things. It’s not
something that you do, as it were, until you’re put in a
situation where you have something that people are interested in. You know, most of us at least do some of our
work on taxpayers’ dollars. And so, in that sense, there’s
an obligation to explain what it is you’re doing and where
you’ve got to so far. Also, because a lot of these things
have a social impact, whether it’s cloning or stem cell
research, it’s important to explain the state of things.
You’ve written a lot about social and ethical issues
related to cutting-edge science, particularly in the area of
reproductive cloning. Some scientists have begun raising
concerns about unethical promises being made for
embryonic stem cell treatments. Should we also be worried
about rogue scientists experimenting with human cloning?
» The thing which provides the most protection at
the present time is the sheer inadequacy of the technology.
But I’ve thought about this, and I think you’re right that
it would become a risk at some stage. I was one of a group
of people led by [author and M.D.] Bernie Siegel to try to
get human reproductive cloning made a crime against humanity. Intriguingly, it was the White House that blocked
that through a surrogate because they wanted to block all
human cloning rather than just reproductive cloning.
{© aaron mcKinney}
As scientists begin to think about
moving into clinical research with
embryonic cells, they have begun to
discuss potential voluntary guidelines to ensure that scientists move
ahead in a measured, safe manner.
Has your perspective on this changed
since Dolly?
life because we could not correct the abnormality. And, of
course, it wouldn’t be without risk to the woman who was
giving birth to the child because there are often difficulties. And so, on those grounds alone, I would have thought
that there would be pretty well a unanimous wish to prevent that sort of thing happening.
My own view has not changed at all that there are
other reasons why reproductive cloning should be prohibited, which are essentially because of the psychological effects of being a clone. We do tend to anticipate and
expect that children will be like their parents. And I think
that would be even stronger if the child were a clone. And
so that’s the reason why I would be concerned about it.
Why do you think a ban on reproductive cloning
is important?
It seems as though there is increasing sentiment among
scientists that some form of reproductive cloning would be
acceptable for clinical purposes. Would you agree?
»
»
Quite apart from anything else, I think it
would be entirely appropriate to get a ban at the present
time because there is a very significant risk of dead babies
or of children with severe abnormalities. The list of abnormalities which we’ve seen in livestock and in mice is
very long and quite horrifying if you think of it in terms of
children. In one lamb, it panted all of its life, even when it
rested, because of restricted blood flow through the lungs.
After two weeks, we decided that it was kinder to end its
There always has been a difference of opinion about that. I think you need to define the terms very,
very closely. As a way of getting people to think about
things, I’ve asked, “Suppose it was possible to use this
technique to correct a genetic error in an embryo?” You
know, say, if you had a family who were inheriting one of
the diseases we’ve already talked about. If you produced
an embryo by in vitro fertilization (IVF), grew out cells,
corrected the mutation, and then cloned to make a new
embryo, you’re using it as a tool for correction of genetic
disease—and that child would not be a genetically identical twin. I personally wouldn’t find anything wrong with
that. Whether it’s likely to happen or not is a very different matter, simply because of the technical challenges
and the costs involved.
And as far as treatment for infertility is concerned,
the odds are that there would be other ways of overcoming the problem. If IVF cells are equivalent in their developmental potential to embryo-derived stem cells, then it
might be possible to produce gametes. So if you have, let’s
say, a man who has no sperm, you produce iPS cells, you
produce sperm, and you can then produce babies through
IVF. Naturally, it would be a much more satisfactory approach, because it is a child who is the product of both
parents and is not a genetically identical twin to anybody.
Have you thought about renewing your effort to get a
cloning ban in place?
»
No, this is the first time I’ve discussed this
for quite a long time. But if Bernie said, “Would we do it
again?” I’d certainly join in, yeah. And I know the British
government was very supportive of this.
65
From accessing and managing information
to designing products through simulations,
electronic devices are transforming all
areas of biotechnology
A
couple of years ago, Merck and the
Moffitt Cancer Center in Tampa,
Fla., took on a gigantic data task.
Working together they set out to
build a dynamic database of information on cancer patients. Moffitt
began collecting information on
normal tissue and tumors—from
the center’s Tampa-area clinics and
hospitals recruited for this collaboration—that then flows
into one of Merck’s global data centers where researchers
perform molecular, genomic and proteomic profiling on
the samples. “You need the clinical and medical context of
the patients associated with these samples, as well as the
outcome information on how they responded to specific
drugs,” says Martin Leach, executive director of basic research and biomarker information technology at Merck.
Connecting such a collection of data creates a complex
challenge in information technology (IT).
“The challenge,” according to Leach, “is to get all of that
flowing from multiple hospitals and systems in a standardized way.” To accomplish that Leach and his colleagues,
plus partners at Moffitt, built a unique information pipeline. Data get encoded at Moffitt and securely transmitted
Connections
Computation
and
By Mike May
66
Assessing the Spectrum
As shown in the Merck–Moffitt collaboration, much of IT’s
task involves connectivity. “We must connect scientists
and provide them with technology so they work seamlessly
with other scientists in China or Japan or at any other site,”
Leach says. Moreover that connectivity covers a range of
forms, including sharing software, providing audio and
video conferencing and letting companies integrate silos
of data to ask complex questions. Leach describes one possible task: “Give me all of the gene-expression data on specific tumors of a particular size and include information
about related samples in our biobank.” He adds, “IT must
make this easy to ask and provide a rapid response.”
Despite the improvements in IT, hurdles remain.
“Our needs are still growing,” says Ajay Royyuru, head
of IBM Research’s Computational Biology Center in Yorktown Heights, N.Y. “We have not reached a point where
we have a maturity in needs and solutions.” He sees three
places where computing must improve to be more useful
in biotechnology.
The first is data. “We are generating more data than
yesterday, and we will generate more data tomorrow.” To
handle that, Royyuru wants smart data storage and analytics that are distributed, standardized and that transform
raw data into new knowledge. “We are
Computers turn up biotechnology: Anything from faster processors—like this
nowhere near maturity here,” he says.
System z10 mainframe processor from IBM(left)—to better software give scienAt Merck Leach also sees the need
tists a closer look at nature to better understand it and to learn how to use it.
for handling more data, and doing it
to Merck’s clinical-data repository. “Then, in-house tools now. He says that Merck’s IT system manages 1.5 to 2 petintegrate this clinical information with molecular-pro- abytes, which is 1.5 to 2 million gigabytes of data, and it’s
filing information. That lets oncologists identify genetic growing at a rate of 30 to 40 percent a year. “Next-genersignatures associated with a drug response or the lack of ation sequencers already generate 4 terabytes in one run,”
a response,” Leach observes. As a result, this information Leach says. “That’s how explosive the data growth is.”
Beyond dealing with the growth in data, Royycan be used to develop more-specific cancer therapeutics
and also aim them at the patients who are the most likely uru says that the scale of computing also matters. “The
magnitude of computing is holding us back. With more
to benefit from particular drugs.
Already, putting IT and computation together increas- power, we’d make more progress.” He adds, “Tomorrow’s
es the ability of biotechnology experts to explore a new needs in biotechnology will require 1,000 or 10,000 times
realm of possibilities, from pharmaceuticals to disease today’s peak computing.”
Finally Royyuru believes that scientists need to know
modeling and beyond. In the future computational tools
more about how to use computing to better understand
could even change the fundamental approach to science.
{
}
67
Simulating Pig Pandemics
Reaching out even farther, scientists can also select
cloud computing, which is a range of computer resources—including processing power and storage—and applications that can be rented. As an example Amazon provides
its Elastic Compute Cloud, or EC2. When asked how much
computing power or storage a customer can use with this
Clusters to Clouds
The need for more powerful computing seems about as old cloud, Peter De Santis, EC2’s general manager, says, “It’s
as computing itself. Whether scientists obtained the lat- not really limited.” He adds, “A customer can get access to
est abacus or the day’s fastest supercomputer, they always supercomputing power. For example, using 10,000 cores is
not absurd.”
wanted the same thing—more.
With cloud computing a user can pay for the amount
In some cases a company gets more computing power
by building it. That’s been Merck’s strategy. In fact, one of of power or storage needed, and vary that over time—all
Merck’s machines, an IBM supercomputer, even ended up without buying any hardware. Using the cloud, however,
on the list of the top-500 computers in the world—ranked demands some skill, although De Santis says that any IT
person can figure out this technology, and it should beat 458 on the June 2008 list.
Instead of building one gigantically powerful ma- come increasingly easier to use as it evolves.
One thing that is clear is the growing number of cloud
chine, some researchers opt instead to link lots of smaller
ones into clusters or grids. As an example IBM created the users. For instance Eli Lilly and Company now rents onWorld Community Grid. This grid relies on people around demand servers and storage from Amazon’s cloud. In
addition scientists from Harvard
Medical School’s Laboratory for
Personalized Medicine use EC2 and
Amazon Simple Storage Service, or
S3, to create models and run simulations. Portability adds to the attraction. Amazon’s cloud services can be
Ajay Royyuru
used anywhere. Scientists at the Max
Planck Institute in Munich, Gerthe world contributing unused compute cycles from the many, already use it, and De Santis says that there has
personal computers on their desks. As of early February been interest from around the world, even in developing
2009 the World Community Grid consisted of nearly 1.2 countries. “All you need to use it is an Internet connecmillion computers connected together. Anyone from a tion,” he says.
To place even more opportunities in its cloud, Amazon
public or not-for-profit organization can apply for time on
this grid. Some of the ongoing projects include models for added public data sets that can be analyzed with Amazon’s
increasing rice yields and quality, searches for new drugs cloud-computing tools. Anyone who wants to upload such
for dengue hemorrhagic fever, and studying protein fold- a data set for public viewing can do so at no cost.
Amazon is not alone in the cloud. Other compaing. “This is not costing anyone a whole lot,” says Royyuru.
“It’s taking what is out there and capitalizing on it, making nies—such as IBM and Microsoft—also offer cloudcomputing resources.
sure that it gets used.”
biology. “How can I model disease or the response to a
drug?” he asks. “That area is not limited by computing or
IT, but by what information we have about the biological
system.” (See sidebar “Simulating Pig Pandemics.”)
“This is not costing anyone a whole lot,
It’s taking what is out there and capitalizing
on it, making sure that it gets used.”
Modeling Antibody Interactions
P
harmaceutical companies already use some
modeling, for example to
determine whether the shape of
a potential compound fits with a
target in a way that could block
a disease. Nonetheless, highperformance computing could
push such simulations even
farther ahead. “We’re looking at
68
how proteins function,” says Ajay
Royyuru, head of IBM Research’s
computational biology center
in Yorktown Heights, N.Y. For
instance, proteins called hemagglutinins stick out from the
influenza virus and help the virus
bind to host cells. “What happens if there is a mutation in this
protein?” Royyuru asks.
To find out, Royyuru and his
colleagues turn to molecular
dynamics. Such simulations can
reveal whether a specific mutation
in hemagglutinin could disguise
the virus from antibodies generated by previous forms of the flu.
“We could eventually test mutants
ahead of vaccine production,” he
says, “but we’re not there yet.”
I
In the Midwest of the United States, pigs on four
small farms get fed garbage carrying the infectious virus that causes foot-and-mouth disease. To keep this disease from spreading wildly,
livestock authorities destroy every pig within one
kilometer of the infected farms. Luckily, the experts knew that killing more pigs—out to three or
even five kilometers—would not have stopped the
spread any faster.
Actually not one pig died in this scenario. This
is just an example run on the North American Animal Disease Spread Model, or NAADSM, which was
created as a collaboration between the Canadian
Food Inspection Agency, Colorado State University,
the Ontario Ministry of Agriculture, Food and Rural
Affairs, the U.S. Department of Agriculture (USDA)
and the University of Guelph. “In the simplest
terms,” says Kimberly N. Forde-Folle, an analytical
epidemiologist with USDA, “NAADSM is a computer program designed to simulate the spread of
infectious diseases in livestock and the potential
effect of control measures.”
Researchers use the NAADSM ahead of trouble, not during it. “After determining the potential
pathways of disease introduction, this program can
be used to try to determine the consequences of
a disease introduced through a certain pathology
and species in a certain area,” says Tracey Lynn,
director of USDA’s Center for Emerging Issues.
In the past, researchers used the NAADSM
to model avian influenza in commercial poultry
operations. “We developed a scenario that could be
used by emergency responders to help prepare for
an outbreak,” Forde-Folle says.
This program is also being used to study pharmaceutical needs. For example one project will
estimate the number of vaccine doses that would
be required if foot-and-mouth disease were to
enter the United States.
The results from these models and others could
help a range of users. “A number of outputs from
these models are useful for policy makers,” Lynn
says. “It could provide an estimation of how long an
outbreak might last, how many animals might be
affected, how many might die.” She adds, “Knowing
those estimates can help planners think through
all of the potential impacts that might happen and
what contingency planning they can do.”
For anyone interested in putting this program
to work, it’s available for free (www.naadsm.org).
Improvements Ahead
Even with supercomputers and clouds of cores, IT scientists want more, much more. Some things on an IT expert’s
wish list sound simple enough, like better search capabilities. “We need some robust tool that will search across databases and repositories,” Leach says. “There is still a gap
in general search capabilities. Even though Merck is using
one of the leading technologies available right now, better
ways to organize the output from a search, and improved
ways to find what we really want are still needed.”
Leach also sees a growing trend toward in silico research. “What if I could compute the entire chemical
space?” he asks. He can’t and doesn’t expect to, since that
consists of about 1060 molecules. “That’s almost infinity, but
what if you could compute the tractable chemistry?” Leach
asks. Maybe IT experts and computer scientists could develop some way to model all of the compounds that might
fit a certain target. Then, that knowledge could be used for
screening molecules in a computer instead of in multiwall
plates. (See sidebar “Modeling Antibody Interactions.”)
Pushing the in silico opportunities even farther, Royyuru says, “There’s the potential for computation to transform how we ask questions and how we seek answers to
them.” For instance, models could be used to see how some
system might work. Royyuru used such modeling to explore the signaling mechanism that connects p53, a protein, with cancer. Then mechanisms that appear in a model
can be tested with traditional biological methods. “That
is,” Royyuru says, “hypothesis generation through computation could help to hypothesize better experiments.”
That scenario completes the range of IT’s breadth—
from creating information to transmitting it, and playing
some role in every step along the way.
69
H
oward R. Asher, president
and chief executive officer
of Global Life Sciences in
San Diego, Calif., not only
watched, but participated
in, the evolution of information technology (IT). He started in
product development at Pfizer, then Baxter and Bayer before founding a series of
his own companies—now doing so for 30
years. During those years, Asher found
that many technical advances depend
on trust. Here, Worldview talks to Asher
about trust in biomedical IT and how it
might be enhanced. This is an edited excerpt of that interview.
Biomedical Information—
A Matter of Trust
A Q&A with howard R. asher
Can a new kind of
ATM change global
healthcare?
b
y carm
e
via
ego
s
n
illustration
What sparked your interest in IT?
»
My interest in IT, essentially, occurred in the
early eighties. In 1978, I founded Advanced Bioresearch
Associates, ABA. We were helping a number of different
types of companies with a number of devices. One was the
first human artificial heart, which came out of Stanford.
That artificial heart was actually in machine code. So I
had to figure out how to comfort the FDA with software
and hardware as it related to an artificial heart, which
is a pretty significant product as trust goes. So it really
kind of brought me out of the closet of IT and really got
me into the concepts of things like software validation.
In helping the FDA accept such technologies, I depended
on a very simple word that’s guided me forevermore, and
that’s trust. How do you trust the IT to do exactly what
it claims it will, and—more important—that it wouldn’t
harm somebody or cause a problem?
{ © carmen segovia}
What range of issues gets impacted by trust in today’s computational information from biotechnology?
70
» If we take a global perspective and look
at the global biotechnology centers, they develop around
medical universities that spill out information and technology and IP, intellectual property. So much of that IP is
coming out of academic institutions that have used computational tools to characterize some of the IP. The issue
71
there becomes interoperability if you will. As we take the
intellectual property that has been developed by computational means, is it something that we—in the big sense of
“general public”—can trust?
Then, as we take that computational process and we
move it into, say, an industrial environment that may
actually start applying other computational processes to
that core IP, we eventually get to a point where that is going to be overviewed by a regulator. Of the 50 nations,
we have 49 various views of: How do I trust the primary
information, be it information that characterized a compound or information that was gathered in the nonclinical studies that proved safety or demonstrated efficacy,
How can the technology behind a money machine improve
biotechnology?
have become so stringent. Then all of a sudden, we’re into
a Phase III, not really getting the data that we really need,
except at the organ level. We’re still in the art form of medicine. We’re not in the science of medicine.
We have to take some harsh looks at what is happening to drug development and therapeutic development, and
it’s not very pretty. We’re seeing about a 99.9 percent failure
rate. So for, say, every 10,000 compounds targeted, we’re
seeing one really get through the process and get market approvals. That’s horrifying when we look at the economics.
» Let’s go through a scenario of what this might
look like in the future. What if right beside our money set
our entire health record? So we have the automated teller
machine, ATM, and next to that we have the automated
telemedicine machine, the new ATM of our medical information from birth. What if we uploaded into our healthcare information our genotype and then—as we experience the environment of life ongoing—we could add our
phenotype? Then, every dental X-ray, every medical record,
every drug, everything we take is uploaded into our medical record. Then let’s imagine that we
have hundreds of millions of people
around the world with their medical
records uploaded into their “ATM.”
What then could theoretically occur
is that—just like we can check a box to
say we are an organ donor—we could
say that we are a genetic-information
donor. Then, we as an industry can
benefit from real human genomic
and therapeutic information related
to disease types. We could structure
and stratify that data. It would be real
human data at the genetic level. We
could then look at how different drug
therapeutics affected different phenotypes and so on. We
could look at biomarkers and start harvesting real information associated with real disease. All of a sudden, we would
have a goldmine of information that we would trust more
when applying it to therapeutic compounds.
Given those bad odds, how can biotechnology put your
ATM analogy into operation to improve the situation?
» We could harvest the genomic and cellular data
What if we uploaded into our
healthcare information our genotype and then—as we experience
the environment of life ongoing—
we could add our phenotype?
With so many stages where IT is involved, you get a pretty
big chain reaction in the requirement of trust.
» That’s absolutely true. As I’ve been flying
around the world and visiting with companies in different countries, the issue of trust makes me ask: When have
we—as the general public—experienced this before? Many
years ago, we’d take money to our branch of our bank and
deposit our cash. They would put it in their vault, and if we
needed to remove some of that money, we had to go back
to that branch and that vault, from which the money was
provided back to us. But now, we have the global ATM. The
only IT that the general public—as a world public—will
trust is the ATM. They do not trust the telephone IT. They
don’t trust the credit-card IT. They don’t trust many, many
other billing mechanisms and other IT stuff, but they do
trust the ATM.
72
on—or even require— the kind of database of information
that you are describing.
Do you say “trust more” in this case partly—or almost
entirely—because the sample size would be big enough to
be really trustworthy?
» Exactly. We would now be dealing with biostatistical
significance that healthcare professionals must truly trust.
Not only would we understand the therapeutic dynamics,
but we would also understand the biomarker outliers.
If we’re at the molecular level and the cellular level,
might we be able to harvest out the information of where
something will therapeutically be effective, what is the
mechanism of action, and where might we get a bad outcome or unanticipated effect that we’re not wanting?
We hear a lot about the medical and pharmaceutical communities wanting to do things like personalized medicine
or gene therapy, but doing this effectively seems to depend
{ © aaron mcKinney}
and how do I trust the IT and statistical assessments
and all of the data management that has gone through
not only the preclinical but including the clinical stages?
From a regulator’s perspective, we want to trust that those
are well-engineered, they are validated systems, and they
are trustworthy in all respects.
» That is really the essence of the point.
The biotech industry is really at an embryonic state with
IT. Part of that is that when we are dealing with data that
are at the cellular and genomic level, we very quickly start
looking at petabytes of information and terabytes of data.
One simplistic concept many times escapes us, and it is: We
want to go from data to information and then to knowledge.
What’s happening is that the interpretation of volumes of
data into truly meaningful and trustworthy information is
not yet complete. We haven’t quite figured out how to make
sure that we have adequate data sample sizes to make an informational set of facts that we as a people can trust. Then,
as we convert the information and set of facts that we can
trust—based on the adequacy of data—then we start getting into the knowledge that we as an industry so desperately need. Vioxx and many other drugs serve as troubling
examples where we have not known what we did not know
when we put a drug or therapeutic to the market.
The current mechanism, the current model, does not
work. We know that fact. We know that the animal data
give us much misinformation. We know that some of the
Phase I, Phase II clinical studies add to the misinformation, partially because the inclusion and exclusion criteria
of humans, associate that with a disease, and look at the
therapeutic potentials with computational predictive
modeling. Then, we could determine in the modeling what
biomarkers are expressed, where a potential therapeutic
would be most effective in which population and equally
important—if not more important—the populations we
should avoid and actually contraindicate—meaning that
if you have a specific biomarker, you should not have this
drug because it will be a bad outcome.
Let’s talk about the toxicological information that
we gain when we go through our current paradigm. We
are actually taking histology and toxicological information from animals. We are trying to associate that with
humans. We are saying that the animal must be pure, a
laboratory controlled animal—not anything reflective of
a human, who would be eating all kinds of different diets,
consuming all kinds of supplemental products, and environmentally they are exposed to everything under the sun.
So right there, just look at the contrast between the human
patient and that animal from which we’re gaining toxicological knowledge. The information provided by that kind
of data is just wrong.
It’s hard to miss the international potential behind your
idea of a medical ATM. If health information from around
the world could be made available, a pharmaceutical
company could access data from most anywhere. Likewise,
this could bring better healthcare to developing countries
if more information were available about medical histories
of their people.
» Absolutely true. If we are going to build a successful therapeutic, it is nothing but naïve if we think that
we only need to conduct our clinical assessments and our
development within, let’s say, the United States. That is
very nearsighted. We have to be global.
73
Magic Nano-Bullets
Advances in nanotechnology could make drug
delivery far more accurate and effective By Charles Choi
74
to evade the immune system. “The
hope,” Langer says, “is to have these
‘magic bullets’ that can hone in on
specific cells.”
Simplification with Self-Assembly
Although the first targeted nanoparticle–drug delivery systems appeared
as early as 1980, creating ones that
work consistently has proven challenging. Each desired feature of a
nanoparticle typically requires laborious sets of chemical reactions. Every step can introduce variability, and
the delicate balance needed between
all these features for a successful
drug-delivery system can readily get
lost. But Langer, along with colleague
Omid Farokhzad at Harvard Medical
School, developed a way for nanoparticle–drug delivery systems to selfassemble in a single step, eliminating
much of the imprecision that could
tests that delivers a chemotherapy
drug in a targeted way. As Farokhzad
says, “In experiments, our targeted
nanoparticles worked significantly
better than traditional chemotherapy and non-targeted nanoparticles.”
BIND will also target cardiovascular disease. Langer and Farokhzad’s
other company, Selecta Biosciences,
focuses on delivering specific diseaselinked molecules to immune cells,
serving as improved vaccines.
The advantage of using polymer
nanoparticles in drug delivery is the
enormous control that scientists have
over the characteristics of the particles—the fruitful results of years of
polymer research. Langer has been on
the forefront of polymeric drug delivery for more than three decades, having invented the first polymer that allowed the controlled release of a drug
in the body.
{
Extending the Nano-Arsenal
“This team is playing a leadership
role internationally in drug delivery.”
– Joseph DeSimone
prevent nanoparticle consistency.
Others in the field respect the
work of Langer and Farokhzad. “My
group follows their work very closely.
They are trendsetters in lots of different ways,” says Joseph DeSimone
at the University of North Carolina
at Chapel Hill. “This team is playing
a leadership role internationally in
drug delivery.”
Langer and Farokhzad have started two venture-backed companies to
commercialize polymer-nanoparticle
drug delivery. BIND Biosciences will
begin clinical trials this year on the
first polymer nanoparticle to enter
Instead of trying to predict which
combination of polymer nanoparticles works best as a delivery agent, as
other labs do, Langer and Farokhzad
create libraries of hundreds of particles—each with its own array of distinct characteristics—and then rapidly
screen them against a particular ailment to find the optimal agent. This
approach has already revealed some
surprises. For instance, researchers
once thought that increasing the number of binding molecules created a better-targeted nanoparticle, but Langer
and Farokhzad’s technique showed
that less sometimes works better.
{© Nicolle Rager Fuller, Sayo-Art}
S
ubmicroscopic techniques
that could kill cancer or
mend weak hearts will
only be used if they target the right cells and
leave others unharmed.
After years of development, Robert
Langer at the Massachusetts Institute
of Technology and his colleagues will
soon begin clinical trials of “magic
bullets” that employ nanotechnology
to deliver drugs only where they are
needed. It’s no surprise to find Langer
guiding such a futuristic approach.
“Langer is a living legend in the area
of drug delivery,” says Chad Mirkin,
a nanomedicine researcher at Northwestern University. “He is to drug delivery what Ford was to automobiles!”
Nanotechnology works with construction blocks that are only nanometers—billionths of a meter—across.
So far more than two dozen nanotechnology therapies have been approved
for clinical use. These are mostly relatively simple improvements of existing drugs, Langer explains. For example, the potent anticancer compound
paclitaxel, commonly known as Taxol,
does not dissolve well in water, and
toxic detergents were used to administer it in the bloodstream. The drug
Abraxane incorporates paclitaxel in
nanoparticles of the human protein
albumin that render the drug soluble
in water, while reducing unwanted
side effects.
Instead of upgrading past drugs,
Langer hopes to bring entirely new
classes of therapies into the clinic
with a Swiss Army knife’s worth of
options. He and his colleagues are
designing biodegradable, organicpolymer nanoparticles that include
therapeutic agents and molecules that
bind to the desired targets. Moreover,
the nanoparticles are formulated
A number of other nanotechnology
approaches toward drug delivery exist. Hongjie Dai at Stanford University and his colleagues have shown that
carbon nanotubes can bring proteins
and DNA into cells, which could potentially deliver drugs or therapeutic
genes. In addition, Donald Tomalia,
scientific director of the National
Dendrimer and Nanotechnology
Center, explores spherical branching molecules named dendrimers,
which resemble bushes in structure.
Scientists can precisely tailor what
each branch tip holds, enabling dendrimers to combine a number of different therapies and delivery tools.
“Carbon nanotubes and dendrimers are both extremely promising
for drug delivery,” Farokhzad notes.
“But carbon nanotubes are really in
their infancy clinically speaking. It’s
Targeting disease: Nanoparticles could deliver
chemotherapy drugs directly to tumors to
increase the impact and reduce side effects.
going to take a number of years before
the safety of these materials is understood. And dendrimers are exciting,
but then there’s the question of how
amenable they are to scaling up in
production. Making polymer particles is a relatively easy process to scale
up, and polymer-particle drugs have
already been approved by the FDA for
15 or so years now.”
One feature that is simultaneously attractive and alarming about
nanotechnology is that objects at the
nanometer scale can take on radically different properties not seen in
their bulk counterparts. For instance,
while gold is normally chemically inert, which keeps gold rings lustrous,
gold nanoparticles can prove highly
reactive. Any unknowns about potential therapies could pose nasty risks,
so when developing nanoparticles for
the clinic, Langer and Farokhzad stick
}
to polymers that are well-understood
and drugs that are already approved.
In their research, however, Langer
and Farokhzad are known to push
the envelope. In 2008, for example,
they developed a nanoparticle that
combined immune-system stealth,
disease targeting and drug release.
It could also detect the location of
tumor cells and indicate when the
nanoparticles delivered the drug to
their targets. “That technology is very
futuristic, and whether so many bells
and whistles are needed with these
nanoparticles is a good question,”
Farokhzad says. “But I’d say we have
to be innovating today if we want the
luxury of applying that technology tomorrow. We might be paving the road
for 30, 40, 50 years from now. The impact of nanotechnology on medicine
is just beginning, and I think it will be
huge in our lifetime.”
75
{
New ways to light up diseases: These yellow peptide
nucleic acids could pick out ataxia-telangiectasia, an
inherited and disabling neurological disease.
PNAs in microbiology
Soon after PNA’s appearance, scientists began synthesizing short
stretches of it to use as probes to detect specific DNA or RNA sequences
inside cells. Although similar techniques had existed for years with
DNA or RNA molecules as probes,
PNA’s extraordinary stability and hybridization strength made it attractive to use instead.
One of PNA’s most successful applications is in detecting and identifying microorganisms. Identifying
pathogens quickly is important for
treating infections in humans and
other animals, as well as for protecting food, beverages and municipal
water supplies. In the late 1990s,
P is the
new d
Peptide nucleic acid
(PNA), a synthetic hybrid
of protein and DNA,
is poised for a world of
applications
By Melissa Lee Phillips
76
faster you can prescribe effective and
appropriate antibiotic therapy.”
PNAs are also used in many other
applications in biotechnology and
medicine. These molecules, which
are essentially hybrids of deoxyribonucleic acid (DNA) and proteins,
are leading to especially promising
inroads in anticancer and gene therapeutic drugs.
The PNA story began in 1991
when researchers from the University of Copenhagen published their
synthesis of the first PNA molecule.
Their idea was to create a molecule
that could physically prevent DNA
from being transcribed into ribonucleic acid (RNA), thereby blocking expression of faulty genes. The
researchers, led by Peter E. Nielsen,
attached the familiar adenine, cytosine, guanine and thymine bases of
DNA to a backbone made of peptide
units similar to those in proteins.
(See Nielsen, PE. 2008. A new molecule of life? Scientific American
299(6):64–71.) This combination
conferred qualities that made PNAs
attractive for some applications that
normally employ DNA. For example, DNA backbones carry a negative electrical charge, but peptide
backbones are electrically neutral.
This difference means that PNA
binds much more strongly to DNA
than does DNA itself. PNA is also
unusually stable inside a cell, because the enzymes that break down
normal proteins and nucleic acids
don’t affect it.
Nielsen and his colleagues found
that PNA could indeed prevent transcription of chromosomal DNA by
displacing one of the strands of the
double helix. But Nielsen and others soon realized that PNA’s unusual
qualities would lend themselves to an
unexpected variety of applications.
bacterium and found that it reliably
differentiated between healthy and
infected samples.
In 2003 the U.S. Food and Drug
Administration approved three
PNA-FISH kits created by AdvanDx,
a company that Stender founded
in Woburn, Mass. These tests—for
Staphylococcus and Enterococcus bacteria plus Candida yeast—are now
used at hospitals around the country. A PNA-FISH test to identify a
microorganism in a patient sample
currently takes hospital microbiologists about two and a half hours—at
least 10 times faster than traditional
diagnostics. Plus, researchers found
that using PNA-FISH to diagnose
staph infections in hospitals reduces
“By inhibiting telomerase, we were able to
slow the growth of tumor cells.” —David Corey
{courtesy of peter landsdorp}
I
n most hospitals, patients
are treated for infections before their doctors can be sure
what’s wrong. Diagnostic
tests take so long that physicians must simply make
their best guess as to appropriate
treatment and then alter it if necessary when test results come back—24
to 36 hours later. Prescribing inappropriate antimicrobial drugs risks
both subpar patient treatment and the
development of drug-resistant pathogens, but there’s little that traditional
microbiological methods can do to
speed up the process. But some hospitals are now using synthetic molecules
called peptide nucleic acids, or PNAs,
to cut the time needed for diagnosis of
common infections to just a couple of
hours. “In clinical microbiology, time
is key,” says Byron Brehm-Stecher of
Iowa State University in Ames. “The
faster you can make a diagnosis, the
}
Henrik Stender, then at Dako A/S
in Glostrup, Denmark, addressed
such issues by adapting a technique
called fluorescence in situ hybridization (FISH) for use with PNA. In traditional FISH, fluorescently labeled
DNA probes are sent inside cells,
where they bind to complementary
DNA or RNA, revealing the presence of the target sequence. The new
technique—called PNA-FISH—uses
PNA probes to target ribosomal RNA
(rRNA), which is found in all organisms, and its sequence is commonly
used to distinguish microbial species.
Stender and his colleagues designed
a PNA probe complementary to the
rRNA sequence of the tuberculosis
antibiotic use, total hospitalization
costs, length of stay and patient mortality. “Faster results allow physicians
to make better decisions regarding
therapy,” Stender says.
PNA-FISH can also be used to
identify environmental contaminants like Listeria and Salmonella
in bottled water, on public beaches
and in wine and food. “It’s broadly
applicable to microorganisms in
any type of sample,” Stender says,
although non-clinical applications
are not yet commercialized. According to Brehm-Stecher, “For
foods and environmental microbiology, PNAs are primarily still in
the research phase.”
Pushing the Potential of PNAs
PNA’s potential goes far beyond microbiology. In 2007 a group at the
University of Oxford reported that
PNA can alleviate symptoms of muscular dystrophy in mice. Muscular
dystrophy is caused by dysfunction
of the protein dystrophin. The researchers injected the mice’s muscles
with PNA that interfered with expression of a faulty part of the dystrophin gene, which then allowed the
mice to make enough normal protein
to function.
PNAs also appear to have anticancer potential. A group led by David Corey at the UT Southwestern
Medical Center at Dallas showed that
PNAs can interfere with the enzyme
telomerase, whose activity can lead
cells to become cancerous. “By inhibiting telomerase, we were able to slow
the growth of tumor cells,” Corey
says. A molecule that is a direct descendent of this PNA is currently in
clinical trials as an anticancer agent.
More recently Corey’s group
published work that furthers the
hope for using PNA as originally
intended: to silence genes by binding to chromosomal DNA. Although some technical problems
have plagued this technique over
the years, Corey and his colleagues
recently found that PNA can access
chromosomal DNA in living cells,
suggesting that PNA might have
many more uses ahead, he says. If
PNA can bind chromosomal DNA,
it might also be able to deliver a
chemical reagent that could correct
a mutation or recruit proteins that
activate gene expression. “All sorts
of other applications start to suggest
themselves,” Corey says.
77
High
Content
is King
By Charles Choi
A
yellow robot arm
moves with a combination of inhuman speed and delicate grace, loading
a microscope with
a plate split up into 1,536 wells, each
filled with ovary cells from Chinese
hamsters. Here the classic image of scientists peering into microscopes to la-
78
{
Automating wide-scale attacks on disease: In a person with spinal muscular
atrophy, fibroblasts (below) could suffer from a deficiency in a protein called
SMN (labeled green), and scientists at Merck use 1,536-well plates (above) to
develop assays to study this disease and search for ways to treat it.
boriously scan slide after slide is gone.
In an instant, the automated microscope at Merck Research Laboratories
in North Wales, Penn., digitally images
all of the specimens simultaneously.
Welcome to the brave new world of
high-content screening (HCS), which
is dramatically scaling up the number
of experiments on cells that researchers can run, just as DNA microar-
}
rays helped revolutionize molecular
biology. Using robots, scientists can
now grow most any kind of tissue in a
variety of conditions, dose those cells
with any of the millions of molecules
that pharmaceutical and biotechnology companies keep in their libraries,
image the effects these molecules have
on cell function using microscopes
and high-resolution digital cameras
and run computer algorithms to mine
the resulting avalanche of data. Operating 24 hours a day, just one HCS
system at Merck can test and image
4.3 million wells per week.
“We’re no longer just sitting there
in front of our microscopes preparing one slide at a time,” says Jeremy
Caldwell, head of Merck’s automated
biotechnology unit. “Automation
frees us up to think much more deeply about the design of experiments,
how we might find what’s important.”
While previous high-throughput
methods focused on a limited number
of chemical markers to figure out what
effect specific molecules have on cells,
high-content screening pays attention
to more: the movement of proteins
in cells; how cells, nuclei or organelles change size and shape; how cellmembrane permeability varies; and
other characteristics. “Instead of what
might be under a lamppost, you’re illuminating what is going on in the rest
of the entire city,” Caldwell says.
“
“By looking at the entire cell,
one can see the whole picture and
hopefully not miss key details.”
Cost-Saving Content
{ images courtesy of merck }
Robotic handlers and
automated imaging are
revolutionizing drug
discovery
ogy screens on cell-based models of
liver, heart, and every other organ of
interest for signs of toxicity,” Collins
says. “By looking at the entire cell and
measuring multiple events, one can
see the whole picture and hopefully
not miss key details—think of it like
a ‘cellular autopsy.’”
Basic researchers also use HCS.
For instance, Merck is learning what
genes do by using small interfering
RNA molecules to knock out specific
genes and seeing what happens. “In
the old days of the genomics era, the
idea was that DNA microarrays could
provide everything you needed to find
In the past five years, HCS has increasingly found its way into drug discovery, to see which potential therapies
are worth developing for clinical
trials. “One can see if potential antiangiogenesis drugs actually do shrink
blood vessels feeding tumors, or see
how many neurites a potential neuronal-regeneration drug causes neurons
to grow,” explains Mark Collins, senior marketing manager for Thermo
Fisher Scientific’s cellular imaging and
analysis group in Pittsburgh, Penn.
The first high-content screening device was introduced a decade ago from
cellular-imaging firm Cellomics, now
part of Thermo Fisher Scientific.
On the flip side, HCS is also employed in toxicology screens to weed
out molecules not worth developing.
“Instead of putting drugs in animals
for tests or getting to humans and
getting a situation like Vioxx after,
perhaps, investing hundreds of millions of dollars, there is an awful lot
of interest in running in vitro toxicol-
—Mark Collins
out what genes should be targeted to
treat a disease, but they just tell you
which genes are activated and which
are not, and to find out which genes
are causal in disease, you really have
to probe cellular function,” Caldwell
says. “High-content screening can
help us follow what is happening in
the cell over space and time to dissect how genes work in relationship to
each other.”
Emerging research proves that
HCS can be effective. For example
Collins notes that researchers at the
Hospital for Sick Children in Toronto
used HCS to discover new drugs that
could reverse the effects of cystic fibrosis, “including the well-known
clinically approved anti-cancer drug
Velcade.” He adds that another study
suggested that a typical pharmaceutical company with about 10 drug discovery projects per year could save
$350 million annually by using HCS
to help determine which potential
therapies are toxic early in the drugdiscovery process.
Even More Content
Analyzing the mountains of data
from faster and more complete technologies creates today’s HCS bottleneck. “It’s a challenge to manage
the terabytes of data that a typical
high content–screening experiment
can generate or analyze 200 multivariate parameters per cell,” Collins
says. Another challenge that Collins
says “keeps me up at night” is finding a way to make it easy enough to
be accessible to a broad spectrum of
researchers. “How can we make sophisticated technology that a scientist
doesn’t have to devote their life learning how to use without dumbing it
down to the point where it’s no longer
valuable?” he asks.
If scientists can put HCS’s gigantic amounts of data to use and keep
the techniques easy enough to run,
a great deal of potential might lie in
wait. For instance, although an HCS
system looks at an entire cell, it typically only follows a few kinds of molecules at once. Instead Merck hopes
to soon monitor the behavior of up to
dozens of kinds of molecules in cells
simultaneously using a novel “polytarget robot system” from the Genomics Institute of the Novartis Research Foundation. This innovation
could help researchers begin to really
understand organisms as complex
systems of interacting processes, the
goal of the field of systems biology as
it was originally envisioned. “All this
rich information could prove invaluable not just for drug discovery but for
basic research,” Caldwell says.
Perhaps the ultimate goal of highcontent screening is to gather enough
data on cells “to build myself a virtual
cell,” Collins says. “I could then—in
silico—answer questions about biology.” Walking through a lab festooned
with the electronic innards of automated biotechnology systems, Caldwell
agrees. “I would love to do that,” he
says. “It’s something we could potentially begin to see in our lifetimes with
the aid of high-content screening.”
79
about 28 million tons, roughly equal
to the commitment Denmark has
made for carbon dioxide reduction
under the Kyoto protocol.
Silent
Green
Cool and Clean
Typically a customer will approach
an enzyme maker with a specific
problem. “Our approach would be to
define the unmet needs of the marketplace, then to screen our libraries
for the best candidate enzymes, and
then to make modifications to those
to improve the performance along the
targeted dimension,” says Janet Ro-
Unsung heroes of
sustainability, industrial
enzymes protect the
environment, while
enhancing a range
of products
P
emer, executive vice president of the
specialty enzymes unit at Verenium
in Cambridge, Mass.
Each enzyme maker has its own
library of potentially useful enzymes.
For Verenium, the library comes
mainly from extremophiles, microorganisms that live in harsh environments where not much else can,
which were collected on various bioprospecting expeditions by corporate
ancestor Diversa. Novozymes, meanwhile, relies on a wide range of fungal, bacterial and other enzymes for
its screening campaigns.
Although the environmental
benefits are a selling point, most industrial customers only adopt an enzymatic process if it also improves
their bottom line. Several years ago,
for example, Novozymes began working with laundry-detergent manu-
{©BASF}
80
the grains in chicken and pig feed,
because that phosphorous gets all
tied up in the plant phytate, and so
the phytase comes in and it really
makes it available to the animal,”
Roemer says.
Before purified phytase was available, farmers had to overload the feed
with inorganic phosphate to meet the
animals’ dietary needs. Inorganic
phosphate isn’t metabolized as efficiently as plant phosphate, so 70 percent of the mineral ended up in the
animals’ feces—wasting the farmers’
money and leading to eutrophication
Although the environmental benefits are a selling point,
most industrial customers only adopt an enzymatic
process if it also improves their bottom line.
By Alan Dove
op quiz: What three
categories of biotechnology products can
provide the greatest
environmental benefits? Most readers, even
those inside the industry, will think
of only two answers: biofuels, which
substitute biomass for fossil-fuel feedstocks, and genetically engineered
crop plants, which can substantially
reduce pesticide use. But what about
industrial enzymes? If that didn’t
spring to mind, don’t feel bad. Industrial biotechnologists are accustomed
to obscurity. “You could say our technology is kind of the software behind
many production processes, or silent products—consumers don’t see
[them], but they contribute to diminishing the environmental footprint,”
says Steen Skjold-Jørgensen, vice
president for research and development at Novozymes North America
in Franklinton, N. C.
The impact of these little known
but shockingly ubiquitous products
is enormous. According to a recent
life-cycle analysis, the enzymes from
Skjold-Jørgensen’s company alone
reduce global carbon emissions by
facturers to solve a problem in their
supply chain. “The detergent producers of course [were] interested in
kind of decoupling their ingredient
purchases from the oil prices in the
Middle East,” Skjold-Jørgensen says.
Substituting stain-removing enzymes
for some of the fossil fuel–derived surfactant compounds in the detergents
accomplished that. At the same time
the detergents became friendlier to
the environment. “You can actually
accomplish stain removal, cleaning,
maintenance of your fabric with these
biocatalysts at lower temperature than
{
A friendly fungus: A few genetic
tweaks can turn Aspergillus niger
into an enzyme factory.
}
you would normally do. That of course
has a bearing on the environmental
impact,” Skjold-Jørgensen says.
As newer washing machines with
lower wash temperatures come on the
market, each household uses a little
less energy with each load of laundry.
It’s not much individually, but the aggregate effect will be huge. According
to Skjold-Jørgensen, if most consumers in Europe could turn down washing-machine temperatures by 10 degrees, it would save two power plants
worth of energy.
Working for Chicken Feed
Reducing carbon emissions, however, isn’t the only way to improve
a product’s environmental profile.
For instance, Verenium’s top-selling
product, Phyzyme, attacks phosphorous—a different but equally insidious pollutant.
Phyzyme is a phytase enzyme.
“It’s used in the animal-feed market
to unlock the phosphorous that’s in
of nearby waterways. Phytase-spiked
feed is much more efficient.
Other companies also produce
phytases, but Verenium took pains
to build some unusual characteristics into theirs. “The product was
developed to be active in the pH of
the upper gut of the animal and deactivated as it passed through the
digestive system, so it does what it’s
supposed to do just in the right place
in the animal’s digestive system,” Roemer says. Phyzyme is also thermostable, so it can be compressed into
pellets. Feed-producing giant Danisco
now incorporates the enzyme into
standard chicken and pig chows.
Besides cleaning up manure and
lowering laundry temperatures, industrial enzymes reduce pollution
in a wide range of other businesses,
including leather tanneries, commercial bakeries, paper mills and
oilseed-processing plants. Eventually maybe they’ll even make it into
a newsroom.
81
Simple Solutions
for Global Health
By
Dawn
Stover
A
survive with better access to healthcare. More than half a
million women die annually during pregnancy or childbirth, and most of these deaths are also preventable. And
despite major progress in the prevention and treatment of
HIV/AIDS, it remains the leading killer of adults in Africa.
Meanwhile new challenges have emerged: Urbanization and globalization make it easier for communicable
diseases to spread. Aging populations are facing chronic
non-communicable illnesses such as cancer and heart disease. Climate change is aggravating health problems, such
as heat stroke, asthma and waterborne diseases.
Across the world, the least expected changes help deliver better care
84
ways come from a lab bench. Moreover the best plans need
not be the most expensive.
It’s surprising to find a model healthcare program in a
nation where per capita income is less than $40 per month.
But when it comes to health, you don’t always get what
you pay for. As poor nations struggle with how to provide
quality care on a shoestring budget and rich nations attempt to rein in runaway costs, governments and charitable organizations throughout the world are searching
for ways to reform healthcare. “We’re finally at the point
where the entire world is in a health crisis,” says Laurie
Garrett, senior fellow for global health at the Council on
Foreign Relations and the author of Betrayal of Trust: The
Collapse of Global Public Health.
Best of Times, Worst of Times
It’s not all bad news. By some measures, the world is
healthier than ever. Compared with 50 years ago, average
life expectancy at birth has increased by almost 27 years in
Asia, 23 years in the Middle East, 21 years in Latin America, 14 years in Oceania and 11 years in sub-Saharan Africa. Infant and child mortality have also improved: Even
though more children are born today than in 1960, the
numbers who die before age 5 have been cut in half.
“There have never been more resources available for
health care than now,” according to the World Health Organization’s World Health Report 2008. Even after adjustments for inflation, global health expenditures grew by a
whopping 35 percent between 2000 and 2005.
Unfortunately the rising tide of money has not lifted all
boats. “Today the gaps in health outcomes, both within and
between countries, are greater than ever before in recent history. Differences in life expectancy between the richest and
poorest countries exceed 40 years,” said Margaret Chan,
director-general of WHO in a February 2009 speech at a
global health forum hosted by Italy’s Aspen Institute and Japan’s Health Policy Institute. A boy born today in Swaziland
will probably not live long enough to see his children graduate from high school, while a boy born at the same time in
Japan is likely to know his great-grandchildren.
Each year about 10 million children under the age of
five die, according to WHO, and almost all of them could
{© karen kasmauski/corbis}
s anyone over 50 knows, deteriorating close-range vision is a universal symptom of middle age.
The cheapest solution? Dimestore reading glasses. But for people living in developing nations,
glasses are neither affordable nor
easy to obtain. Without them it’s
difficult to do essential daily activities such as reading,
sewing or sorting seeds for planting.
In Bangladesh, one of the world’s poorest and most
densely populated countries, the nongovernmental organization BRAC (formerly known as the Bangladesh Rural
Advancement Committee) and a New York-based nonprofit called VisionSpring teamed up to solve this problem by sending an army of “vision entrepreneurs” into the
countryside to sell inexpensive reading glasses. It’s not
uncommon for a customer to burst into tears after trying
on a pair for the first time. Some 500 women have already
been trained in how to prescribe the $2 glasses, and each
has received a special briefcase containing the tools of the
trade and product samples. The women keep a portion of
the revenues and use some of the money to pay back small
loans that cover their training.
“Reading Glasses for Improved Livelihoods” is just one
of many simple but innovative initiatives sponsored by
BRAC, which reaches more than 92 million Bangladeshis
through its network of 68,000 volunteer healthcare workers—mostly poor, rural women. Besides prescribing reading glasses BRAC volunteers sell medicines, make home
visits, vaccinate children and collaborate with the government on programs to improve sanitation and combat tuberculosis and malaria. BRAC even runs its own school of
public health, as well as a dairy and a chain of handicraft
stores. By taking a holistic approach that combines health
programs with economic development and education,
BRAC has evolved from a donor-funded organization into
one that is 80 percent self-supporting—and so successful
that it has expanded to Afghanistan, Sri Lanka, Tanzania,
Uganda, Pakistan and southern Sudan.
As this shows, sometimes low-biotech can improve
lives and even save them. Likewise innovation does not al-
{
Delivering health and hope: A volunteer with the
Bangladeshi Rural Advancement Committee (BRAC)
dispenses antibiotics to infants.
The biggest challenge of all is the “delivery gap,” says
Jim Yong Kim of Harvard Medical School’s department
of global health and social medicine. Despite unprecedented financial investments and medical advances,
care often does not reach those who need it most. Bureaucracy and corruption siphon money, and programs
sometimes reflect the interests of donors rather than the
needs of recipients. Even when needs and funding are
aligned, there is a crucial shortage of doctors, nurses,
pharmacists, dentists, optometrists, lab technicians and
other workers.
}
society & culture
85
A Promise to Buy
An estimated 4.2 million health workers are needed
worldwide to bridge the gap, according to the Global
Health Workforce Alliance. “We’re not going to be able to
fill that void in our lifetime and probably not in our children’s lifetime,” Garrett says. “It takes a long time to train
doctors and nurses, and as fast as they are trained, they are
recruited to the rich world.” Even there, supply is not keeping up with demand.
Focus on Primary Care
To tackle these enormous challenges, governments and
organizations around the world are developing blueprints
for better health systems. Virtually all of these plans emphasize the importance of primary, preventive care.
WHO, for example, is using Millennium Development
Goals adopted in 2000 to guide its actions. Among the healthrelated objectives: reducing worldwide deaths during pregnancy and delivery by three-quarters between 1990 and 2015,
and achieving universal access to reproductive healthcare by
2015—both of which will require training more workers.
Health workers need not be doctors or even registered
nurses. In Rwanda, for example, community health workers
called “accompagnateurs” make home visits to administer
drugs and check on patients with HIV and tuberculosis.
Using this rudimentary health-delivery system, together
with programs to fight poverty, Rwanda hopes to provide
Of the 234 million major surgeries performed annually around the world, an estimated 7 million or
more result in complications—half of which are
preventable. To improve the safety of surgical care,
the World Health Organization (WHO) developed a
checklist that can be used in any operating room.
Tested at eight hospitals in different regions, the
Surgical Safety Checklist reduced surgery-related
deaths and complications by one-third, according
to a study published in January in the New England
Journal of Medicine. WHO hopes to have 2,500 hospitals using the checklist by the end of this year.
The checklist requires surgeons, anesthesia providers and nurses to pause at three points during an
operation—before inducing anesthesia, before
cutting into the patient and before the patient leaves
the operating room—to answer a few questions. For
example: Does the patient have a known allergy?
How much blood do we expect him or her to lose?
Are we missing any instruments or sponges?
Short, simple checklists could improve healthcare
in other specialties too, says Atul Gawande, who led
the international team that developed the surgery
checklist. “They could become as essential in daily
medicine as the stethoscope.”
{Photo courtesy of Justin Ide/Harvard University News Office}
Safer Surgery
Developing new vaccines and bringing them to market in developing
countries can take more than 15
years. The GAVI Alliance—a partnership that includes governments, the
World Health Organization, UNICEF,
the World Bank, foundations and
pharmaceutical companies—is testing a way to accelerate this process.
Governments and private-sector
donors make an Advance Market
Commitment (AMC) to purchase a
vaccine at a guaranteed price if it is
successfully developed. That gives
the pharmaceutical company an incentive to invest in researching and
manufacturing the vaccine.
The pilot AMC—launched two years
ago with $1.5 billion donated by
the governments of Canada, Italy,
Norway, Russia and the U.K., along
with the Bill & Melinda Gates Foun-
basic healthcare for the entire country by 2011 at a price tag
of only $200 million. The Global Health Delivery Project
(GHDP), co-founded by Kim and Harvard Business School
professor Michael Porter, did a case study of this grassroots
approach and found that it improved health outcomes and
lowered costs.
“...we can avert at least
36 million premature
deaths by 2015.”
Comprehensive care emphasizes disease prevention
and healthy lifestyles, rather than the treatment of specific diseases. For communicable diseases like malaria and
measles, that means preventive care such as insecticidal
bed nets and childhood vaccinations.
Although communicable diseases are often the focus of
international efforts, chronic non-communicable diseases
such as heart disease and lung cancer are already responsible for 60 percent of deaths worldwide, and 80 percent of
these deaths occur in low- and middle-income countries,
reported a team of 19 global-health researchers in a November 2007 paper in the journal Nature. “With concerted
action, we can avert at least 36 million premature deaths
by 2015,” they noted.
The researchers compiled a list of the top-20 policy and
research priorities for chronic non-communicable diseases. Some of their recommendations are as simple as “increase the availability and consumption of healthy food”
and “promote lifelong physical activity.” WHO estimates
that at least 80 percent of deaths from cardiovascular disease and strokes could be prevented through healthy diet,
exercise and the elimination of tobacco use—which is high
in many countries.
Better health systems are not necessarily expensive.
While the U.S. might offer the best care available if you
need a complicated surgical procedure, its citizens do not,
{
86
Taking medicine to the needy: Jim Kim (right), co-founder of Partners in
Health, meets
site administrator
Moses Phakis (left) and medical doctor
Scientific
American
| WorldView
Jen Furn (center) at a clinic in Bobete, Lesotho, in South Africa.
}
dation—is for a vaccine that targets
pneumococcal disease, a major
cause of pneumonia and meningitis,
which kills as many as 1 million children annually. By January 2009, the
GAVI Alliance had approved support
for introducing the pneumococcal
vaccine in 11 countries, mostly in
Africa. Rwanda and Gambia are expected to receive the first shipments
later this year.
on the whole, enjoy longer or healthier lives than people
in some less well-endowed nations. Costa Ricans, for example, are as healthy as people living in the U.S.—in spite
of spending one-tenth as much on healthcare on average.
Something as simple and inexpensive as a sheet of paper can produce major improvements in health outcomes.
In one recent pilot study, a safety checklist developed by
WHO lowered deaths and complications during surgery
by a third. (See sidebar “Safer Surgery.”)
However, some essential medical technologies and
pharmaceuticals—such as vaccines to immunize children
against bacterial diseases—are expensive and time-consuming to develop. One possible solution now being tested
offers vaccine makers a guaranteed market in exchange for
advance funding. (See sidebar “A Promise to Buy.”)
Health Entrepreneurs
Market incentives might also be the key to attracting and
retaining healthcare workers. Many countries currently
rely on volunteers to provide basic healthcare, and these
workers get discouraged when they don’t have the skills
and equipment they need, much less a salary. “Franchise”
models such as the VisionSpring reading-glasses initiative
provide volunteers not only with training and tools but
also with an opportunity to earn money providing health
services to others.
Garrett developed a similar franchise model, called
Doc-in-a-Box, with architects at Rensselaer Polytechnic
Institute. Doc-in-a-Box is a shipping container retrofitted to serve as a ready-made primary-care clinic. At such
a clinic, workers could examine patients, dispense drugs
and administer vaccines and screening tests. The workers running the clinic would charge for their services and
would quickly make back their initial investment in training and equipment. “The average poor person in the third
world is an instinctual entrepreneur,” Garrett says. Tapping into that motivation could create an army of healthcare workers dedicated to their jobs.
In the end, only a combination of approaches can provide healthcare around the world.
society & culture
87
Sharing the Wealth
of Data
B
y the late 1990s, avalanches of data
were pouring into GenBank—the
genetic sequence database operated by the U.S. National Institutes
of Health. In 1999 GenBank contained about two billion base pairs.
That number jumped to 11 billion
in 2000, nearly 45 billion in 2004
and nearly 86 billion by 2008. As
that database and many others grow, it becomes increasingly valuable to share knowledge, but doing so becomes
ever more difficult. Speed makes up part of the problem,
but policy hurdles also block the way.
Around 2003 the speed of sharing data concerned Wu
Feng, then at Los Alamos National Laboratory and now an
associate professor in the departments of computer science
and electrical & computer engineering at Virginia Tech in
Blacksburg. Feng knew that the number of bases in GenBank was growing faster than the ability to search them,
especially with the popular basic local alignment search
tool, better known simply as BLAST. So Feng and his colleagues created mpiBLAST, which lets multiple computer
processors tackle the same sequencing query as a team.
This new software made sequence searches faster—often
several orders of magnitude faster—but Feng and his colleagues would soon be searching for more ways to increase
the speed of data sharing.
Meanwhile many other researchers pursued different
approaches to connecting biological and biomedical information around the world. Although making these data
connections demands solving technological and sociological challenges, the results can change the approach to basic
research and even the business of biotechnology.
Combining knowledge is
fundamental to innovation.
Doing it right requires
new technologies, policies
and ways of interacting
By Mike May
Illustrations by Brian Stauffer
88
Sharing Spreads More than Data
“Today more than ever, researchers recognize the impact
of sharing,” says Henry Rodriguez, director of clinical proteomic technologies for cancer (CPTC) at the U.S. National Cancer Institute (NCI). He adds, “Advances in science
and healthcare are made possible through widespread and
barrier-free access to research and the data produced by
that research.”
In fact Rodriguez sees at least five ways that data sharing benefits research. First, data sharing encourages open
scientific enquiry. “This lets conclusions from research be
validated or refuted by peers, and that adds more strength
society & culture
89
to the results,” Rodriguez explains. Second, sharing data
from past experiments triggers new ones. As Rodriguez
says, “Existing data can lead to new insights that the
first investigator might not have recognized.” He adds,
“Programs in genomics and all of the ‘omics are producing vast amounts of data, but connecting the data and
extracting knowledge from the data are critical.” Third,
Rodriguez points out that making data openly available
creates huge test sets that can be used to assess the quality of new informatics software. Fourth, combining information creates data sets that cannot be generated by any
individual. “Putting it all together is the key,” Rodriguez
says. Last, he believes that sharing data openly reduces
unnecessary duplication. “Some duplication provides rigor,” Rodriguez
says, “but accessing data from others
can also push science further.”
In part the very nature of biotechnology demands data sharing.
“Almost by definition,” says Kenneth
H. Buetow, associate director for bioinformatics and information technology at NCI, “biotechnology and biomedicine are international enterprises.” He
adds, “There are immediate challenges from that globalization, especially how to get continuity of information
and connecting information.”
Nonetheless, some information in biotechnology,
such as proprietary data generated inside biotechnology
and pharmaceutical companies, will never be readily released—at least not right after it’s collected. But that is not
necessarily the bulk of biotech information. “There are
tons of resources nowadays,” says Buetow, “that are precompetitive. So while this information is not necessarily
proprietary, it is a disadvantage if a company cannot access the information and has to generate it.” For example
he points out that genome-wide association studies could
be helpful to many researchers—in basic research and
business—even though the commercial value is largely
limited. “That information should be shared on a broad
scale,” Buetow says. “It is invaluable.”
Still, Buetow knows that some information will not
be made open to everyone. For example a pharmaceutical
company is not going to openly share information about
binding between a candidate drug and a disease target.
But even that information will need to be shared inside the
company. Likewise in a multinational clinical trial, data
might be shared between a pharmaceutical company and
a contract research organization or local physicians collecting data. As Buetow says, “Some data need to be bound
for intellectual property reasons or through licensing, but
I would argue that even that needs to be shared. The issue
there is: What is the legal framework under which you negotiate to get access?”
Obstacles to Interaction
In the late summer of 2008, NCI’s CPTC convened an international summit in Amsterdam to discuss data-sharing
challenges and solutions. (See sidebar “Outcomes from
Amsterdam.”) Although that group focused on proteins,
the challenges apply to sharing almost any sort of biotechnology data. According to Rodriguez, data sharing faces
three categories of challenges: technology, infrastructure,
and policy. “Moreover, each of those impacts the other
two,” says Rodriguez. So the challenges can be described
individually, but they interact in practice.
The technology challenge in molecular biotechnology
consists of several pieces. First, in genomics, proteomics
“… information should be shared
on a broad scale. It is invaluable.”
90
–Kenneth H. Buetow
and other fields, researchers use a range of technologies,
such as mass spectrometry, tandem mass spectrometry,
liquid chromatography and so on. That makes a variety
of data that must somehow be compared. Worse still, the
same instrument used in two labs can create different results just because the instrument gets calibrated in different ways. “So data from the same kind of instrument used
with the same reagents but in two different labs can pump
out data that are not comparable,” Rodriguez says. The next
technological challenge comes from the “flavor” of data
being used—raw or processed. The raw data is just like it
sounds, uncooked, not processed in any way, or as little as
possible. If the data are processed, different data sets can
only be compared when the exact processing can be taken
into account, and the data must be adjusted accordingly.
Even if a researcher can get raw data from an instrument,
that device could put the information in a proprietary format that is incomprehensible to other devices or analysis
packages. And that analysis makes up the last technological
challenge in data sharing. “Researchers use multiple computational tools—the algorithms that extract knowledge,”
says Rodriguez. Those algorithms pull out relationships
that might be missed otherwise, but it proves difficult to
compare data that were analyzed in different ways.
To get at the infrastructure behind data sharing, imagine a transportation analogy: Cars, trucks, trains, jets,
ships and so on make up the data; and garages, roadways,
waterways, skies and such make up the infrastructure. So
the infrastructure determines where the data can be stored
and the paths that data can take from one spot to another.
“No international or centralized network has emerged,”
Rodriguez says. “Since the ones available use their own
Outcomes from Amsterdam
W
hen proteomic experts gathered in Amsterdam on August 14, 2008, to attend the
International Summit on Proteomics Data
Release and Sharing Policy, they focused on ways
to get proteomic data into the public domain. “Our
primary focus was on policy,” says Henry Rodriguez, director of clinical proteomic technologies
for cancer at the U.S. National Cancer Institute.
One policy decision involved when data should
be released. In Amsterdam, Rodriguez and his colleagues concluded that it depends on the source
of the data. If the data come from an individual
researcher’s lab, the data should be released
when the work gets published. For large-scale
community projects designed to advance science
in general, however, the data should be released
as they are generated, provided that appropriate
procedures exist to control the data quality.
In Amsterdam, the experts also considered
what kind of data should be made available. “Raw
data are the data that should go into the public
domain,” Rodriguez says. “Even if you agree to
release raw data, though, they must be extremely
well annotated with metadata. That defines the
quality of the data itself.”
Although many details must still be resolved,
the intent is certain. “It is clear to me and others,”
Rodriguez says, “that data sharing expands and
expedites research findings, especially where they
are applicable to disease.”
fixed formats, researchers cannot gather information from
all of the sites.” He adds, “Today’s repositories are a benefit,
but it will remain problematic if they are not interoperable.”
Policy makes up the last category of data-sharing challenges. “In terms of proteomics,” Rodriguez says, “the
challenge here is really fundamental. It will be responsible
for establishing and ultimately enforcing the guidelines for
the proteomics community, including the requirements
for submitting data and the metrics that will be used to
determine the quality of the data.” For example, standards
should require researchers to provide the metadata that
explain the details behind the experiments that produced
the actual data.
For data related specifically to healthcare, other policy
considerations also arise. Patrick L. Taylor—deputy general counsel and chief counsel for research affairs at Children’s Hospital Boston and assistant clinical professor at
Harvard Medical School—writes often about data sharing,
and he sees several obstacles, such as avoiding misuse of
the data and creating a level playing field that takes into
account the goals of commercial interests and patients. He
says, “Managing access to data and its uses in ways that respect people’s privacy but meets everyone’s goals in public
health is a real challenge.”
So far, though, Taylor thinks that companies could
do a better job of sharing data. “Huge amounts of tissue
and data get collected in clinical trials,” he says, “but that
just gets banked away, used in for-profit directives, even
though the research subjects just volunteered.” Despite
that company–patient imbalance, Taylor adds, “I don’t
want to demonize companies. They operate in their own
environment.”
Moreover, Taylor does not encourage a forced approach to data sharing. Instead he wants to find ways that
encourage data sharing and help everyone along the way.
“We could create data pools and give companies some level
of access in exchange for sharing some of their own data.”
With such data pools, Taylor says, multiple companies
might not need to reproduce the same data, which they
do today.
Putting Sharing to Work
In some areas, technology already makes data sharing possible. (See sidebar “Putting Patients Together.”) One example is the cancer biomedical informatics grid, or caBIG,
which was started by NCI and still run by it. Buetow describes caBIG as the “information technology framework
that supports 21st-century biomedicine.” He adds, “It’s a
way that we can interconnect the entire biomedical enterprise using current-art information technology.” So caBIG
takes available technology and uses it to connect basic researchers, biomedical scientists, physicians and anyone else
interested in cancer—and, actually, healthcare in general.
society & culture
91
Just as others have to meet the challenges of sharing
proteomics data, caBIG developers needed to make it possible for users to access a range of data types and to make
sense of how they interact. Much of the problem revolves
around translation—finding ways that software can unravel all of the medical community’s vocabularies. To do this,
caBIG provides a range of web services that are designed to work with anything that connects to caBIG. “A key
component of caBIG is interoperability,” Buetow says. “We are technologically neutral. Information can come
from Oracle, a MySQL database and
others.” For example, caAdapter can
be mounted on top of a data resource
to make that information available on
the caBIG framework.
Virtually anyone around the
world can use the caBIG technology.
Some international biotechnology
operations are already underway.
For instance NCI formed a partnership with Duke University related to international clinical trials. “So Duke
established a partnership with the Beijing Cancer Hospital to get participation with Chinese colleagues,” Buetow says. “They are using caBIG so that a trial being run
in Durham, North Carolina, can recruit participants in
Beijing, China.”
In addition NCI developed a partnership with the Institute of Cancer Research in London. “They are installing a
framework called Onyx that will be interoperable with caBIG. So we can interconnect between the U.K. and the U.S.”
Despite being called a cancer grid, caBIG goes beyond
cancer. “There is nothing cancer-specific about it,” Buetow
“Managing access to data and
its uses in ways that respect
people’s privacy but meets everyone’s goals in public health is a
real challenge.”–Patrick L. Taylor
says. Instead NCI scientists hope that this system can draw
together a range of health professionals around the world.
“In developing countries in particular,” Buetow say, “this
technology could help scientists become part of a bigger
framework. These scientists could contribute their expertise to the field without building all of the components required in biotechnology or biomedicine.”
Speeding up Data Transmission
Many of the desired applications of data sharing, though,
still hit information bottlenecks. As Feng and his colleagues found with BLAST, sequence searches could run
faster by adding the parallel-computing capabilities of
mpiBLAST. But even mpiBLAST is not always enough.
Sequence searches—even when done fast—still produce large amounts of data, which are not easy to move.
So Feng and Pavan Balaji of the Argonne National
Laboratory worked with some colleagues to develop
ParaMEDIC, which stands for: parallel metadata environment for distributed I/O and computing. In fact,
I/O—the input/ouput, or simply getting information into
and out of computing resources—can really slow down
data sharing.
To get around that, Feng and Balaji use ParaMEDIC
to turn the original data into a code. With sequences, for
example, ParaMEDIC uses GenBank Identifiers, which
represent sequence strings. So instead of needing to grab
a long length of bases—cytosine, guanine, thymine, cytosine and so on—ParaMEDIC just uses an identifier.
To see how well ParaMEDIC could really work,
Feng and Balaji took on a tough problem. Scientists at
the Virginia Bioinformatics Institute at Virginia Tech
wanted to find the missing genes in 567 genomes from
microbes, which required 2.63 x 1014 sequence searches.
To do those searches, Feng and Balaji created a team of
researchers, plus eight supercomputers scattered across
the United States. The results consisted of 0.97 petabytes
of data—almost a quadrillion bytes. To add the I/O side,
they planned to send the results—by Ethernet—to Tokyo. Sending the data in the conventional way would
have taken about three years. With ParaMEDIC, the super computers cranked out the sequence searches, then
crunched the results into a GenBank Identifier code. That
crunching step turned the 0.97 petabytes into about four
gigabytes, or reduced the data by roughly 250,000 times.
As a result, the Feng and Balaji team computed the missing genes, sent the information from the Unites States to
Japan, and had computers in Japan turn the code back
into the original data—all in just 10 days.
This application could find lots of uses in biotechnology. “Say that you are a pharmaceutical company that
has petabytes of sequence-search data stored around the
world and you need to bring it to one place for some reason—back-up store or large-scale experiment,” Feng says.
“ParaMEDIC will enable the information to be shipped
and reconstituted in a fraction of the time that it would
take to recompute all the information locally.”
In general, sharing data will remain under development, probably indefinitely. New research tools and
growing data pools will require ongoing technological
advances to keep the sharing doable. With every advance,
though, sharing data will increase around the world.
Putting Patients Together
I
n 2004 a trio of M.I.T engineers—brothers Ben and Jamie
Heywood and long-time friend
Jeff Cole—founded PatientsLikeMe.
In fact, this project really started
in 1998, when another Heywood
brother, Stephen, was diagnosed
with amyotrophic lateral sclerosis
(ALS), often called Lou Gehrig’s
disease. Although ALS is always
fatal, slowly destroying the central
nervous system, the Heywoods
started looking for ways to give
Stephen the best life that he could
have. In 1999 Jamie founded the
ALS Therapy Development Institute
to speed up the generation of new
treatments. Beyond finding new
molecules, though, the Heywoods
and Cole wanted to do even more.
92
As described on the PatientsLikeMe
website: “Our goal is to enable
people to share information that
can improve the lives of patients
diagnosed with life-changing diseases. To make this happen, we’ve
created a platform for collecting
and sharing real world, outcomebased patient data (patientslikeme.
com) and are establishing datasharing partnerships with doctors,
pharmaceutical and medical device
companies, research organizations
and non-profits.”
This work goes beyond ALS. In
fact, PatientsLikeMe plans to soon
cover more than 50 diseases. It
already provides communities for
people with depression, HIV/AIDS,
multiple sclerosis, Parkinson’s dis-
ease and other afflictions. Perhaps
most important of all, PatientsLikeMe reveals some of the breadth
behind the ways that people can
collect and distribute information.
“PatientsLikeMe consists of groups
of people coming together to share
data in dramatically new ways,”
says Patrick L. Taylor, deputy
general counsel and chief counsel
for research affairs at Children’s
Hospital Boston and assistant clinical professor at Harvard Medical
School, and a well-known expert on
data sharing. “These data become a
source of further data sharing. It’s
patient-specific, phenotypically interesting, longitudinal data shared
by patients themselves.”
society & culture
93
Feeding the world requires more than genetic modifications, because much of the trouble arises from
social and political constraints By Emily Waltz
{
94
O
n a summer day
in 1997 Dennis Gonsalves, a
plant pathologist
at Cornell University, boarded a
flight to Thailand with papaya plants
in his carry-on luggage. He and his
colleagues had spent a decade genetically altering the plants to resist
a lethal virus called ringspot, which
was destroying papaya crops worldwide. The technology was working
in Hawaii—it eventually saved the
state’s papaya industry—and officials
at Thailand’s Department of Agriculture had asked Gonsalves to bring
his plants to Thailand to transfer the
technology to varieties there. It was
urgent. Thailand had already lost half
of its papayas, a staple food that many
Thai people eat three times a day.
Gonsalves and his Thai colleague
Vilai Prasartsee set up experiments
at the Thai Department of Agriculture’s research station in Tha Pra in
the northeast province Khon Kaen.
Within two years, the group had
grown rows of papaya trees nearly
100-percent resistant to the ringspot
virus. “They were beautiful field trials,” Gonsalves says.
In 2004 Gonsalves’ team was
working toward regulatory approval when activists from Amsterdam-based Greenpeace broke into
the site wearing respiratory masks
and pulled the fruit off the trees.
Pre-alerted members of the media
snapped pictures, and the activists
accused the research station of illegally distributing seeds. Two months
later Thailand’s prime minister ordered the destruction of all genetically modified (GM) crops in the
country and banned all GM field trials. Workers at the Tha Pra research
From ruins to rainbows: Dennis Gonsalves developed a genetically
disease-resistant papaya—the rainbow papaya—that saved this fruit
in Hawaii but hit a wall of Greenpeace muckraking in Thailand.
}
station chopped down the papaya
trees and buried them in pits.
The remainder of Gonsalves’ virus-resistant papaya seeds have sat in
a locked refrigerator for the past five
lege and author of Starved for Science:
How Biotechnology is Being Kept Out
of Africa. Some African governments
think they should do the same. Such
governments also fear that if they
One-third of the African
population is chronically hungry.
years as ringspot has decimated Thailand’s papayas. Villagers near the research station still ask Prasartsee for
GM seeds, she says, but she cannot
give them any. “I know in my heart
that the northeast farmers would love
to have this papaya,” Gonsalves’ wife
Carol recently wrote in a letter to him.
Carol had worked in her husband’s
lab, accompanying him to Tha Pra.
“As I sit here writing, the sadness just
envelops me, and tears are streaming
down my face.”
Continental Clashes over Crops
{courtesy of dennis gonsalves}
Hungry for GM Crops
The extreme regulatory precaution
taken by some developing countries
like Thailand has thwarted the efforts
of countless researchers who hoped
to bring GM crops to hungry people.
“The barriers have prevented scientists from making the impact they
could have had,” says Roger Beachy,
president of the Donald Danforth
Plant Science Center in St. Louis, Mo.
A global map of GM crops shows
the world’s caution. Nearly 86 percent
of all transgenic crops are grown in
only four countries: Argentina (the
second largest GM-crop grower in the
world), Brazil, Canada and the United
States (the world’s leading GM-crop
grower). Europe’s lead in questioning
the technology has influenced much
of the rest of the world. “There’s a
natural deference to the way Europe
does things,” says Robert Paarlberg,
a political scientist at Wellesley Col-
grow transgenic crops, Europe will
stop accepting their food exports. Although according to Sharon Bomer,
Executive VP of the Food and Agriculture Division of the Biotechnology
Industry Organization, attitudes are
starting to change.
It is a fair concern since GM crops
and foods remain controversial in the
European Union (EU). In February
2009, in fact, EU experts came to a
stalemate when asked to approve the
planting of two kinds of GM corn.
Nonetheless, a range of GM products—such as specific types of corn,
cotton, soybeans and so on—are
approved for use as food and feed.
Recent news of genes from GM corn
appearing in traditional crops in
Mexico, however, will probably fan
the GM hesitation in the EU.
In general, wealthy nations can
get away with repudiating GM crops
because they know they will remain
well fed without new technology, says
Paarlberg. Not so in developing countries. One-third of the African population is chronically hungry. China
over the past few years has been tapping its rice stockpiles, and by 2020
it will have to increase its grain production by about 25 percent to feed its
growing population.
Europe has rejected transgenic
crops with tight regulations. But the
barriers in developing countries are
as much about under-regulation as
over-regulation. Developing coun-
tries often lack the scientific expertise
needed to draw up Euro-style biosafety laws. Without some kind of process
in place, crop developers have no clear
path for regulatory approval—effectively a ban on transgenic crops.
Meanwhile discouraged publicsector scientists in the United States
have stopped asking for grants for
field trials. “Many of us in academia
have shied from attempting to develop products for the market and have
stuck to conducting fundamental research because product development
appears out of reach,” Beachy says.
Golden Rice to the Rescue?
This downtrodden field needs a success story, says Gonsalves, who now
works for the U.S. Department of
Agriculture. “We just need one example,” he says. The creators of Golden
Rice hope to provide it. Golden Rice
has been modified to contain vitamin
A, and after eight years of political
delays, field trials finally began in the
Philippines in 2008. “We will prevail
in this project, and we are going to
get it to the people,” declares Adrian
Dubock, who is part of the Golden
Rice Humanitarian Board.
To avoid situations like what Gonzalves faced, some research groups
are taking a proactive approach. The
Danforth Center, for example, has
created a Biosafety Resource Center
that is addressing regulatory concerns
in tandem with their development of
GM crops for developing countries.
For Vilai Prasartsee in Thailand,
the barriers surrounding transgenic
papaya, particularly the efforts of
anti-GM activists, have been mentally exhausting, she says. This summer she plans to finish one last papaya project—a non-GM variety that
shows some resistance to the ringspot
virus. “I want to release these seeds to
the farmers and then retire,” she says.
“I hope Greenpeace doesn’t come.”
society & culture
95
Silver lining in Sao Paulo sugarcane:
This cane compost gets transformed
into biofuel and fertilizer.
The Beauty of Biomass
from lignocellulosic biomass. Several
companies have explored plans to
produce ethylene—one of the most
common precursor chemicals—from
bio-based sources.
Plant material—often wasted—could fuel 8 percent of the world’s energy needs by 2020
A
By Bill Caesar, Nicolas Denis, Jens Riese and Alexander Schwartz
96
grown specifically to produce energy
or chemicals. Finally, forest biomass
could also be used because current
forest operations produce waste wood
and, later, sawdust that can be converted to energy or chemicals.
Based on existing and expected
regulatory targets we project that the
energy created with biomass will at
least triple between 2005 and 2020.
These projections for energy from
biomass will require supplies of 2 billion tons a year. Given an estimated
3.3 billion tons of sustainable biomass
available in 2020 (based on a McKinsey & Company land use and biomass
model), the regulatory targets seem to
be reasonable from a supply potential
point of view, even assuming fairly
of energy must come from renewable
sources by 2020.
A big advantage of bioenergy
plants over other renewables is that
biomass, unlike sunshine and wind,
is easily stored. This means that biomass provides a constant, predictable
supply of energy and needs no backup
capacity. For energy producers, using
biomass as a feedstock allows them to
hedge price risks in their fuel supply
and meet increasingly strict limits on
carbon emissions. Together these developments make biopower and biofuel production increasingly attractive
as investments based on both commercial and environmental thinking.
The variety of biomass sources is
balanced by the range of applications.
Overcoming Obstacles
A big advantage of bioenergy
plants over other renewables is
that biomass, unlike sunshine
and wind, is easily stored.
rapid growth in demand for food and
only conservative increases in agricultural productivity.
Biomass Benefits
In most regions regulation is the
driving force behind biomass development. Many governments want to
depend less on foreign oil and reduce
greenhouse-gas emission, and most
are also keen to support local farmers. Moreover, regulators in many
countries already use subsidies,
feed-in tariffs or supply mandates
to encourage the use of biopower
or biofuels. In Europe, for example,
regulations require that 20 percent
Heat and power, for example, can be
produced by burning biomass. It can
also be co-fired in existing coal power plants, which is one of the simplest
available means of tapping its advantages. Existing coal power plants can
be co-fed with as much as 30 percent
biomass with no, or little, new investment, as already demonstrated by
some European utilities. Companies
could also build dedicated biomass
power plants, but that requires new
investment and related higher-business risks.
Biomass will also be an important
source of transportation fuel. McKinsey research indicates that the current
{© carlos cazalis/corbis}
mid rising concerns over oil supplies and climate
change, alternative
sources of energy
are becoming increasingly important. Biomass is one
with exciting environmental and
commercial potential. Research with
our colleagues at McKinsey & Company suggests there are sufficient sustainable sources of biomass—which
includes all plant matter—to meet 8
percent of world energy demand by
2020 and create a market worth hundreds of billions of dollars. Biomass
could also be a significant sustainable
feedstock for producing bulk chemicals and plastics. It won’t solve all our
energy and resource problems and
challenges lie ahead, but biomass is
well positioned to play a major role in
the future sustainable world economy.
Biomass for energy and chemicals
comes from four main sources. Food/
feed crops could be used for bioenergy production. Some food/feed
plants—for example corn, sugarcane
and wheat—contain fermentable carbohydrates, and other food plants—
such as soy and rapeseed—contain
vegetable oils. These crops though,
often require carbon dioxide–intense
fertilizer and can be costly to produce
and convert.
Biomass can also come from agricultural residues, which are “leftovers”
from normal agricultural production,
such as corn stalks and bagasse, the
waste from processing sugarcane.
Farmers often leave these residues
behind, but about 30 percent could
be taken from fields without damaging soils. Biomass can also come from
energy crops, which are plants—such
as switchgrass, miscanthus and fastgrowing trees, including poplar—
annual use of 19 billion gallons of biofuels—14 billion gallons of bioethanol
and 5 billion gallons of biodiesel—
could grow to 70 billion gallons—10
and 60 billion gallons of biodiesel and
bioethanol, respectively—by 2020.
Moreover these figures assume a shift
from food crops to inedible lignocellulosic biomass as the primary feedstock for bioethanol.
Biomass can also be used as a substitute for fossil-fuel feedstocks in the
production of chemicals and plastics.
Indeed, some chemicals, such as vitamin B2 and citric acid, are already
fermented from sugar and starch.
Bioplastics, such as polyhydroxybutyrate (PHB) or polylactic acid (PLA),
are already available in large scale.
Going forward there will be synergies
between biofuel-production technology and biochemicals; since the first
step in their fermentation is the same,
large-scale investments in developing biofuel also speeds up the commercial expansion of biochemicals
Although the world has almost twice
the biomass it needs to supply 8 percent of our energy requirements in
2020, significant challenges lie ahead.
Regional supplies for instance do
not always match regional demand,
so large amounts of biomass might
need to be transported, requiring
the development of adequate supply
chains. Moreover McKinsey models
of the potential for biomass assume
that the biomass will come only from
sustainable sources. As the value of
biomass rises, however, some groups
might try to expand supply through
deforestation, and changes in land
use that would compromise biodiversity or increase greenhouse-gas
emissions. Preventing such negative
consequences will depend on welldesigned and well-enforced regulations. Finally, energy crops still need
to be optimized, agricultural practices must be adjusted to the new plants,
and biorefineries that use non-food/
feed sources yet need to grow out of
the pilot phase. In some cases, new
harvesting machinery will also have
to be built.
Given the advantages of biomass
to a world in need of new, sustainable
energy sources, we are confident that
these challenges can be overcome. Indeed our research shows that biomass
is already starting to fulfill its considerable potential to the needs of the
world economy without significant
cost to the environment.
Bill Caesar is a principle in McKinsey’s
Atlanta office, Nicolas Denis is an associate
principle in the Brussels office, Jens Riese is
a principle in the Munich office and Alexander Schwartz is an expert in the climatechange practice of McKinsey in Vienna.
society & culture
97
}
around to finding out exactly how the
ormia hears a cricket.
Twenty years later Daniel Robert
arrived as a new postdoctoral student in my lab at Cornell University
in Ithaca, N.Y. Robert had worked
on hearing in locusts for his doctoral
thesis, in Switzerland. We chatted
about potential projects and remembering Cade’s work, I suggested that
he head to the southeast United States
to bring ormia back to my lab—where
I’ve spent most of my career studying
the acoustic communication of insects. That very cold day in February,
Robert liked the idea of warming up
in Florida, so he agreed to take on the
project of determining the kind of ear
that permits this fly to hear crickets
and home in on them.
Kudos for Collaborating
Big Ideas from
Small Places
By Ronald R. Hoy
A fly—plus animal behavior and nanotechnology—
teaches us how to hear the world around us
A
small yellow fly
lands on the back
of a common field
cricket. To entomologists, this fly
is Ormia ochracea.
It has no common name, so we’ll
simply call it the ormia fly. In order
for this fly to reproduce, a female
finds a cricket, deposits her larvae,
which burrow into the cricket’s
body, grow, mature and then dig
their way out so the maggots can
pupate—killing the host in the act
of egress. Beyond revealing another
98
of nature’s secrets, this gruesome
scene launched a completely unexpected trip into biotechnology.
This journey began in the 1970s,
when Bill Cade—then a graduate
student at the University of Texas
at Austin and now president of the
University of Lethbridge in Alberta,
Canada—discovered the parasitic
action of ormia on crickets. Moreover Cade showed that these flies
find their cricket host by hearing
and homing in on the male cricket’s
calling song—that familiar summer
chirp. Nonetheless Cade never got
When Robert returned with enough
flies to start a colony, he started
looking for the ears. For Robert, this
turned out to be relatively easy. His
trained eyes homed in on a pair of
thin, transparent membranes just
behind the fly’s head that look a lot
like the “eardrums” of crickets and
grasshoppers—some of the many insects that I’d studied over the years.
Sure enough, they turned out to be
this fly’s ears.
The next step was to measure
this ear’s response to sound—in ormia’s case, to cricket-like sounds.
For measuring vibrations, the gold
standard is Doppler laser vibrometry
(DLV), which engineers use to study
mechanical structures—for example,
spinning hard drives. With a price
tag of $150,000 or more, though,
DLV instruments exceed the budget of most biologists. Added to that
operating one takes technical knowhow—like a mechanical engineer’s
knowledge. My lab lacked the instrument and the engineer.
Around this time a department
party brought together faculty, family and close friends. Carol Miles, another postdoc in my lab, brought her
husband, Ron to the party. As it turns
out, Ron is a mechanical engineering
professor from Binghamton University, about an hour away from Cornell. We soon learned that Ron Miles
is an acoustics expert—one who has
a DLV. Moreover Miles once worked
at Boeing, where he used DLV to
study the vibrations of various parts
of the 747. At that party, Miles started
thinking about moving his attention
from problems large to small—from a
jumbo jet to a fly’s ear. We developed
an ongoing collaboration.
Working together, we quickly
revealed that an ormia’s ears—each
about half a millimeter across—provide great sensitivity and directional
… this fly-ear design was remarkable
as a piece of acoustical engineering.
(Images:© Dennis Kunkel Microscopy, Inc ,Samples provided by Dr. Neil Evenhuis, Bishop Museum & Dr. Andrew Mason,
University of Toronto / lower right: reprinted with permission from Miles RN, et al, Journal of the Acoustical
Society of America, 125(4):2013–2026, 2009. © 2009, Acoustical Society of America.)
{
Parasite to prosthetic:
The ormia fly showed a scientist
and an engineer how they might
make a better hearing aid.
{
Insect nanotech: The mechanics
of a fly’s ear (top) inspired this
prototype microphone (bottom).
}
information with which this fly can
locate a singing cricket with unerring
accuracy. Even more interesting, the
design of this fly’s ears is unique—at
least among any known in the animal
kingdom. This fly’s paired eardrums
are anatomically and mechanically
coupled to each other, such that they
form a resonating system in which
the two eardrums vibrate in a push–
pull manner.
Bioacoustics to Biotechnology
This was a very nice discovery, delighting us biologists because we
could claim to have uncovered a new
mechanism for directional hearing.
Plus we had solved the ormia-ear
problem. Moreover Miles realized
immediately that this fly-ear design
was remarkable as a piece of acoustical engineering. The ears are really tiny, yet they are very sensitive to
sound volume and direction. Miles
wondered whether these features
could spawn a new kind of directional microphone—one on the order of 1 millimeter across, built of a
thin silicon membrane and designed
to respond to directional sounds as
can an ormia’s eardrums. Modern
nanofabrication facilities, like the one
in Cornell’s engineering college, easily make silicon devices on this scale,
and cheaply, too.
Miles’s insight was to apply a
strategy called “biomimicry.” This
means taking a biological system for
solving some problem—like sound localization in an insect’s auditory system—and applying similar features to
a device for human applications.
One obvious application for an ormia-inspired directional microphone
is in the field of hearing-aid technology. Currently, directional hearing
aids are very expensive, but a hearing aid in which several directional
microphones could be mounted and
that fits into the ear canal—the most
popular and desirable type—would
constitute a design breakthrough.
The key to commercialization is cost,
which could be one advantage of an
ormia-microphone design. Since the
microphone membrane would be
made of a very small chip of silicon,
fabricated en masse by nanofabrication techniques, the promise of a
cheap directionally sensitive microphone might be possible. Although
it is still early days in this project, its
progress is promising.
It is very satisfying as a biologist
to realize that a discovery made in an
animal—especially one completely
neglected except by entomologists—
turned out to be interesting for its
unique biological features and might
form the basis for a biomedical-engineering project that could enhance
the quality of life for the hearing impaired. As this story shows the pursuit of knowledge for its own sake,
no matter how seemingly trivial or
irrelevant it might sound at first, may
yield solutions for problems, which
scaled up, just might be put to good
use by people.
Ronald R. Hoy is the David and Dorothy
Merksamer Professor in Biology at Cornell
University.
society & culture
99
By Luiz Inácio Lula da Silva, Fernando Haddad & Miguel A. L. Nicolelis
Illustration by Aaron McKinney
L
An Innovation Call
to Arms: Brazil’s Option for Science Education
A nationwide plan to enfranchise all citizens through
education will allow Brazil to reach its full potential
100
ess than a quarter of a
century after emerging
from a military dictatorship, Brazilians have
built a stable and vibrant
democracy in which
more than 80 million voters freely decide the future of their beloved country in each and every election. Lately,
by becoming a world leader in food
production, spearheading the search
for biofuels as a new source of renewable energy and seeking ways to grow
its economy while still protecting its
unique natural ecosystems, Brazil has
started to address a broad range of
difficult and unavoidable issues that
currently challenge most developing
nations worldwide.
Brazil had to work arduously during the past decade to achieve its present economic stability and prosperity.
Yet at this crucial juncture of its history, the country faces the daunting
task of translating its political and
economic stability into social poli
cies and programs that can improve,
at long last, the quality of life for millions of Brazilians who, until very
recently, would have had no hope of
sharing in the country’s enormous
wealth. But how do you empower millions of citizens, particularly young
people, to become true participants in
a global society that is continuously
changing at a stunning pace as a result of the never ending incorporation
of new knowledge and technologies?
The answer is straightforward:
systemic high-quality education, disseminated to reach the entire territory, including the most remote and
impoverished communities of this
vast country, so that all Brazilians can
acquire the means to become creative
and critical thinkers, capable of developing their own opinions and becoming true contributors to solve the
challenges involved in constructing a
fair and democratic society.
Three tenets serve as the main
foundations of the Brazilian Plan for
the Development of Education (PDE):
systemic, territorial and empowering
education. Enacted by the current
administration, this plan outlines a
broad range of executive measures
aimed at rescuing the quality, reach
and long-term impact of the Brazilian
education system.
In addition to promoting actions
to improve the basic training of teachers, to establish a national evaluation
system, and to define the basis for a
close collaboration between the federal government and the states and
municipal authorities, the PDE pro-
the-art science as an agent of social
and economic transformation for
one of the least-developed regions of
the country. Among its social initia
tives, the Edmond and Lily Safra International Institute of Neuroscience
of Natal (ELS-IINN) has established
a science-education program that today reaches 1,000 children enrolled in
one of the poorest performing public
education districts in Brazil.
By bringing their vision, efforts
and experience together, the Brazilian government, through the Federal
University of Rio Grande do Norte,
and the ELS-IINN have partnered
to establish the Natal Campus of
the Brain and to use this multidisciplinary, scientific-social initiative to
launch the Alberto Santos-Dumont
Brazil is sending a loud message to its
citizens and the global community that this
giant of the tropics has finally awakened and
is now ready to fulfill its potential as a true
country of the future.
vides, from its fourth year on, an extra 19 billion reals (almost $11 billion)
earmarked for education.
The PDE also enacts new directives and guidelines for the creation of
the Federal Institutes for Education,
Science and Technology (IFET in
Portuguese), which will result in the
establishment of a network of 354 institutes dedicated to teaching science
and technology to high schoolers and
training thousands of new teachers in
the public education system.
Inspired by the example set by
Alberto Santos-Dumont, the great
Brazilian inventor and aviator, who
in 1901 became the first man to fly a
controllable airship powered by an
engine, a group of Brazilian scientists decided in 2003 to establish, in
the city of Natal, in the northeast of
Brazil, a research institute dedicated
to using the production of state-of-
Science Education Program for Children. The goal of this initiative is to
enroll one million children from the
public school system nationwide in
the most comprehensive science and
technology education program in
Brazilian history.
By clearly choosing to disseminate
high-quality education and science
education in particular throughout
its entire territory, Brazil is sending
a loud message to its citizens and the
global community that this giant of
the tropics has finally awakened and
is now ready to fulfill its potential as a
true country of the future. For Brazilians, a bright future starts now.
Luiz Inácio Lula da Silva (top) is the president of Brazil. Fernando Haddad is Brazil’s
minister of education (left). Miguel A. L.
Nicolelis (right) is scientific coordinator of
the ELS-IINN and co-director of the Center
for Neuroengineering at Duke University.
6 WorldView 09

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