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ECONOMICECONOMIC PERSPECTIVESPERSPECTIVES eOCTOBER 2005

THETHE PROMISEPROMISE OFOF BIOTECHNOLOGYBIOTECHNOLOGY

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Economic Perspectives / October 2005 eJOURNALOURNAL USA ABOUT THIS ISSUE

ew technologies, whether they are in organic waste and bacteria engineered to break Nmedicine, industry, or agriculture, down environmental pollutants to crops that often initially generate public skepticism. add vitamins to what we eat and novel drugs Nowhere is this currently more evident than for treating human diseases such as Alzheimer’s in biotechnology, where issues of health and and diabetes. environment are hotly debated. As National Science Adviser John Marburger “Bioconservative intellectuals are fully writes in the introduction to this publication: cognizant of the tendency for our species to “Our aim is not simply to understand disease, be suspicious of the new and the strange, and but to cure it; not only to consume whatever they clearly want to harness that suspicion as a edible we find, but to make it safer, more strategy to restrain biotechnological progress,” nutritious; not just to harvest nature’s random writes author Ronald Bailey in his 2005 book products for our manufacturers, but to make Liberation Biology. them stronger, safer, and more adapted to our But as Bailey points out, public opinion needs.” is highly changeable, and the benefits from We hope that readers will take the time to technological progress are not always well review each of the articles and gain from them understood. He cites in vitro fertilization and a greater understanding of the tremendous optical laser technologies as just two examples potential that biotechnology offers for where the public had fears and/or doubts but improving the quality of life for all people now broadly supports the technologies and throughout the world. appreciates the huge gains from them. This issue of Economic Perspectives explores some of the most promising applications of biotechnology, from microorganisms The Editors engineered to produce hydrogen gas from

eJOURNALOURNAL USA Economic Perspectives / October 2005 ECONOMIC PERSPECTIVES U.S. DEPARTMENT OF STATE / OCTOBER 2005 / VOLUME 10 / NUMBER 4 http://usinfo.state.gov/journals/journals.htm

CONTENTS THE PROMISE OF BIOTECHNOLOGY

4 Introduction 17 Plant Biotechnology: Advances in JOHN MARBURGER, DIRECTOR, OFFICE OF SCIENCE AND Food, Energy, and Health TECHNOLOGY POLICY, EXECUTIVE OFFICE OF THE PRESIDENT RICHARD HAMILTON, CHIEF EXECUTIVE OFFICER, CERES, INC.; RICHARD B. FLAVELL, CHIEF SCIENCE OFFICER, 6 Global Challenges and Biotechnology CERES, INC.; ROBERT B. GOLDBERG, PROFESSOR OF MOLECULAR, JENNIFER KUZMA, ASSOCIATE DIRECTOR, CENTER CELL, AND DEVELOPMENTAL BIOLOGY, UNIVERSITY OF FOR SCIENCE, TECHNOLOGY, AND PUBLIC POLICY, CALIFORNIA, LOS ANGELES UNIVERSITY OF MINNESOTA Advances in agricultural biotechnology will result in Governments and other organizations need to invest in crops that have improved tolerance to drought, heat, biotech research and development tailored toward and cold; require fewer fertilizer and pesticide products that can help developing countries. applications; and produce vaccines to prevent major communicable diseases. 10 Sidebar: A Chemical Reaction for Biotechnology: The 2005 Nobel Prize 21 Sidebar: Biotech Bugs Cheryl Pellerin, State Department Science Writer 22 Designing Novel Materials and 11 The Transforming Power of Medical Molecular Machines Biotechnology SHUGUANG ZHANG, ASSOCIATE DIRECTOR, CENTER BILL SNYDER, SENIOR SCIENCE WRITER, FOR BIOMEDICAL ENGINEERING, MASSACHUSETTS VANDERBILT UNIVERSITY MEDICAL CENTER INSTITUTE OF TECHNOLOGY The future refinement of “targeted therapies” aimed at One day mankind may be able to use nano devices the biological underpinnings of disease should to repair body parts or to rejuvenate the skin, dramatically improve drug safety and efficacy, and the enhance human capabilities, harness the unlimited development of predictive technologies may lead to a solar energy, and achieve other feats that seem new era in disease prevention. impossible today.

15 Sidebar: The Race Against Gene Doping 27 Sidebar: Whither Nanotechnology? Huntington F. Willard, Director, Duke University Akhlesh Lakhtakia, Distinguished Professor of Institute for Genome Sciences and Policy, and Vice Engineering Science and Mechanics, Pennsylvania Chancellor for Genome Sciences, Duke University State University Medical Center

Economic Perspectives / October 2005 eJOURNALOURNAL USA 29 The International Rice Genome 36 U.S. Regulation of Agricultural Sequencing Project: A Case Study Biotechnology C. ROBIN BUELL, ASSOCIATE INVESTIGATOR, INSTITUTE FOR GENOMIC RESEARCH 38 Glossary of Biotechnology Terms A “map” of rice’s genetic makeup will enable rice breeders to accelerate their breeding programs and 42 Bibliography develop more hearty rice varieties, and farmers to improve their growing methods and extend their 44 Internet Resources growing seasons.

32 The Birth of Biotechnology: Harnessing the Power of DNA DINESH RAMDE, THE ASSOCIATED PRESS The speed at which the biotech industry took off, the magnitude of its success, and the scope of its impact have surprised even its pioneers.

eJOURNALOURNAL USA Economic Perspectives / October 2005 INTRODUCTION

iotechnology is the most recent step in Life, in other words, can be surveyed today for the humankind’s long endeavor to use nature’s own first time in history throughout its entire spectrum, from Bprocesses to advance the human condition. the smallest to the largest scales. The tools that made this The word itself joins knowledge to practice, science possible draw heavily from other fields of science and to technology. We might have used it to describe the require large investments that normally only governments emergence of agriculture, or of pharmacology, or even can make. The insights revealed by these tools, however, the training of athletes—activities that have grown from can be analyzed and exploited with relatively modest ancient roots into exotic and very contemporary forms. resources. That is just as well because small-scale nature is In each case, accumulating knowledge of nature has stunningly complex. We are nowhere near understanding suggested ways of making life safer, healthier, and more all that we can see, and even with powerful new tools, productive. While biotechnology is a relatively new word exploring the terrain of life will consume the energies with narrower connotations, it is good to keep in mind its of entire communities of scientists. The territory is vast, link to the past, especially when speaking of its benefits for and the mapping and developing of it are international cultures separated from the traditions of modern science. enterprises. Biotechnology begins with the study of plants and This vastness of the universe of living things extends animals, intricate and beautiful even in their smallest not only in numbers of species and types of organisms and features. Great artists have struggled to capture the details the varieties of chemicals that make them function, but of birds, flowers, and insects that underlie their wonderful also to the processes of life. From the numerous systems variety. Each advance in our ability to see things at a of chemical reactions, material transport, information smaller scale has brought new wonders into view, new flow, and mechanical support at the smallest scale to the patterns and behaviors that explain the mysteries of functions of organs and the behavior of organisms at the larger parts. During the past quarter-century, these the largest, the sheer volume of information required to advances have brought us to one of nature’s major understand even simple life-forms is staggering. It is not milestones: We can now “see” the elemental atoms of enough to see these things. To comprehend them requires which all normal matter is constructed. Below this level storing a huge amount of information, retrieving it is a yawning gap to the dense kernels of atomic nuclei, a efficiently, and processing it to test ideas about causes and hundred thousand times smaller than the smallest atom, effects. Biology can only now produce its own technology where a new world—an equally beautiful but lifeless because the technology of information has matured in our world—is being explored by physicists. era.

Economic Perspectives / October 2005 4 eJOURNALOURNAL USA Seeing small with X-ray diffraction, magnetic Biotechnology is the application of the three resonance, and electron microscopes, and thinking big ingredients to accomplish human goals. Our aim is with fast computers, gigantic databases, and wide-band not simply to understand disease, but to cure it; not transfer, are two of three ingredients that permit a “bio” only to consume whatever edible we find, but to make technology. The third ingredient is the ability to make it safer, more nutritious; not just to harvest nature’s things happen at the smallest scale. The means of doing random products for our manufactures, but to make so are varied, and they often recruit life’s own processes them stronger, safer, and more adapted to our needs. to execute our direction. This is an old idea, not unlike Nature’s complexity, once a barrier to these aims, is now the use of bees for pollination. Today we use bacteria revealed to us as a rich source of opportunities to achieve and viruses to carry out our microscopic husbandry. them. How we seize these opportunities for the good of But we also use lasers and tiny probes and activated humankind is what we call biotechnology.  molecules whose effectiveness we learned from laborious experiment. The manipulation of matter at this scale is John Marburger part of what nanotechnology is all about, and it is no Director accident that nanotechnology, information technology, Office of Science and and biotechnology are growing up together. They are convergent technologies, and they feed each other in a Technology Policy complex ecology of discovery, innovation, and increased Executive Office of the President human effectiveness.

eJOURNALOURNAL USA 5 Economic Perspectives / October 2005 GLOBAL CHALLENGES AND BIOTECHNOLOGY Jennifer Kuzma

AP/WWP/NREL A bus runs on diesel fuel made from soybeans.

Biotechnology, if used appropriately, has the potential to Science can only ascertain what is, but not what should provide more and healthier foods, reduce dependence on fossil be, and outside of its domain, value judgments of all fuels, and offer more effective cures for diseases. Enzymes that kinds remain necessary. can break down plant material into biofuels such as ethanol — Albert Einstein will eventually lead to the more cost-effective production of sustainable bioenergy products. A new bioengineered form of or centuries, humans have harnessed the power of rice bolstered with vitamin A may help reduce blindness stem- biological systems to improve their lives and the ming from vitamin defi ciency in developing countries. Fworld. Some argue that biotechnology began thou- But these and other applications carry risks that need to sands of years ago, when crops were fi rst bred for specifi c be addressed through regulatory and safety regimes. Govern- traits and microorganisms were used to brew beer. Others ments and other organizations also need to step in and invest defi ne the beginning of biotechnology as the emergence in biotech research and development tailored toward products of techniques allowing researchers to precisely manipu- that can help developing countries and assist these nations in late and transfer genes from one organism to another. building the capacity to benefi t from bio-innovation. The discovery of the structure of deoxyribonucleic acid (DNA) in the 1950s marks the start of this era. Genes are Jennifer Kuzma is associate directordirector of the CenterCenter for made up of DNA and are expressed into proteins, which Science, Technology, and Public Policy at the University of do chemical work and form structures to give us specifi c Minnesota. traits. In the 1970s, scientists discovered and used the power of natural “scissors”—proteins called restriction enzymes—to specifi cally remove a gene from one kind of organism and put it into related or unrelated organ- isms. Thus, recombinant DNA technology, or what most experts now label as modern biotechnology, was born. The pioneers of biotechnology could not have en- visioned our current abilities to engineer plants to resist disease, animals to produce drugs in their milk, and small

Economic Perspectives / October 2005 6 eJOURNALOURNAL USA particles to target and destroy cancer cells. However, THE ENERGY CHALLENGE, CLIMATE CHANGE, biotechnology is more than engineering—it is also a set AND THE ENVIRONMENT of tools for understanding biological systems. Genomics is based on these tools and is the study of genes and their Fossil fuels are a fi nite energy resource, and we are functions. We have determined the composition of, or “se- expending them more quickly than nature can replenish quenced,” the entire set of genes for humans and several them. Biotechnology has a role to play in the use of more other organisms using biotechnology. Genomic informa- renewable sources of energy. Biomass energy, for example, tion is helping us better to evaluate the commonalities is a carbon-neutral energy source, as plants eventually and diversity among organisms and human beings and to take as much carbon from the atmosphere as they release. understand and cure disease, even tailoring treatments to Researchers are engineering better cellulases—enzymes that individuals. can break down plant material into biofuels such as etha- Biotechnology, or really any technology, does not nol. Better cellulases will eventually lead to the more cost- exist in a vacuum. It is derived from human efforts and effective production of sustainable bioenergy products. affected by social, cultural, and political climates. Society Some believe that climate change will have the great- drives and regulates technology, attempting to minimize est impacts on the poor, who do not have the resources to the downsides and maximize the benefi ts. Many natural move or adapt when natural disasters strike or their and physical scientists would prefer that the separation surroundings change. Not only would a transition to between social and ethical concerns and science and tech- biomass energy have positive environmental effects; it nology be well defi ned. Recent controversies over the use could also lead to economic development in rural com- of genetically engineered organisms in food and agricul- munities all over the world. Farmers could grow crops for ture have illustrated that this boundary is not so clear. Not their food, feed, and energy needs. However, they must only are there safety concerns about genetically engineered have access to the technology that makes biomass con- organisms, but there are also cultural differences in accep- version possible. Getting technologies to rural areas and tance of the products. building capacity to operate such systems will be International contexts for technologies are important challenging. and should be considered. Biotechnology is not a pana- Other examples of the energy and environmental cea for global problems, but it is a tool that holds a great applications of biotechnology include microorganisms deal of promise if used appropriately. On the other hand, engineered to produce hydrogen gas from organic waste, there are social systems that are affected by new technolo- plants engineered to make biodegradable polymers, mo- gies and fears of creating greater divides between rich and lecular machines based on plant photosynthetic proteins poor if technology is not accessible to all sectors of society. to harness energy from the sun, bacteria engineered to With this context in mind, this article outlines several break down environmental pollutants, and biosensors de- global challenges and considers how biotechnology can be veloped to rapidly detect harmful environmental contami- harnessed to meet them in sustainable and equitable ways. nants. The environmental applications of biotechnology are often overlooked and underfunded, yet the sustainabil- ity of our planet in the face of an increasing population is an issue of utmost importance.

AGRICULTURE, FOOD QUALITY, AND SECURITY

Biotechnology has taken off in areas of food and agri- culture. For example, cotton, soybeans, maize, and other crops have been engineered to contain proteins from the bacterium Bacillus thuringiensis (Bt) that protectprotect them from insect pests. Bt crops are grown widely in many countries. The cultivation of Bt cotton in China has sig- nifi cantly reduced the use of chemical pesticides that are dangerous to human health, benefi ting rural farmers. Nati Harnik/AP/WWP On the other hand, there have been concerns associat- Pellets of plastic made of maize are poured into a dish.

eJOURNALOURNAL USA 7 Economic Perspectives / October 2005 ed with Bt crops. Starlink was a Bt maize variety approved treating human diseases such as Alzheimer’s and diabetes. only for animal feed in the United States, given questions Although the vast majority of people agree that cloning to about its potential to be a human allergen. However, it produce humans (reproductive cloning) is unacceptable, eventually contaminated some maize-based products in therapeutic cloning, in which the cloning process is used the human food supply. Also, the genes for Bt proteins only to harvest stem cells, is hotly debated. Therapeu- have been discovered in Mexican maize varieties, although tic cloning could supply stem cells that exactly match a Mexico has a moratorium on planting Bt maize. This patient, minimizing the serious risks associated with tissue contamination has caused concern because Mexico is the rejection. These methods hold great promise. However, geographic center of diversity for maize, and many want the ethical, cultural, and policy issues associated with to preserve native varieties for cultural and agronomic rea- them will continue to occupy scientists and politicians in sons. Therefore, in order to reap the benefi ts of genetically the foreseeable future. engineered crops, it is important that good international A fundamental application of biotechnology to medi- biosafety regimes be developed to avoid future mishaps cine is in drug discovery. Humans have discovered drugs and enhance confi dence in the use of these crops. from natural sources by trial and error since the begin- Healthier and more nutritious foods are also being ning of history. Now genomics and its companion fi eld developed via biotechnology. For example, more than 100 for proteins—proteomics—have allowed us to discover million people are affected by vitamin A defi ciency, which drugs more systematically. The automation of biochemical is responsible for hundreds of thousands of cases of blind- binding assays in small chips called microarrays enables ness annually. Researchers have engineered a variety of scientists to screen thousands of chemical compounds rice to supply the metabolic precursor to vitamin A. This for their effectiveness against disease-causing proteins in “golden rice” is being bred with local varieties to enhance a very short time. This high-throughput screening, as it its properties for growth in developing countries. Intel- is called, would not have been possible without years of lectual property hurdles have been overcome to distribute serious investment in basic biotechnology research. the rice for free to subsistence farmers—this is especially With microarray analysis, the activity of thousands important because the cost of seed could otherwise be of genes can be quickly measured. Many researchers are prohibitive. Researchers are developing other crops that harnessing this tool to determine early gene activity when have increased quantities of iron, vitamin E, essential amino acids, and healthier oils. For the future, additional applications of biotechnology to food and agriculture could prove useful. The United Nations Environment Program ranks freshwater shortages as the second greatest environmental problem, behind climate change, for the 21st century. Drought- and salin- ity-tolerant crops tailored to developing countries could greatly enhance food security in areas where a combina- tion of natural disasters and marginal land are sure to lead to famine in a given year. Through genomics and modern biotechnology, we are getting closer to understanding, identifying, and engineering the many traits that control water use and salt utilization in plants. Jay Laprete/AP/WWP A patient undergoes gene therapy.

HEALTH AND MEDICINE humans are infected with pathogens. Rapid, noninvasive Medical applications of biotechnology are better screens are envisioned for the future, and they will be known in the public’s eye. Stem cells and cloning have especially important for infections that require immediate gained unusual prominence in national and international treatment in order to reduce spread and save lives, such politics. Stem cells are the early-stage cells in an organism as infections resulting from a bioterrorist attack. Nano- that have been shown to give rise to different kinds of tis- sensors are being developed from particles that are about sues. They have successfully replaced or repaired damaged 50,000 times smaller than the diameter of human hair tissue in animal models, and they hold great promise for to detect protein and gene expression in individual cells

Economic Perspectives / October 2005 8 eJOURNALOURNAL USA in the body, thus allowing the assessment of the health sterile) or isolate the pharmaceutical crops (for example, in of cells at early stages of disease. The U.S. government is greenhouses). spending millions of dollars on nanosensors that can be THE CHALLENGES placed in the blood of astronauts to monitor continuously for space radiation exposure. It is striking that a number of the above examples relate Gene therapy, in which genes are delivered to specifi c to the Millennium Declaration, an agreement reached diseased organs or tissues in the body to overcome meta- in 2000 by more than 170 countries to address poverty, bolic defi ciencies or other disease, is another area of great economic development, and environmental preservation. promise. The use of viruses to deliver genes has shown Yet science and technology are seldom integrated with risks to human health, making trials with these viruses international programs focused on social and economic development. There has been signifi cant progress in meet- ing some of the goals of the Millennium Declaration, such as reducing poverty, increasing primary education and gender equality, and lowering child mortality. However, less progress has been made in fi ghting global disease and improving environmental sustainability. These are chal- lenges in which biotechnology can play a role. Investments in science and technology by any nation will eventually bear economic fruit. However, investments to address the social, political, cultural, and ethical issues surrounding applications of biotechnology are equally im-

Markus/Matzel/Peter Arnold, Inc. Arnold, Markus/Matzel/Peter portant. There are good ways to foster open dialogue on A micro device for a retina implant. such issues. We may never agree on some applications of controversial. The convergence of nanotechnology with biotechnology, such as therapeutic cloning, but dialogue biotechnology will allow for safer gene delivery methods leads to better understanding of each other’s views and that are not based on viruses. Chemically synthesized respect for our differences. nanoparticles that carry genes or therapeutics specifi cally We should not minimize the potential health and envi- to diseased cells are currently being tested in animals. ronmental risks of biotechnology. We need to fund studies Biotechnology also plays an important role in prevent- of these effects by independent organizations. Regulatory ing disease. Vaccines produced by recombinant DNA systems should be streamlined to be effective, effi cient, methods are generally safer than traditional vaccines and transparent. Currently, there are few incentives for the because they contain isolated viral or bacterial proteins, independent study of regulatory systems and policy. as opposed to killed or weakened disease-causing agents. Finally, we need to invest in technologies that are However, many citizens in developing nations do not tailored toward helping developing countries and building have access to any vaccines, let alone ones derived from capacity in their communities, for example, through edu- biotechnology. Currently, most vaccines require cold stor- cation, training, and assistance with intellectual property age and professional administration through injection. issues. Biotechnology investments have primarily been Therefore, researchers are working on genetically engi- made in developed countries and on products that will neered plants to deliver vaccines through food. The cost offer fi nancial returns. This focus is natural for the private of plant-derived, orally administered hepatitis B vaccine is sector, but a broader agenda is needed. Governments and estimated to be one-sixth that of current hepatitis B vac- other organizations should step in and invest in research cines. Enough antigen to immunize all babies in the world and development in developing countries and in products each year could be grown on approximately 80 hectares of that can benefi t those countries. Through increased aware- land. However, as with Bt crops, there are general con- ness of the social context of biotechnology and commit- cerns about pharmaceutical crops because they may cross- ments to resolve existing issues, one can envision a future pollinate with food crops in the fi eld. It will be especially in which biotechnology is harnessed responsibly to help important to develop biosafety regimes that either use all nations and all people.  crops that do not cross-pollinate (for example, male The opinions expressed in this article do not necessarily refl ect the views or policies of the U.S. government.

eJOURNALOURNAL USA 9 Economic Perspectives / October 2005 A CHEMICAL REACTION FOR BIOTECHNOLOGY: The 2005 Nobel Prize

Cheryl Pellerin

chemical reaction with great commercial carbon chain and the catalyst combine to form a single A potential in the pharmaceutical, biotechnology, ring. The ring then breaks apart, and a carbon atom and food industries caught the eyes of the Royal from the carbon-metal double bond has changed places Swedish Academy of Sciences this year. The academy with a carbon atom from the carbon-carbon double awarded the 2005 Nobel Prize in Chemistry to bond. The resulting two substances are a new chemical three scientists—Americans Robert Grubbs and compound and a modified catalyst. Synthesizing this Richard Schrock, and Frenchman Yves Chauvin—for new compound in any other way would have been very developing a reaction that streamlines the development complicated and required many more reaction steps. and industrial production of bioengineered drugs, “The discovery of metathesis involved finding plastics, and other materials in a way that makes such ways to break [the carbon-carbon] bonds and reform production less expensive and more environmentally them very easily under very mild conditions,” friendly. according to Charles Casey, professor of chemistry at “Metathesis is ... an important weapon in the hunt the University of Wisconsin and past president of the for new pharmaceuticals for treating many of the American Chemical Society. world’s major diseases,” the Royal Swedish Academy Many industrial biotechnology companies use of Sciences said in announcing the prize. The work by olefin metathesis to produce candidates for drugs and the Nobel Prize winners, it said, will aid researchers in other compounds. Metathesis can also be used to their efforts to develop biotech medicines to address synthesize a naturally occurring substance, such as an such illnesses as bacterial infections, hepatitis C, cancer, insect hormone, and produce it in large quantity for Alzheimer’s disease, Down’s syndrome, osteoporosis, use as a natural insecticide. arthritis, inflammation, fibrosis, and HIV/AIDS. “There are all kinds of complex organic molecules The reaction that Grubbs, Schrock, and that we’d love to synthesize,” Casey said, “and these Chauvin developed is called “olefin” metathesis. [metathesis reactions] are some of the most efficient Olefin metathesis starts with a carbon chain that has ways to do it.”  a carbon-carbon double bond, which is ordinarily hard to break. A special catalyst—a substance that increases the reaction rate without being consumed Cheryl Pellerin is a State Department science writer. in the process—that has a carbon-metal double bond is added. During the reaction, all the elements of the

Economic Perspectives / October 2005 10 eJOURNALOURNAL USA THE TRANSFORMING POWER OF MEDICAL BIOTECHNOLOGY

Bill Snyder Elise Amendola/AP/WWP Elise Samples of purified DNA are being prepared for sequencing; a part of the Human Genome Project.

Tremendous progress has been made since the early gene hirty years ago, more than 100 of the world’s splicing experiments from which the biotechnology industry leading scientists gathered at the Asilomar emerged. New drugs and vaccines, improved and accelerated TConference Center in Pacifi c Grove, California, drug discovery, better diagnostic capabilities, and other to debate the potential risks of genetic engineering. medical uses attest to it. But the progress so far is viewed Concerned that the technology of DNA (deoxyribonucleic by many scientists as only a beginning. They believe that, acid) recombination could transform harmless microbes in the not-so-distant future, the refi nement of “targeted into dangerous human pathogens, the scientists agreed to therapies” aimed at the biological underpinnings of disease a voluntary moratorium on certain experiments. should dramatically improve drug safety and effi cacy, and The dire predictions proved unfounded. On the the development of predictive technologies may lead to a contrary, gene splicing has fomented multiple revolutions new era in disease prevention, particularly in some of the in medicine: quick methods for detecting an infection world’s rapidly developing economies. Yet the risks cannot be or monitoring cholesterol levels, development of new disregarded as new developments and discoveries bring new vaccines and completely novel classes of therapeutics, questions, particularly in such areas as gene therapy, the ethics and breakthroughs in understanding diseases as diverse as of stem cell research, and the use of genomic information. cystic fi brosis and cancer. Out of the early gene-splicing experiments, the lively— Bill Snyder is senior science writer at the Vanderbilt and highly profi table—biotechnology industry emerged. University Medical Center in Nashville, Tennessee. DNA recombination made possible the sequencing of the human genome and laid the foundation for the nascent fi elds of bioinformatics, nanomedicine, and individualized therapy. Within the next two decades, many scientists

eJOURNALOURNAL USA 11 Economic Perspectives / October 2005 believe, the refi nement of “targeted therapies” aimed at the myeloma cells, scientists were able to generate antibodies biological underpinnings of disease should dramatically that would, like “magic bullets,” hone in on specifi c targets improve drug safety and effi cacy, while development of including unique markers, called antigens, on the surfaces predictive technologies such as proteomics may lead to a of infl ammatory cells. new era in disease prevention. Early examples include monoclonal antibodies that Yet concerns remain about the risks of gene therapy, can prevent the body’s immune system from rejecting the ethics of stem cell research, and the potential misuse organ transplants, and the much-heralded Herceptin, of genomic information. Depending on one’s point of approved for treatment of advanced breast cancer in 1998. view, biotechnology brims with promise or peril or a Other monoclonal antibodies have been approved for the combination of the two. treatment of multiple sclerosis and rheumatoid arthritis, and they currently are being tested in patients as potential THE INITIAL STEPS treatments for asthma, Crohn’s disease, and muscular dystrophy. The fi rst “bioengineered” drug, a recombinant form When tagged with radioisotopes or other contrast of human insulin, was approved by the U.S. Food and agents, monoclonal antibodies can help pinpoint the Drug Administration (FDA) in 1982. Until then, insulin location of cancer cells, thereby improving the precision was obtained from a limited supply of beef or pork of surgery and radiation therapy, and showing—within 48 pancreas tissue. By inserting the human gene for insulin into bacteria, scientists were able to achieve bacterial production of large quantities of the life-saving protein. In the near future, patients with diabetes may be able to inhale insulin, eliminating the need for injections. The fi rst recombinant vaccine, approved in 1986, was produced by slipping a gene fragment from the hepatitis B virus into yeast. The fragment was translated by the yeast’s genetic machinery into an antigen, a protein found on the surface of the virus that stimulates the immune response. This avoided the need to extract the antigen from the serum of people infected with hepatitis B. Today there are more than 100 recombinant drugs and vaccines. Because of their effi ciency, safety, and relatively low cost, molecular diagnostic tests and recombinant vaccines may have particular relevance for combating long-standing diseases of developing countries, including leishmaniasis (a tropical infection causing fever and lesions) and malaria.

IMPROVED DIAGNOSTIC CAPABILITIES

Biotechnology also has dramatically improved David David Parker/Photo Inc.Researchers, diagnostic capabilities. The polymerase chain reaction, a A cervical cancer vaccine based on a genetically engineered virus. method for amplifying tiny bits of DNA fi rst described in the mid-1980s, has been crucial to the development hours—whether a tumor is responding to chemotherapy. of blood tests that can quickly determine exposure to the The proteins also can deliver a lethal dose of toxic drug to human immunodefi ciency virus (HIV), for example. cancer cells, avoiding collateral damage to normal tissues The development of monoclonal antibodies in 1975 nearby. led to a similar medical revolution. The body normally produces a wide range of antibodies—immune system proteins—that root out microorganisms and other foreign invaders. By fusing antibody-producing cells with

Economic Perspectives / October 2005 12 eJOURNALOURNAL USA TRANSGENIC ANIMALS bacteria and discovering “weak spots” vulnerable to attack by compounds identifi ed via high-throughput screening. Genetic testing currently is available for many This kind of work led in 2000 to the approval of Zyvox, rare disorders, such as hemophilia, which is caused the fi rst entirely new antibiotic to reach the market in 35 by a mutation in a single gene. Little can be done to years. prevent or slow some of these diseases, however, and Lytic bacteriophages, viruses that infect and kill the underpinnings of more complex illnesses such as bacteria, may be another way to counter resistance. First cancer, heart disease, and mental illness are as yet not well used to treat infection in the 1920s, “phage therapy” understood. was largely eclipsed by the development of antibiotics. That situation is changing, thanks in part to the ability, Earlier this year, however, researchers in the former Soviet achieved in the early 1980s, to insert DNA from humans republic of Georgia reported that a biodegradable polymer into mice and other animals. impregnated with bacteriophages and the antibiotic Cipro Because they now express human genes, “transgenic” successfully healed wounds infected with a drug-resistant animals can be studied as models for the development of bacterium. diabetes, atherosclerosis, and Alzheimer’s disease. They Nanomedicine is another rapidly moving fi eld. also can generate large quantities of potentially therapeutic Scientists are developing a wide variety of nanoparticles human proteins. For example, a recombinant “clot-buster,” and nanodevices, scarcely a millionth of an inch expressed in the milk of transgenic goats, currently is being in diameter, to improve detection of cancer, boost tested in patients. immune responses, repair damaged tissue, and thwart The sequencing of the human genome, completed atherosclerosis. Earlier this year, the FDA approved a just two years ago, also has given scientists an incredibly nanoparticle bound to the cancer drug Taxol for treatment rich “parts list” with which to better understand why and of advanced breast cancer. Another nanoparticle is being how disease happens. It has given added power to gene tested in heart patients in the United States as a way to expression profi ling, a method of monitoring expression of keep their heart arteries open following angioplasty. thousands of genes simultaneously on a glass slide called a Studies of human embryonic stem cells aimed at microarray. This technique can predict the aggressiveness replacing cells damaged by diabetes, cancer, or Alzheimer’s of breast cancer in certain instances. disease have been controversial in the United States Another rapidly developing fi eld is proteomics—the because of concerns that such research requires the use of technologies such as mass spectrometry to detect destruction of potential human life. Research, however, is protein biomarkers in the blood that may indicate early progressing rapidly in privately funded labs in the United signs of disease, even before symptoms appear. One such States and throughout the world. marker is C-reactive protein, an indicator of infl ammatory changes in blood vessel walls that presage atherosclerosis. THE CHALLENGE OF GENE TRANSFER High-throughput screening, conducted with sophisticated robotic and computer technologies, enables Some biotech approaches to better health have proven scientists to test tens of thousands of small molecules to be more challenging than others. An example is gene in a single day for their ability to bind to or modulate transfer, the replacement of a defective gene with a the activity of a “target,” such as a receptor for a normally functioning one. The normal gene is delivered to neurotransmitter in the brain. The goal is to improve the target tissues in most cases by an adenovirus that has been speed and accuracy of drug discovery while lowering the genetically altered to render it harmless. cost and improving the safety of pharmaceuticals that The fi rst gene transfer experiment, conducted in 1990 make it to market. at the National Institutes of Health (NIH), successfully corrected an enzyme defi ciency in a four-year-old girl. RESPONSE TO ANTIBIOTIC RESISTANCE Nine years later, however, the death of a different patient, apparently from an overwhelming immune reaction to the Biotechnology also is solving the urgent and growing gene-carrying virus, led to stricter safety requirements in problem of antibiotic resistance. clinical trials. With the help of bioinformatics—powerful computer Progress has been slow since then, although gene programs capable of analyzing billions of bits of genomic transfer currently is being studied in patients in the sequence data—scientists are cracking the genetic codes of United States and other countries as a potential treatment

eJOURNALOURNAL USA 13 Economic Perspectives / October 2005 through the best care modern medicine can provide,” says Dr. Harry R. Jacobson, Vanderbilt’s vice chancellor for health affairs. Biotechnology is a neutral tool; nevertheless, its capabilities raise troubling ethical questions. Should prospective parents be allowed to “engineer” the physical characteristics of their embryos? Should science tinker with the human germline, or would that alter in profound and irrevocable ways what it means to be human? More immediately, shouldn’t researchers apply biotechnology—if they can—to eliminating health disparities among racial and ethnic groups? While

Lawrence Lawrence Jackson/AP/WWP genetic variation is one of many factors contributing Howard University researchers are building a genetic database on African-Americans. to differences in health outcome (others include environment, socioeconomic status, health care access, for peripheral arterial disease, Parkinson’s disease, and stress, and behavior), the growing ability to mine DNA certain forms of cancer. The Chinese government recently databases from diverse populations should enable approved the fi rst marketed gene transfer for treatment of scientists to parse the roles these and other factors play. head and neck cancer. “Understanding the genetic underpinnings of heart Scientists do not believe they will fi nd a single gene for disease and cancer will aid the development of screening every disease. As a result, they are studying relationships tools and interventions that can help prevent the spread between genes and probing populations for variations in of these devastating disorders into the world’s most the genetic code, called single nucleotide polymorphisms, rapidly developing economies, including the Far East,” or SNPs, that may increase one’s risk for a particular says Dr. Jeffrey R. Balser, associate vice chancellor for disease or determine one’s response to a given medication. research at Vanderbilt. This powerful ability to assign risk and response Biotechnology cannot solve complicated health to genetic variations is fueling the movement toward problems alone. Supportive health care infrastructures “individualized medicine.” The goal is nothing short must be put in place to guarantee access to the new of prevention, earlier diagnosis, and more effective screening tests, vaccines, and medications, and cultural, therapy by prescribing interventions that match patients’ economic, and political barriers to change must be particular genetic characteristics. overcome. Research must include more people from disadvantaged groups, which will require overcoming PURSUING NEW POSSIBILITIES long-held concerns some of them have had about medical science. In response to concerns that information about disease “It will also be critical to make sure that new risk could be used to deny people health insurance or knowledge and technologies are not used to discriminate employment, a raft of legislation at both the state and inappropriately against individuals and groups,” says federal levels has been passed in recent years in the United Dr. Ellen Wright Clayton, co-director of the Vanderbilt States to prohibit genetic discrimination. Center for Biomedical Ethics and Society. “The laws that Meanwhile, the NIH, a major supporter of medical have already been passed are a step in the right direction, research in the United States, is encouraging academic but more work remains to be done to ensure the kind of institutions to pursue the new science and new inclusive and healthy society to which we aspire.”  possibilities. Vanderbilt University Medical Center in Nashville, Tennessee, for example, is revising its research enterprise strategic plan to emphasize personalized The opinions expressed in this article do not necessarily refl ect the views or policies of the U.S. government. medicine, drug discovery, and population health care— how best to deliver health care to populations.

The pursuit of cutting-edge research “brings us closer to our ultimate goal of eliminating disability and disease

Economic Perspectives / October 2005 14 eJOURNALOURNAL USA THE RACE AGAINST GENE DOPING Huntington F. Willard

n the last few Gene doping, Iyears, public the nontherapeutic discussion of use of DNA and/or performance- cells to enhance enhancing drug usage athletic performance, in sports has reached has the potential a fever pitch. After to offer the cheater swearing to the U.S. a “souped-up,” or Congress in March supercharged, body 2005 that he had that can run faster never used steroids, and jump higher but Baltimore Oriole whose modifications baseball player Rafael are virtually Palmeiro, a one- undetectable. If an

time certainty for Roberto Borea/AP/WWP athlete injects himself the Baseball Hall of U.S. baseball player Rafael Palmeiro dives to grab a ball. with additional Fame, was given a 10-game suspension in August. His copies of a gene already present in his body, how is transgression? A positive test for steroids. Earlier leaked one to distinguish the original from the copy? Only an grand jury testimony in an investigation into a San expensive and invasive muscle biopsy could detect the Francisco laboratory appeared to implicate several other presence of a slightly altered synthetic gene. high-profile ballplayers and track and field stars in We know that a high proportion of our physical steroid usage. Elsewhere, anti-doping officials regularly prowess is hardwired in our genomes. A recent study of test competitive cyclists and sanction those who test young adult males undergoing cycle training suggested positive for drug use. A recent retrospective test of 70 that as many as 500 genes and DNA markers scattered urine samples from the 1998 Tour de France found 40 across the genome may be associated with athletic to be positive for EPO, a hormone that promotes the performance and health-related fitness. Mice lacking formation of red blood cells and can increase stamina. the myostatin gene, for example, tend to develop huge No reliable test for EPO was available in 1998. muscles, the result of more and bigger muscle fibers— For all of the recent headlines about anabolic steroid these rodents have been nicknamed “Schwarzenegger usage in American football and synthetic hormone mice.” How many body builders could resist that? usage in European cycling, high-tech gene doping As with other doping methods, the safety issues may soon have the dubious honor of rendering them surrounding gene doping should be enough to give obsolete. Commissioner of the National Football athletes pause. Abuse of EPO, for example, can have League Paul Tagliabue, appearing before Congress devastating consequences. EPO can thicken the blood barely a month after Palmeiro issued his denial, said to such an extent that it will cause heart failure, as much: “When [gene doping] happens, the [drug especially in elite athletes whose resting heart rates tend doping] issues that our society is discussing today ... to be extraordinarily slow. Not long after the arrival of will be as irrelevant as the blacksmith in the automobile EPO in cycling, 18 Belgian and Dutch cyclists died age.”

eJOURNALOURNAL USA 15 Economic Perspectives / October 2005 suddenly of heart attacks. So it is fair to ask: What stricter steroid-testing regimen, the Office of the will the risks of EPO gene doping be once the EPO Commissioner of Baseball released the names of gene can be administered without fear of detection? 41 minor league players who had failed spring- Some have training drug tests. argued that Remarkably, these the best way to players stayed on control gene the “juice” (banned doping is to drugs), even though legalize it. After they knew they all, they say, if were likely going to Tiger Woods be tested, caught, can have Lasik and publicly eye surgery to identified. And improve his what of Palmeiro? vision to 20/10 If he knowingly and thereby help took steroids, could his golf game, he somehow not why shouldn’t a have known he cyclist be able to would be instantly modify his genes? transformed from Moreover, this hero to pariah if he Michel Spingler/AP/WWP argument goes, Cyclists ride in Paris during a Tour de France race. were caught? by making gene Conventional doping legal and regulating it, safety standards could doping may be going the way of the blacksmith, but be imposed. there appears to be little doubt that gene doping will But would gene doping violate the spirit of sports? soon be here to stay. What will that mean for the So far the official response is yes. In recent years, both games we play?  the International Olympic Committee and the World Anti-Doping Agency have added gene doping to their lists of banned substances (the International Cyclists’ Huntington F. Willard is the director of the Duke University Institute for Genome Sciences and Policy and the vice chancellor Union has been strangely quiet on the subject). for genome sciences at the Duke University Medical Center in Whether a practical means of enforcing those bans can Durham, North Carolina. be developed remains to be seen. In our competitive culture, the desire to win is The opinions expressed in this article do not necessarily reflect the views ever present. In early 2005, after U.S. Major League or policies of the U.S. government. Baseball was shamed into imposing a somewhat

Economic Perspectives / October 2005 16 eJOURNALOURNAL USA PLANT BIOTECHNOLOGY: Advances in Food, Energy, and Health

Richard Hamilton, Richard B. Flavell, and Robert B. Goldberg

The world will need to produce more food, feed, and fi ber And we will need to do this on a decreasing amount of during the next 50 years than in the entire history of human- land that is suitable for agriculture and crop production. kind. The technological revolution created by genomics pro- This presents several major challenges for 21st-century vides a unique opportunity to achieve this goal. Genetically agriculture: engineered herbicide- and insect-resistant crops are delivering • Crop yields need to be increased beyond the spectac- benefi ts through more affordable food, feed, and fi ber that ular gains of the 20th century in order to meet increasing require fewer pesticides, conserve more soil, and provide for demand and save open space. a more sustainable environment. And contrary to criticism, • Inputs required for intensive agriculture, such as biotech crops have proven to be as safe as, or safer than, those water and fertilizers, need to be reduced. produced by conventional methods. In the future, advances • Crops need to be developed that can fl ourish in harsh in agricultural biotechnology will result in crops that have conditions so that substandard land can be used to grow improved tolerance to drought, heat, and cold; require fewer important crops, growing seasons can be extended, and fertilizer and pesticide applications; produce vaccines to pre- yields are not decreased by drought, heat, cold, and other vent major communicable diseases; and have other desirable stresses. traits. • The environmental impacts of agriculture resulting from the use of pesticides, herbicides, and fertilizers need Richard Hamilton and RichardRichard B. FlavellFlavell are,are, respec-respec- to be reduced. For example, crops need to be engineered tively, chief executive offi cer and chief science offi cer of Ceres, that are resistant to pests, that take up nutrients more Inc., a privately held biotechnology company. Robert B. effectively from the soil, and that can out-compete weeds Goldberg is professorprofessor of molecular,molecular, cell, and developmentaldevelopmental for water and sunlight. biology at the University of California, Los Angeles. • Food crops need to be optimized for human health and nutrition, providing essential vitamins, amino acids, lants and agriculture have played an important role and proteins to help eliminate malnutrition and disease. in the development and advancement of civiliza- • Novel energy crops need to be developed that are Ption. Plants provide sustainable supplies of food high yielding and that can be used as a renewable source for humans, feed for animals, fi ber for construction and of biomass for fuels to limit our dependence on a petro- clothing, medicines and drugs, perfumes, chemicals for leum-based energy system. industrial processes, energy for cooking and heating, and, • We need to go “back to the future” and engineer most recently, biomass to meet the increasing demand for specialty crops that can be used as factories to produce transportation fuels. Plants also play a major environmen- chemicals and proteins for industrial and medical appli- tal role by preventing soil erosion, boosting levels of oxy- cations—for example, plastic precursors and vaccines to gen in the atmosphere, reducing carbon dioxide emissions combat human and animal pathogens. from burning fossil fuels, and enriching soils with nitro- gen, which they cycle between soil and the atmosphere. These challenges will require application of the most sophisticated breeding and molecular techniques available AGRICULTURE IN THE 21ST CENTURY today, as well as the development of new ones. Neverthe- less, there has never been a more exciting time for plant If population growth continues as predicted, we will biology and agriculture, and the technological revolution need to produce more food, feed, and fi ber during the created by the genomics era provides a unique opportu- next 50 years than in the entire history of humankind. nity to achieve these goals over the next two decades or sooner.

eJOURNALOURNAL USA 17 Economic Perspectives / October 2005 USING BIOTECHNOLOGY TO DEVELOP NEW CROPS

Most of the crops that we grow today did not spring forth from a mythical Garden of Eden and do not grow “naturally.” To the contrary, most major crops were engi- neered by our ancestors thousands of years ago from wild relatives by selecting and breeding for traits that optimized crops for human use. These early genetic engineers learned how to recognize random mutations that appeared in wild plant populations and to use this genetic variability to cre- ate the food crops that we use today. For example, maize was bred from teosinte grass 10,000 years ago by selecting Volker Steger/Peter Arnold, Inc. Arnold, Steger/Peter Volker for a few genes that control cob size, seed structure and Mold-resistant bioengineered tomatoes and regular tomatoes over time. number, and plant architecture. Almost all of the crops that we use today, such as wheat, soybean, rice, potato, THE GROWTH AND BENEFITS OF BIOTECH CROPS cabbage, broccoli, and tomato, were engineered in an analogous manner; that is by use of breeding technologies The fi rst genetically engineered crops developed in the to create new gene combinations within a crop species and early 1980s were resistant to herbicides and insects. Today, then selecting for better traits in the progeny. these two traits—herbicide and insect resistance—account The most signifi cant innovations that are transforming for the majority of biotech crops. Over the past 20 years, agriculture are genetic engineering technologies that allow there has been a worldwide effort to isolate genes that will novel genes to be isolated, manipulated, and re-inserted provide a long list of traits that breeders, farmers, consum- into crop plants; the ability to regenerate almost any plant ers, and industrialists have nominated for improvement in species from tissue culture into a fertile plant; and the a variety of crops. Plant biotechnology and genetic engi- development of high-throughput genomic technologies. neering is now a major activity in the public and private The latter permits the mapping and sequencing of entire sectors and is becoming a signifi cant part of plant breed- plant genomes and the identifi cation of genes that control ing on all continents. In fact, there has never been a more all plant processes, including those that can contribute to exciting time for agriculture because powerful genomic meeting the challenges of agriculture in the future, such as technologies make it possible to identify genes that have genes for disease resistance, drought resistance, seed size, the potential for revolutionizing crop production over the and number. next 50 years. At the genetic level, crop breeding depends on ran- In 2005, we celebrate 10 years of biotech crop cultiva- domly introducing mutations, or genetic variability, into a tion. During that period, 400 million hectares of geneti- plant’s genome and then selecting from a large population cally enhanced biotech crops have been grown. Biotech the small subset of changes that result in a positive change. crops have been adopted by farmers all over the globe at a In the vast majority of cases, the genetic changes that are rate faster than any crop varieties in the history of agricul- made are unknown. By contrast, genetic engineering af- ture—even faster than high-yielding hybrid maize during fords a more precise alternative to breeding, and, because the last century. Since their introduction in 1996, the use of its precision, it can be used to develop new, valuable of genetically enhanced biotech crops has grown at a rate traits in a small fraction of the time required to pursue the of more than 10 percent per year, and in 2004, according relatively imprecise techniques of breeding. Genes that to a report of the International Service for the Acquisition have been characterized extensively can be introduced of Agri-biotech Applications, their adoption increased 20 into crop plants in a precise and directed way in order to percent. The main crops carrying new biotech genes are generate novel, genetically enhanced crops with traits that soybean, maize, cotton, and canola, accounting, respec- would not be possible to achieve using classical breeding tively, for 56 percent, 14 percent, 28 percent, and 19 procedures. percent of the worldwide acreage for these crops. Together, they occupy nearly 30 percent of the global area devoted to these crops. In the United States, biotech soybean (her- bicide resistant), maize (herbicide and insect resistant), and cotton (herbicide and insect resistant) account for

Economic Perspectives / October 2005 18 eJOURNALOURNAL USA are the most tested and studied crops in human history, agricultural biotechnology is not without controversy. Opposition to the use of biotechnology and genetically engineered organisms derived from it is largely confi ned to Europe, where a small but vocal group of activists have fomented public opinion against the technology. In an environment where non-biotechnology-related food scares over mad cow disease and dioxin have eroded the European public’s confi dence in the regulatory over- sight of their food supply, activist groups have been able to generate substantial distrust of agricultural biotechnol- ogy. This distrust is misplaced: The hypothetical fears have failed to materialize after more than 10 years of safe use and more than 400 million hectares of cropland planted with genetically enhanced varieties. There are no known examples of ill effects of these crops in humans, and there are demonstrable environmental benefi ts. In fact, major studies, which have been published in peer-reviewed jour- nals over the past fi ve years, indicate that biotech crops are substantially equivalent to their non-biotech counterparts, that yields have been increased, that pesticide applica- tions have been reduced, that large amounts of soil have been conserved, and that management practices have been successful in preventing or minimizing the resistance to Betsy Blaney/AP/WWP A cotton field.

approximately 85 percent, 75 percent, and 45 percent of the total acreage for these crops. The United States is the leading grower of biotech crops, with more than 48 million hectares, followed by Argentina (16 million hectares), Canada (6 million hect- ares), Brazil (4.8 million hectares), and China (4 million hectares). The value of biotech crops is nearly $5 billion, representing 15 percent and 16 percent of the global crop production and seed markets, respectively. Biotech crops are delivering benefi ts through more affordable food, feed, Joerg Boethling and fi ber that require fewer pesticides, conserve more Genetically modified rice plants. soil, and provide for a more sustainable environment. In addition, the annual income of poor farmers in the insect-resistant crops. Although no technology is without developing world has increased signifi cantly from the use zero risk, biotech crops have proven to be as safe as, or of biotech crops, according to recent data from the United safer than, those produced by conventional methods. Nations Food and Agriculture Organization. Most of the value added has gone to those farmers rather than to the WHAT ABOUT THE FUTURE? technology providers. In the next decade, further advances in agricultural CONCERNS LIMITING THE GROWTH OF biotechnology will result in crops that have improved tol- BIOTECH CROPS erance to drought, heat, and cold; require fewer fertilizer and pesticide applications; produce vaccines to prevent Although crops produced by using biotechnology and major communicable diseases; have increases in seed size, genetic engineering have been adopted at warp speed and

eJOURNALOURNAL USA 19 Economic Perspectives / October 2005 to simple sugars that can, in turn, be fermented into fuels such as ethanol. Recent estimates from the U.S. Depart- ment of Energy indicate that the United States could obtain 30 percent or more of its transportation fuels from biomass sources by 2020. Agricultural biotechnology has the potential to increase this number even further by enhancing biomass yield density, improving the processing characteristics of the biomass feedstock, and decreasing the need for agronomic inputs such as water, fertilizer, and pesticides. Several key countries, notably the United States and China, are pushing ahead in agricultural biotechnology, Scott Olson/Getty Images Various corn hybrids are grown for use in ethanol production. making the necessary investments in research and devel- opment and providing a viable regulatory system for the number, and nutritional content; and are able to regener- introduction and commercialization of new bio-enhanced ate in the absence of fertilization—fi xing hybrid vigor. crops. Crops will also be generated that are enhanced nutrition- If we are going to create a new kind of agriculture in ally to help alleviate malnutrition in the developing world. the 21st century that is both sustainable and productive Currently, “golden rice 2” cultivars undergoing fi eld with respect to food security and energy self-suffi ciency, testing are capable of delivering as much as 30 micrograms we will need to use all of the scientifi c tools and discover- of beta-carotene, a precursor to vitamin A, according to a ies at our disposal, including biotechnology and genetic recent article by Jacqueline Paine and others. The authors engineering, and to follow the continuous path of agricul- estimate that this amount of beta-carotene should provide tural breakthroughs that have advanced human progress at least 50 percent of the recommended daily allowance for thousands of years.  for vitamin A in a typical child’s portion of 60 grams of rice. The opinions expressed in this article do not necessarily refl ect the views or Beyond applications to increase production of food, policies of the U.S. government. feed, and fi ber, biotechnology is making a substantial contribution to the energy area. Advances in biotechnol- ogy have enabled the production of large amounts of inexpensive cellulases that can be used to convert cellulose

Economic Perspectives / October 2005 20 eJOURNALOURNAL USA BIOTECH BUGS

ollowing miracle cures and miracle foods, genetically GM mosquitoes Fmodified (GM) bugs are generating a buzz in the carry a promise of scientific community as possibly the next “miracle” in a clean and radical the field of biotechnology. The successful application of solution to the malaria GM insects could dramatically improve public health, problem. Scientists particularly in developing countries, enhance agricultural want to genetically production, and improve the natural environment, modify male insects, according to some scientists. It also could make one AP/WWP/USDA which then could hesitate whether to hit a mosquito on one’s neck because be bred, sterilized, and released into the wild to mate it can fight rather than carry a disease. with females. Such skewed reproducing would lead to There are two types of GM insects under research: the eradication, or at least a dramatic reduction, of the paratransgenic and transgenic. Paratransgenic insects natural mosquito population. are created by integrating a piece of DNA manipulated Another approach is to infiltrate genes for malaria in the laboratory (referred to as the transgene) into resistance into the existing population of these insects. the microbes that naturally inhabit their alimentary Introduced at high enough frequencies, such infiltration canal. Genes expressed in these microbes can alter the could decrease transmission of the disease, according to characteristics of the host insect. Transgenic insects are Anthony James, professor of biology and biochemistry at the product of the physical integration of transgenes into the University of California, Irvine. the chromosomes of an insect. The first confined field trials with different GM Genetically altering an insect so that all of its insects have already been conducted, and some projects descendants will also be genetically altered requires are expected to reach full environmental release within that the initial integration of the transgene occur in the three to five years. But a swarm of GM insects is chromosomes of cells that will produce sperm or eggs nowhere near on the horizon. Technological and other (most insect reproduction is sexual). GM insects must obstacles will prevent scientists and businesses from have characteristics readily visible so scientists or other wide-scale releases of transgenic bugs for at least 5 to stakeholders can have a way of controlling them during 10 years or more, according to Luke Alphey of Oxford research, for example, in order to separate male from University’s Department of Zoology. female insects. Scientists and regulators also need to deal with Scientists are working to develop a broad array of uncertainty about the lasting effects these insects could insects with new characteristics that could make them have on ecosystems, public health, and food safety. useful in fighting the spread of infectious diseases, What is more, the fact that insects do not respect controlling noxious weeds and insect pests, and borders creates international regulatory challenges that producing pharmaceuticals. For example, honeybees can the world has never faced with GM crops. The United be genetically altered in a way that makes them resistant States and many other governments currently have no to diseases and parasites, and genetically engineered comprehensive policies on how transgenic insects will silkworms can produce industrial proteins for application be reviewed, and international organizations are not in the creation of novel materials. involved yet in the relevant regulatory process. As a But no matter how productive those GM honeybees result, a 2004 report by the Pew Initiative on Food and and silkworms can be, the greatest interest lies in GM Biotechnology concludes that the research threatens to bugs that may be able to save lives. Mosquitoes spread outpace regulatory preparedness. The report says that if malaria, which infects 300 million to 500 million people regulators and scientists want to have a clear set of rules and kills over 1 million annually, according to the World in place before unconfined field testing is ready to occur, Health Organization. Chemical pesticides currently they will need to start discussions now.  being used have negative effects on human health and the environment. And the emergence of insects resistant Source: Adapted from materials produced by the Pew Initiative on Food and Biotechnology, including September 2004 conference papers to many pesticides has undermined the efficacy of these on biotech bugs. pesticides.

eJOURNALOURNAL USA 21 Economic Perspectives / October 2005 DESIGNING NOVEL MATERIALS AND MOLECULAR MACHINES Shuguang Zhang

By imitating nature, scientists are designing completely new such as new materials to repair damaged tissues and mo- molecular patterns that can serve as a blueprint of new mate- lecular machines to harness solar energy from the smallest rials and sophisticated molecular machines. In the emerging molecular amino acids and lipids will likely have an enor- fi eld of nanotechnology, basic natural building blocks such as mous impact on our society and the world’s economy. amino acids are used to create structures such as peptides and Modern biotechnology has already produced a wide proteins for applications in medicine and energy. Nanobio- array of useful products, such as humanized insulin and technologists have begun to exploit molecular self-assembly as new vaccines. But what lies ahead can be even more a fabrication tool for building new nanobiostructures such as revolutionary. That is why governments small and large, nanotubes for metal casting, nanovesicles for drug encapsula- and industries local and global, are increasingly seeking to tions, and nanofi ber scaffolds for growing new tissues. They attract biotechnology talent and investment. There is no also have constructed an extremely high-density nanoscale doubt that biotechnology, helped by the tools of nano- photosystem and ultra-lightweight solar-energy-harvesting technology, is expanding at an accelerating rate, and that molecular machines. With better understanding of these seem- the best is yet to come. ingly intractable phenomena, one day mankind may be able to use nano devices to repair body parts or to rejuvenate the IMITATING NATURE skin, enhance human capabilities, harness the unlimited solar energy, and achieve other feats that seem impossible today. Nature itself is the grandmaster when it comes to build- ing extraordinary materials and molecular machines atom Shuguang Zhang is associate directordirector of the CenterCenter for by atom and molecule by molecule. Shells, pearls, corals, Biomedical Engineering at the Massachusetts Institute of bones, teeth, wood, silk, horn, collagen, muscle fi bers, and Technology. extra-cellular matrices are just a few examples of natural materials. Multifunctional macromolecular assemblies, such as hemoglobin, polymerases, and membrane chan- About 10,000 years ago, humans began to domesti- nels, are all essentially exquisitely designed molecular cate plants and animals. Now it’s time to domesticate machines. molecules. Through billions of years of molecular selection and — Susan Lindquist, Whitehead Institute for evolution, nature has produced a basic set of molecular Biomedical Research, Massachusetts building blocks that includes 20 amino acids, a few Institute of Technology nucleotides—the structural units of nucleic acids such as ribonucleic acid (RNA) and deoxyribonucleic acid iotechnology, which is known primarily by its (DNA)—a dozen or so lipid molecules, and two dozen medical and agricultural applications, is increas- sugars. From these seemingly simple building blocks, Bingly being focused on the building of new natural processes are capable of fashioning an enormously biological materials and machines in an astonishing diverse range of fabrication units that can further self- diversity of structures, functions, and uses. The advent of organize into refi ned structures, materials, and molecular nanotechnology has accelerated this trend. Learning from machines that not only have high precision, fl exibility, and nature, which over billions of years has honed and fash- error-correction capacity, but also are self-sustaining and ioned molecular architectural motifs to perform a myriad evolving. For example, the photosynthesis systems in some of specifi c tasks, nanobiotechnologists are now designing bacteria and all green plants take sunlight and convert it completely new molecular patterns—bit by bit, from the into chemical energy. When there is less sunlight, as, for bottom up—to build novel materials and sophisticated example, in deep water, the photosystems must evolve to molecular machines. Over the next generation, advances become more effi cient to collect the sunlight.

Economic Perspectives / October 2005 22 eJOURNALOURNAL USA In the early 1990s, biotechnologists began to learn how Furthermore, scientists have also shown that the designer to manipulate natural building blocks with at least one self-assembling peptide nanofi bers can stop bleeding relevant dimension being between one nanometer (one instantly, a characteristic useful in surgeries. New peptides billionth of a meter) and 100 nanometers to fabricate new are proving to be remarkably useful in drug, protein, and molecular structures, thus ushering science and technol- gene deliveries, because they can encapsulate some water- ogy into the age of designed molecular materials. Much insoluble drugs and ferry them into cells and other areas like clay and water can be combined to make bricks with of the body. They also are essential to fabricating bio-solar, multiple uses that, in turn, can be used to build walls such energy-harvesting molecular machines that use the photo- as the Great Wall of China, houses, or roads, basic natural system from spinach and tree leaves. building blocks such as amino acids can be used to create structures such as peptides and proteins that can be used MOLECULAR SELF-ASSEMBLY for a variety of purposes. For example, animals grow hair or wool to keep themselves warm, shellfi sh grow shells to All biomolecules, including peptides and proteins, protect their tissue from harm, spiders spin silk to capture naturally interact and self-organize to form well-defi ned insects, and our cells make a lot of collagens to keep cells structures with specifi c functions. By observing the pro- together to form tissues and organs. cesses by which these biological molecular structures are If we shrink the construction units one billion times to assembled in nature, nanobiotechnologists have begun to the nanoscale, we can construct molecular materials and exploit self-assembly as a fabrication tool for building new machines from prefabricated units in a way similar to that nanobiostructures such as nanotubes for metal casting, in which a house is assembled from prefabricated parts. nanovesicles for drug encapsulations, and nanofi ber scaf- Peptides formed from amino acids are molecular archi- folds for growing new tissues. tectural units that are proving very useful in the develop- Molecular self-assembly involves mostly weak bonds— as does human handholding—that can be joined and disjoined quickly. This is in sharp contrast to the very strong bonds that join our arms to our body. Individu- ally, weak molecular forces are quite insignifi cant. Col- lectively, weak interactions such as the hydrogen bond and the ionic bond play an indispensable role in all biological structures and their interactions. The water-mediated hydrogen bond, in which numerous water molecules work as a bridge to connect two separate parts, is especially im- portant for biological systems, since all biological materi- als interact with water. The bond, found in all collagens, works to increase the moisture for an extended time. As to molecular building blocks, the designed peptides resemble the toy Lego bricks that have both pegs and holes arranged in a precisely determined manner and can be assembled into well-formed structures. Often referred to as “peptide Legos,” these new molecular bricks under certain environmental conditions spontaneously assemble

CGhim Wei Ho/Mark Welland, Nanostructure Center, University of NanostructureCambridge Center, Welland, Ho/Mark Wei CGhim into well-formed nanostructures. A 3-D nanomaterial grown from tiny droplets of a liquid metal In water, peptide Lego molecules self-assemble to form on a silicon surface. well-ordered nanofi bers that further associate to form scaffolds. One such nanofi ber scaffolding material that ment of new nanobiological materials. In water and in the has been commercially realized is PuraMatrix, so called body fl uids, these peptides form well-ordered nanofi ber because of its purity as a biotechnologically designed scaffolds useful for growing three-dimensional (3-D) tis- biological scaffold. Biomedical researchers currently use sue and for regenerative medicine. For example, scientists it worldwide to study cancer and stem cells, as well as to have fabricated artifi cial cartilage and bones to replace repair bone tissue. damaged tissue using the biological scaffolds and cells.

eJOURNALOURNAL USA 23 Economic Perspectives / October 2005 Since these nanofi ber scaffolds contain 5 to 200 nano- these proteins, we may be able to produce more effective meter pores and have extremely high water content, they and effi cient drugs with few or no side effects. are of potential utility in the preparation of 3-D cell and tissue growth and in regenerative medicine. In addition, HARNESSING SOLAR ENERGY the small pore size of these scaffolds may allow drugs to be released slowly so people do not have to take their medi- Detailed molecular study of how membrane proteins cine several times a day but rather once over a longer pe- function is just an exercise in understanding them. By riod. A slow-release nanoscaffold device can be implanted deepening our knowledge of how cells communicate with on the skin with medicine supplies suffi cient for months or their surroundings, we learn how all living systems respond years. to their environments. With this know-how, modern nanobiologists have begun to fabricate advanced molecu- CREATING MORE BUILDING BLOCKS lar machines able to develop extremely sensitive sensors for medical detection or to harness bio-solar energy. For Using nature’s lipids as a guide, a new class of lipid-like example, ancient Chinese doctors smelled a patient to peptide detergents has been designed. These peptides have diagnose a medical problem because they believed that an seven to eight amino acids, giving them a length similar to illness can change a patient’s body odor or secretion. In naturally occur- Solar power from spinach modern medi- ring lipids, which ResearchersResearchers havhavee fabricated a solar cell that cal science, make up cell walls uses plant prproteinotein to convertconvert light into a number of 20,000 times electrical energy. instruments are thinner than the SSpinachpinach used to make 1. Sunlight shines popowerwer cell diameter of a piece through glass. an accurate ElectrodeElectrode made of of human hair. 2. Photosynthetic transparenttransparent glass coated diagnosis. In Simple lipid- proteins absorb light. with thin laylayerer of gold the future, a Light like peptide 3. Electrons pass into SpinachSpinach and smell sensor as detergents produce organic semiconductor bacterial prproteinotein sophisticated and collect in the silvsilverer remarkably com- electrodeelectrode and produceproduce a Electron OrganicOrganic semiconductor as a dog’s nose plex and dynamic current. ElectrodeElectrode made of silver could help dis- structures in the tinguish people The prprototypeototype cells can generate same way that currentcurrent for up to 21 days, The Boston Globe with medi- convertingconverting only 12 perpercentcent of SOURCES:SOURCES: MarcMarc Baldo,Baldo, MIT ResearchResearch Lab; the assembly of the absorbed light into electricityelectricity.. Nanoletter,Nanoletter, JuneJune 2004 cal problems MostMost conventionalconventional solar cells areare numerous simple GLOBE STAFF GRAPHIC/HWEI WEN FOO from healthy 20 to 30 percent efficient. Courtesy of bricks can make ones. In the many different and Figure 1. The spinach chip and bio-solar energy-harvesting molecular machine. The photons United Kingdom, distinctive architec- (either from the sun or any other light) can be directly converted into electric energy dogs have already using the combination of a natural green plant photosynthetic system and semiconducting tural structures. material carbon C and conducting materials—gold and silver electrodes. demonstrated their Some peptide 60 ability to identify detergents have been found to be excellent materials for people suffering from cancer by sniffi ng their odors. stabilizing notoriously hard-to-stabilize membrane pro- No one would argue that affordable, sustainable, and teins—protein molecules attached to or associated with the environmentally sound energy is requisite for the welfare of membrane of a cell—thus opening a new avenue for over- modern civilization. With environmental damages caused coming one of the biggest challenges in biology: obtain- by fossil fuel pollution and the demand for energy bur- ing clear pictures of the ubiquitous and vital membrane geoning worldwide, the world’s energy problems are now proteins. more urgent than ever. Alternative solutions, long debated Numerous drugs exert their effect through membrane but rarely seriously pursued, are now being pursued with a proteins. But how these drugs interact with vital mem- sense of urgency. brane proteins at the fi nest molecular level remains largely Further, the increasingly mobile nature of computing unknown. The designed peptide detergents promise to and communication, and the nanonization of materials change this. If we can fully understand the interactions of and molecular machines, demand that smaller, lightweight, self-sustaining energy sources be developed. An obvious

Economic Perspectives / October 2005 24 eJOURNALOURNAL USA source of infi nite energy is the sun. Nature has produced WHAT LIES AHEAD? an effi cient system to directly convert photons into elec- trons and further into chemical energy; green plants and The continued development of nanobiotechnology other biological organisms have been using this system for materials and molecular machines will deepen our under- billions of years. standing of seemingly intractable phenomena. Nanoscale Most energy on earth is obtained from photosynthesis engineering through molecular design of self-assembling through photosystems, the most effi cient energy-harvest- peptides is an enabling technology that will likely play an ing system. If a way to harness the energy produced by increasingly important role in the future of biotechnol- natural photosystems can be developed, we will have a ogy and will change our lives in the coming decades. For clean and nearly inexhaustible energy source. example, aging and damaged tissues can be replaced with Borrowing from the bacterial and green plant en- the scaffolds that stimulate cells to repair body parts or to ergy-harvesting photosystem, nanobiotechnologists have rejuvenate the skin. We also might be able to swim and demonstrated that photons can be converted directly into dive like dolphins or to climb mountains with a nanoscaf- electrons by newly designed bio-solar molecular machines. fold lung device that can carry an extra supply of oxygen. Through a combination of precision engineering and It is not impossible to anticipate painting cars and houses biological engineering of the photosystem, they have con- with photosynthesis molecular machines that can harness structed an extremely high-density nanoscale photosystem the unlimited solar energy for all populations on every and ultra-lightweight solar-energy-harvesting molecular corner of the planet, not just for the wealthy few. machines. We are just at the beginning of a great journey and will Two key components are required to fabricate a bio- make many unexpected discoveries. Although nano- solar energy-harvesting molecular machine—a bio-solar technologists face many challenges, they will actively energy production system (photosystem) from leaves of pursue many issues related to the molecular fabrication green plants, and the designed peptide detergents. For of composite materials and molecular machines. Biotech bio-solar energy production, a simpler photosystem was self-assembling peptides can be considered the building used. Scientists originally purifi ed the photosynthesis blocks for emerging materials and for fabricating future system from spinach, and they have recently reported man-made molecular machines. These peptides can also successfully purifying photosynthetic systems from maple, be designed in combination to incorporate other build- pine, and oak trees and from bamboo leaves. The entire ing blocks such as sugars, lipids, nucleic acids, and a large photosystem complex—only about 20 nanometers in number of metal crystals. Nature has inspired us and height—was anchored onto a gold surface with an upright opened the door to its secrets. It is up to our imagination orientation. to expand upon its materials and molecular machines.  Experimentation is continuing to devise ways to increase the amount and duration of energy produced by this exciting new molecular-energy-harvesting machine The opinions expressed in this article do not necessarily refl ect the views or (fi gure 1). policies of the U.S. government.

eJOURNALOURNAL USA 25 Economic Perspectives / October 2005 Examples of New Nanobiotechnological Materials Peptide Lego

5 nm

Peptide Detergents

2 nm

Peptide Ink

4 nm

Peptide Lego, also called ionic self-complementary peptide, has 16 amino acids, about five nanometers in size. Peptide Lego molecules form nanofiber scaffolds that can be used in studies of cancer cells and stem cells, as well as for bone tissue repair in medicine. Peptide detergents, about two nanometers in size, can self-assemble into nanotubes and nanovesicles with a diameter of about 30 to 50 nanometers. These nanotubes go on to form an interconnected network that can be used in the development of more effective and more efficient drugs with fewer side effects. Peptide ink, about four nanometers in size, can be used as ink for an inkjet printer to directly print on a surface, instantly creating any pattern. The peptide ink, like blue and red inks, is useful to instantly alter the surface property so that cells can directly attach on to it. It can be used for developing cell-based sensors and coating for medical implants. When the peptide ink is applied along a certain pattern or shape on the surface, rat neural cells can spell, for example, M.I.T., as shown here.

Economic Perspectives / October 2005 26 eJOURNALOURNAL USA WHITHER NANOTECHNOLOGY? Akhlesh Lakhtakia

“ hink small, dream big” is a typical slogan Nanoscale sensors exploiting the fluorescent properties Tabout the promise of nanotechnology within of disks called quantum dots (which are 2 to 10 the scientific research community. Once relegated nanometers in diameter) and electrical properties of to pure fiction, nanotechnology is becoming carbon nanotubes (which are 1 to 100 nanometers increasingly linked with advances in biotechnology and in diameter) represent evolutionary nanotechnology, information technology. With annual expenditure for but their development is still in the embryonic stage. nanotechnology research in Radical nanotechnology, the stuff the United States estimated to of science-fiction thrillers, is be in excess of $2.6 billion in nowhere on the technological 2004, the word “nano” is even horizon. finding its way into popular Material properties at the culture, from daily horoscopes nanoscale differ from those in to newspaper cartoons. bulk because of extremely large Yet the relatively small surface areas per unit volume number of applications at the nanoscale. Quantum that have made it through effects also come into play to industrial uses represent at the nanoscale. Nanoscale “evolutionary rather than properties and effects should revolutionary advances,” transform current practices according to a 2004 panel in integrated electronics,

report from the Royal Society www.cartoonstock.com optoelectronics, and medicine. of London and the Royal But the translation from Academy of Engineering. the laboratory to mass Nanotechnology is not a manufacturing is fraught with single process; neither does it significant challenges, and involve a specific type of material. Instead, the term reliable manipulation of matter at the nanoscale in a nanotechnology covers all aspects of the production desirable manner remains very difficult to implement of devices and systems by manipulating matter at the economically. And very little data exist on the health nanoscale. hazards of nanotechnology. Take an inch-long piece of thread and chop it into Nanotechnology is emerging at a crucial stage 25 pieces, and then chop one of those pieces into a of our civilization. A remarkable convergence of million smaller pieces. Those itty-bitty pieces are about nanotechnology, biotechnology, and information one nanometer long. The ability to manipulate matter technology is occurring. Some of the extremely pleasant and processes at the nanoscale undoubtedly exists in prospects of their symbiosis, among others, are new many academic and industrial laboratories. At least medical treatments, both preventive and curative; one relevant dimension must lie between 1 and 100 monitoring systems for buildings, dams, ships, aircraft, nanometers, according to the definition of nanoscale and other structures vulnerable to natural calamities by the U.S. National Research Council. Ultra-thin and terrorist acts; and energy-efficient production coatings have one nanoscale dimension, and nanowires systems that produce very little waste. and nanotubes have two such dimensions, whereas all The convergence of the three technologies is to three dimensions of nanoparticles are at the nanoscale. be expected. Protein molecules such as kinesin are Nanotechnology is being classified into three types. being developed to transport cargo molecules over The industrial use of nanoparticles in automobile paints distances on the order of a millimeter on silicon wafers and cosmetics exemplifies incremental nanotechnology. for eventual use in smart nanosensor systems and

eJOURNALOURNAL USA 27 Economic Perspectives / October 2005 molecular manufacturing systems. Cells, bacteria, organizations, as well as private-sector scientific and viruses are being used to manufacture complex panels, must be given greater authority to oversee this templates to precipitate medically useful molecules research. At the same time, laws must be formulated without producing medically harmful molecules to guide the conduct of individuals in charge of in pharmaceutical factories. Nanotechnology also government programs and private contractors on is being used to fabricate laboratories-on-a-chip to nanotechnology. carry out tests of biological fluids, with the data Nanotechnology today is probably like Mozart being optically accessed and electronically stored and when he was five years old: bursting with promise, processed. Nano drug delivery systems are expected with the best yet to come after a few years of to be used inside living organisms to modify specific nurturance.  biological functions, for example, to develop or boost immunities against specific pathogens. The convergence also makes urgent the need for Akhlesh Lakhtakia is distinguished professor of engineering science and mechanics at Pennsylvania State University. better regulation and oversight. With most of the work being conducted under governmental auspices, The opinions expressed in this article do not necessarily reflect the views citizen watchdog groups and nongovernmental or policies of the U.S. government.

Economic Perspectives / October 2005 28 eJOURNALOURNAL USA THE INTERNATIONAL RICE GENOME SEQUENCING PROJECT: A Case Study

C. Robin Buell Peter Beyer/University Peter of Freiburg Golden and regular white rice.

What started as a Japanese research project evolved into an rice is essential to meet the needs of the world’s popula- international research venture that delivered a key tool for tion. While conventional plant breeding has signifi cantly advancing a second “green revolution.” By involving research- increased rice output, international collaborative efforts ers and resources from many countries, the International Rice have resulted in a better understanding of the rice genome Genome Sequencing Project (IRGSP) in 2005 produced a that promises the development of rice varieties with even “map” of rice’s genetic makeup. This map will enable breeders greater yields and disease resistance. to accelerate their breeding programs and develop more hearty rice varieties, and farmers to improve their growing methods A SECOND GREEN REVOLUTION and extend their growing seasons. Also, scientists have been able to utilize the complete rice genome to further their stud- Over the past 40 to 50 years, scientists were able to ies on other cereals. make major improvements in the yield, pest resistance, and nutritional content of rice as well as of other crops. C. Robin Buell is an associate investigatorinvestigator with the They achieved these results through the implementa- Institute for Genomic Research and was a participant in the tion of conventional breeding involving genetic crosses IRGSP. between varieties of plants and selection by the breeder for the most desirable progeny. This phase of improvements n ancient Chinese proverbproverb states that “precious“precious in agricultural output was termed the Green Revolution, things areare not pearls and jade but the fi v vee grains,grains, and Norman Borlaug, a key geneticist, was awarded the Aof which rice is the fi nest.” nest.” I ndeed,Indeed, based based on on daily daily Nobel Peace Prize in 1970 for his achievements in enhanc- worldwide consumption, rice is more precious than pearls: ing agricultural production. Some 50 percent of the inhabitants of the planet consume However, in the 21st century, the growing worldwide rice every day. For a large percentage of these people, rice population, coupled with reduced acreage for agricultural is the major, and possibly the only, caloric source. production, will present serious challenges to the world’s abil- Being able to provide suffi cient and nutrient-rich ity to feed itself. Thus, a second “green revolution” is needed.

eJOURNALOURNAL USA 29 Economic Perspectives / October 2005 in the human genome. Analysis of other rice genome sequences with the IRGSP sequence resulted in the identi- fi cation of more than 80,000 new genetic markers—genes that produce a recognizable trait—that will enable breeders to accelerate their breeding programs and develop more hearty rice varieties. Even before the IRGSP had completed its task, the project’s investigators were making their fi ndings publicly available to scientists around the world for use in a broad range of plant biology research. One fi nding was the criti- cal gene involved in controlling fl owering time in rice. Day length—the hours of daylight versus darkness that change throughout the seasons—controls when a plant such as rice fl owers and consequently when it sets seed. By identify- Takuji Sasaki Takuji IRGSP participants; the author is third from the left in the front row. ing the mechanism of fl owering time, scientists can now attempt to develop rice varieties that fl ower earlier in the One tool now in use that can advance this second green planting season, thus expanding the growing season for revolution is genomics, which involves understanding the farmers. genes within an organism and how they function in the BROADER IMPLICATIONS growth and development of the organism. The science of genomics took a major step forward about 10 years ago Although rice has a substantial role in worldwide agri- when researchers at the Institute for Genomic Research culture, it has another role for scientists. It is well known in the United States were able to determine the complete that primates such as humans and chimpanzees have sequence (a map of the genetic makeup) of a free-living similar genes and genomes. The same relationship occurs microorganism, Haemophilus infl uenzae, a bacterium that with rice and its close relatives—cereals such as wheat, causes the fl u. The techniques developed at the institute are maize, barley, oats, sorghum, and millet. For technical and now widely used to determine the genetic makeup in all fi nancial reasons, a complete genome sequence is available types of organisms, including animals, plants, and fungi. only for rice. But with the close relationship between the cereals, scientists who work on other cereals have been able THE RICE GENOME PROJECT to utilize the rice genome to further their studies. Indeed, researchers were able to use the rice genome sequence to In the early 1990s, Japanese scientists began research identify a key barley gene involved in resistance to a fungal on sequencing the rice genome. In 1998, in an effort to pathogen responsible for a disease known as powdery accelerate this work and utilize international expertise, a mildew. group of scientists from several countries, led by Japanese The benefi ts of the rice genome project are clear: researchers, initiated the International Rice Genome Se- quencing Project. With funding from many countries—in- • As new crop and hardier crop species are developed, cluding Japan, China, Korea, Thailand, India, France, Bra- and as the understanding of basic plant biology accelerates, zil, and the United States—and from Taiwan, hundreds of countries will be better positioned to meet the needs of a scientists from around the world contributed to sequencing growing population in the 21st century. the rice genome. The international collaboration enabled • The IRGSP’s collaborative format demonstrates the the division of labor and distribution of costs among the scientifi c leaps that can be accomplished when experts participants. It also allowed participating countries to from around the world have access to each other’s research. have a defi ned stake in the project and get recognition for • The IRGSP has shown that state-of-the-art scientifi c completing a part of or an entire chromosome. The project endeavors do not have to involve only highly developed was completed in December 2004, and the results were countries, and that collaborative international efforts can published in August 2005. serve to enable less developed nations to acquire cutting- The IRGSP was able to identify in excess of 37,000 edge technologies. genes in the rice genome, more than the number of genes • The IRGSP experience will likely yield new efforts with stronger collaborative features. This has already begun

Economic Perspectives / October 2005 30 eJOURNALOURNAL USA with the International Rice Functional Genomics Consor- The benefi ts have far outweighed any challenges. tium—a collaboration among international scientists to In addition to providing an invaluable resource for the expand understanding of rice’s 37,000+ gene functions so world’s scientists and farmers, the successful completion as to meet increasing production needs. of the IRGSP demonstrates that international scientifi c collaborations are productive and serve purposes greater PUBLIC-PRIVATE PARTNERSHIPS than their initial goals. Certainly for other large scientifi c endeavors, international collaborative efforts should be Clearly, completing the mission of the IRGSP was a considered as a viable strategy.  challenge, and there were bumps in the road. The largest issue that the IRGSP had to address involved the paral- lel efforts to sequence the rice genome by Monsanto and The opinions expressed in this article do not necessarily refl ect the views or policies of the U.S. government. Syngenta, two large, international agribusinesses, and the Beijing Genomics Institute, a research center in China. The IRGSP subsequently collaborated with Syngenta and Monsanto, establishing a highly productive public-private partnership. This partnership incorporated private sector data into the public research results.

eJOURNALOURNAL USA 31 Economic Perspectives / October 2005 THE BIRTH OF BIOTECHNOLOGY: Harnessing the Power of DNA Dinesh Ramde

The ascent of biotechnology from in discrete biological units that the discovery of the DNA struc- would be later known as genes. ture to experimental gene therapy Six years later, Swiss biochemist has been marked by revolutionary Johann Friedrich Miescher iso- discoveries and fascinating technical lated from white blood cells the advances. These developments have substance that would be called created a sense that we can make deoxyribonucleic acid, or DNA. dramatic improvements in health It would be another 75 years care, agriculture, energy produc- before the two discoveries were tion, and other areas. But the speed linked. In 1944, Canadian biolo- at which the biotech industry took gist Oswald Avery suggested that off, the magnitude of its success, DNA was the mechanism by and the scope of its impact have which bacteria passed on their surprised even its pioneers. These hereditary material. However, considerations, industry experts say, Avery’s explanation was met with

give them even more confi dence that Barrington A. Brown/Photo Inc.Researchers, skepticism by those who believed biotechnology will deliver on its The discoverers of the DNA structure, James Watson, at left, that the genetic information of and Francis Crick, look at their model of a DNA molecule. early promise in the not-so-distant an organism was far too complex future. to be contained in DNA. Then in 1953, American biologist James Watson and Dinesh Ramde is a writer with The AssociatedAssociated PPress.ress. British molecular biologist Francis Crick determined the double-helix structure of DNA, which, in turn, led ocusing on the history of biotechnology is like writ- to a cascade of new discoveries of how DNA works at a ing an autobiography as a teenager—it seems odd molecular level. Fto focus on the past when so much more is yet to These discoveries were advancements only in the fi eld come. of biochemistry. It was not until 1972 that scientists pio- Still, the biotech industry has taken a wild ride from neered a way to combine biochemistry with a technique its humble beginnings in austere laboratories a quarter of that led to the birth of biotechnology. That was the year a century ago. The industry’s growth has been marked by that American biochemists Herbert Boyer, Paul Berg, and innovative scientifi c techniques and breakthrough discov- Stanley Cohen developed recombinant DNA, a modifi ed eries around the globe. DNA molecule created by combining DNA from two Biotech intrigues not because of how far it has come unrelated organisms. but because of the new frontiers it has yet to explore. Every cell in a living organism, from a bacterium to a Scientists foresee revolutionary changes in how we feed the human, contains DNA. In turn, DNA is made up of four world, how we vaccinate our children, and how we clean building blocks called bases, the names of which are ab- our air and water. breviated A, T, G, and C. In the same way the 26 letters of As biotechnology grows up, we take a look back at its the English alphabet can be arranged, repeated, and strung birth and infancy, in part through the eyes of the scientists together to make meaningful sentences, so too are series of and entrepreneurs who fathered it. the four DNA bases strung together in an order unique to every living creature. THE BIRTH OF BIOTECH DNA is a permanent blueprint that gives rise to tempo- rary analogs of itself called ribonucleic acid, or RNA, that In 1863, Austrian botanist Gregor Mendel discovered ultimately instructs cellular machinery to create unique that pea plants passed on traits from parent to progeny

Economic Perspectives / October 2005 32 eJOURNALOURNAL USA proteins. Each string of DNA bases that codes for one it into something protein is called a gene. meaningful in the One can think of a gene as a set of instructions that tells way of providing a cell’s machinery how to put amino acids together to form medicines and a protein. The machinery of any cell, bacterial or human, drugs to benefi t will use that set of instructions to create exactly the same people,” Boyer sequence of amino acids, and hence create exactly the same says. protein. Genentech did If that is the case, reasoned Boyer and his colleagues, not take long to what if we take a human gene that creates a vital protein, make its mark insert that gene into bacterial DNA, and compel the bacte- with the develop- ria to pump out continuous supplies of that protein? When ment of a human his team did just that, creating recombinant DNA that insulin drug pro- combined human and bacterial DNA, biotechnology was duced by geneti- born. The scientists had fi gured out a way to turn organ- cally engineered isms as simple as bacteria into factories, tiny assembly lines bacteria. The

that manufacture essential human proteins such as insulin AP/WWP/Paul Sakuma Food and Drug and human growth hormone. A bioprocess in a cell development room at Administration, Genentech. a U.S. govern- THE BUSINESS WORLD RESPONDS ment regulatory agency, approved the drug in 1982. In the ensuing years, other companies followed suit with drugs The fl edgling technology and the genetically modifi ed similarly derived from modifi ed bacteria, drugs that fought organisms it yielded inspired fear as much as it did excite- kidney transplant rejection, replenished white blood cells ment. “We had to be terribly cautious—you can’t put these in chemotherapy patients, and treated hemophilia. things back in a bottle,” says George Rathmann, the fi rst Plants were also the benefi ciaries of recombinant DNA chief executive offi cer (CEO) of the biotech fi rm Amgen technology. In 1987, Advanced Genetic Sciences created a based in Thousand Oaks, California. “You might end up genetically modifi ed bacterium that prevented frost from with a new infective agent that is more lethal than smallpox developing on strawberry and potato plants. This technol- or strep, and it would be even worse if it were combined ogy has enabled the production of more hardy and nutri- into a viral organism.” tious foods. For example, rice has been genetically modifi ed Concerns like these led scientists in 1975 to convene the to be high in vitamin A, and tomatoes have been modifi ed Asilomar Conference in Pacifi c Grove, California. At the to produce less of the substance that causes them to rot. conference, about 140 scholars created strict rules to dic- These were changes that could not be brought about by tate the limits to which recombinant DNA research must simple selective breeding. be restricted. It mandated, for example, that the technology Critics of the technology say that genetically modifi ed could be applied only to organisms that cannot live outside foods carry health risks that do not exist in crops produced a laboratory on their own, and it could not be used in through traditional breeding techniques, a claim that has genes that might be active in humans. never been scientifi cally proven. Some also argue that “It was a concern, to be sure, throughout the industry,” companies that create modifi ed crops may ultimately claim Rathmann says. “In Abbott Labs, they were so concerned intellectual, and by the same token fi nancial, rights to those about recombinant DNA that their workers had to wear crops to the detriment of the poor in developing nations. suits, helmets, almost literally a whole spacesuit. Some So far, the opposite has been happening, with farmers in companies were so cautious—to the point of overkill—that developing countries benefi ting with increased yield from they never got off the ground.” biotech crops. Other companies embraced the new technology. Boyer teamed up with venture capitalist Bob Swanson to found SPAWNING NEW SCIENCE Genentech in South San Francisco in 1976. From the beginning, Boyer saw the potential of the new technol- Techniques that have enabled the manipulation of DNA ogy. “This was very exciting, a challenging opportunity to have allowed scientists to pursue revolutionary tech- take this academic endeavor that I was a part of and turn nologies. In the 1980s, PPL Therapeutics in Edinburgh,

eJOURNALOURNAL USA 33 Economic Perspectives / October 2005 Scotland, used genetic engineering to create Rosie, a cow The goals of the project were threefold: to identify whose milk contained the human protein alpha-lactalbu- every human gene; to determine the order of the three min. This milk can be administered to premature babies billion pairs of bases—that is, the building blocks A, T, G, who are too small to nurse, and the protein enhancement and C—that comprise human DNA; and to make the se- provides amino acids essential to the infants’ development. quence available to researchers. The project was completed in 2003, two years ahead of schedule, and scientists are currently studying the data for medical gene therapy.

EXCEEDING ALL EXPECTATIONS

The biotechnology industry grew and evolved with a speed that neither Boyer nor Rathmann could possibly envision. “Seeing what’s happening today, it staggers the mind,” Boyer says. “We certainly had great expectations, and when we started we were like kids in a candy shop with

Gusto/ Photo Inc.Researchers, any number of directions to go in. I remember thinking Ian Wilmut and his creation, Dolly, the first sheep cloned from an adult in the early days when we developed recombinant DNA sheep cell. techniques, that this technology is unlimited. But we still Rosie’s embryos have been used to create clones of the couldn’t foresee all of this.” cow, clones that will be allowed to reproduce normally to Rathmann left a comfortable career in medical diagnos- create a herd of enhanced dairy cows. The cloning process tics to become Amgen’s CEO and third employee, a move involved removing DNA from one of Rosie’s cells and us- he says testifi es to his tremendous confi dence in the tech- ing it to replace the DNA of a separate cow embryo. The nology. “The decision was easy for me because the science resulting calf is then genetically identical to Rosie. Such was so powerful,” he says. “But it’s absolutely wrong to experiments had been performed for years on frogs, mice, suggest the industry evolved the way we thought it would. and sheep. It’s not surprising it was so successful, but the magnitude In 1997, researchers at the Roslin Institute in Scotland of its success, its importance to human medicine, it’s really made an even more dramatic announcement: They had quite unbelievable.” cloned a sheep by taking DNA from a sheep cell and put- Rathmann recalls seeing government fi gures in the ting it in a mammary cell, not an embryo, proving for the 1980s suggesting that the biotech industry could one day fi rst time that even “adult” cells can change into different grow into a $4 billion industry. “That shows you how cells. Until then, the process was mostly thought limited poorly we imagined,” he says. “Amgen alone turned into a to immature stem cells. $95 billion company.” A year later, American developmental biologist James To Rathmann, however, the money is a secondary con- Thompson fi rst cultivated human embryonic stem cern. At 77, the former Amgen CEO takes Epogen, one of cells—cells that are prized for their ability to grow into Amgen’s genetically engineered drugs, almost every day in specifi c cells. Scientists are studying whether stem cells his battle against kidney disease. He believes the industry’s can be used to replace dead or injured cells, thereby giving fi rst 25 years are only the beginning of something grand. patients with brain or organ failure hope for a cure. “The future was terribly bright in 1980, and it’s even In addition to cloning technology, another revolution- more exciting today because there’s been such a great track ary DNA project was under way in the 1990s. Ever since record of success across the board,” he says. “I think we’ll Watson and Crick deduced the molecular structure of see a continuing blossoming of the effects of biotechnol- DNA, scientists hoped to identify every single gene in ogy. This is a beautiful, beautiful science.”  human DNA, a daunting task considering a human has between 20,000 and 25,000 genes. By 1990, technology was suffi ciently advanced for a worldwide consortium to The opinions expressed in this article do not necessarily refl ect the views or policies of the U.S. government. undertake this bold venture, called the Human Genome Project.

Economic Perspectives / October 2005 34 eJOURNALOURNAL USA BIOTECHNOLOGY’S FIRST 142 YEARS

Gregor Mendel discovers that pea plants pass on hereditary information in 1863 distinct units that will be later called genes.

1869 Johann Friedrich Miescher isolates DNA from human white blood cells.

Studying pneumococcus bacteria, Oswald Avery et al. determine that DNA is 1944 the herhereditaryeditary material. James Watson and Francis Crick discover the molecular double-helix structure 1953 of DNA. 1955 Fred Sanger determines the amino acid sequence of insulin. Paul Berg, Herbert Boyer, and Stanley Cohen develop recombinant DNA 1972-73 techniques. Scientists express concern that recombinant DNA can lead to the development 1975 of dangerdangerousous organisms. AtAt the Asilomar Conference,Conference, a groupgroup of scientists draw up strict rrestrictionsestrictions aroundaround the use of recombinantrecombinant DNA techniques.

1976 Herbert Boyer and Bob Swanson found biotech pioneer firm Genentech.

Somatostatin becomes the first human protein developed using recombinant 1978 technology.technology.

Chiron Corporation announces it has cloned and sequenced the entire HIV 1984 genome.

Plants genetically engineered to be resistant to insects and viruses are 1985 field-tested for the first time.

GenPharm International, a biopharmaceutical company, creates the first 1990 transgenic dairdairyy cocow,w, which prproducesoduces human milk prproteinsoteins for infant formula.

1990 The Human Genome Project is launched. The U.S. Food and Drug Administration concludes that genetically 1993 engineeredengineered foods areare not inherentlyinherently dangerous.dangerous.

1997 Researchers at Scotland’s Roslin Institute report they have cloned a sheep.

1998 Two research teams succeed in growing embryonic stem cells. 2003 The Human Genome Project is completed. Korean researchers announce the successful cloning of a human embryonic 2004 cell.

eJOURNALOURNAL USA 35 Economic Perspectives / October 2005 U.S. REGULATION OF AGRICULTURAL BIOTECHNOLOGY

Three U.S. government agencies—the U.S. Department of fi eld test reports. The agency evaluates a variety of issues, Agriculture (USDA), the Environmental Protection Agency including the potential for plant pest risk; disease and (EPA), and the Food and Drug Administration (FDA)—are pest susceptibilities; the expression of gene products, new responsible for oversight of genetically engineered plants and enzymes, or changes to plant metabolism; weediness and products. Their responsibilities are complementary, and in impact on sexually compatible plants; agricultural or some cases overlapping. USDA’s Animal and Plant Health cultivation practices; effects on non-target organisms; and Inspection Service has jurisdiction over the planting of geneti- the potential for gene transfer to other types of organisms. cally engineered plants. EPA has jurisdiction over the testing, A notice is fi led in the [government-published]Federal distribution, and use of pesticides engineered into plants, and Register, and public comments are considered on the envi- FDA has jurisdiction over the food and feed uses of all foods ronmental assessment and determination written for the from plants. The following excerpt is a brief overview of the decision on granting the petition. Copies of the USDA- role these agencies play in regulating genetically modifi ed APHIS documents are available to the public. organisms. For further information, visit http://www.aphis.usda.gov/brs/. U.S. DEPARTMENT OF AGRICULTURE ANIMAL AND PLANT HEALTH INSPECTION SERVICE Under the Virus, Serum, Toxin Act, USDA-APHIS Veterinary Services inspects biologics production ithin USDA, the Animal and PlantPlant HHealthealth establishments and licenses veterinary biological sub- InspectionInspection ServiceService (AP(APHIS)HIS) is rresponsibleesponsible for stances, including animal vaccines that are products of Wprotectingprotecting agricultureagriculture fromfrom pests and dis- biotechnology. eases. Under the Plant Protection Act, USDA-APHIS has regulatory oversight of products of modern biotechnology For further information, visit that could pose such a risk. Accordingly, USDA-APHIS http://www.aphis.usda.gov/vs/. regulates organisms and products that are known or suspected to be plant pests or to pose a plant pest risk, in- U.S. ENVIRONMENTAL PROTECTION AGENCY cluding those that have been altered or produced through genetic engineering. These are called “regulated articles.” The EPA, through a registration process, regulates USDA-APHIS regulates the import, handling, interstate the sale, distribution, and use of pesticides in order to movement, and release into the environment of regulated protect health and the environment, regardless of how the organisms that are products of biotechnology, includ- pesticide was made or its mode of action. This includes ing organisms undergoing confi ned experimental use or regulation of those pesticides that are produced by an fi eld trials. Regulated articles are reviewed to ensure that, organism through techniques of modern biotechnology. under the proposed conditions of use, they do not present The Biopesticides and Pollution Prevention Division a plant pest risk through ensuring appropriate handling, of the Offi ce of Pesticide Programs, under the Federal confi nement, and disposal. Insecticide, Fungicide, and Rodenticide Act, regulates the USDA-APHIS regulations provide a petition process distribution, sale, use, and testing of pesticidal substances for the determination of nonregulated status. If a petition produced in plants and microbes. Generally, experimental is granted, that organism will no longer be considered a use permits are issued for fi eld testing. Applicants must regulated article and will no longer be subject to oversight register pesticidal products prior to their sale and distribu- by USDA-APHIS. The petitioner must supply informa- tion, and the EPA may establish conditions for use as part tion such as the biology of the recipient plant, experi- of the registration. The EPA also sets tolerance limits for mental data and publications, genotypic and phenotypic residues of pesticides on and in food and animal feed, or descriptions of the genetically engineered organism, and

Economic Perspectives / October 2005 36 eJOURNALOURNAL USA establishes an exemption from the requirement for a toler- Federal Food, Drug, and Cosmetic Act, it is the respon- ance, under the Federal Food, Drug, and Cosmetic Act. sibility of food and feed manufacturers to ensure that the products they market are safe and properly labeled. In ad- For further information, visit dition, any food additive, including one introduced into http://www.epa.gov/pesticides/biopesticides. food or feed by way of plant breeding, must receive FDA approval before marketing. (The term “food additive” The EPA’s Toxic Substance Control Act Biotechnology refers to substances introduced into food that are not pes- Program of the Offi ce of Prevention and Toxic Substances ticides and are not generally recognized as safe by qualifi ed currently regulates microorganisms intended for gen- scientifi c experts.) eral industrial uses. The program conducts a pre-market The FDA ensures that food and feed manufacturers review of “new” microorganisms, that is those microor- meet their obligations through its enforcement author- ganisms formed by deliberate combinations of genetic ity under the Federal Food, Drug, and Cosmetic Act. To material from organisms classifi ed in different taxonomic help sponsors of foods and feeds derived from genetically genera. engineered crops comply with their obligations, the FDA encourages them to participate in its voluntary consulta- For further information, visit tion process. All foods and feeds from genetically engi- http://www.epa.gov/oppt/biotech/. neered crops currently on the market in the United States have gone through this consultation process. With one U.S. FOOD AND DRUG ADMINISTRATION exception, none of these foods and feeds was considered to contain a food additive, and so did not require approval The FDA is responsible for ensuring the safety and prior to marketing. proper labeling of all plant-derived foods and feeds, including those developed through bioengineering. All For further information, visit foods and feeds, whether imported or domestic and http://www.cfsan.fda.gov/~lrd/biotechm.html whether derived from crops modifi ed by conventional breeding techniques or by genetic engineering techniques, must meet the same rigorous safety standards. Under the Source: United States Regulatory Agencies Unifi ed Biotechnology Web Site: http://usbiotechreg.nbii.gov/roles.asp

eJOURNALOURNAL USA 37 Economic Perspectives / October 2005 GLOSSARY OF BIOTECHNOLOGY TERMS

Alpha helix: A common protein structure, found Bt corn: A maize plant that has been developed though especially in hair, wool, fingernails, and animal horns, biotechnology so that the plant tissues express a protein characterized by a single, spiral chain of amino acids that is toxic to some insects but nontoxic to humans and stabilized by hydrogen bonds. other mammals.

Amino acids: The most basic building blocks of all life. Cell: The basic structural and functional unit of all Amino acids are molecules that contain both amino and organisms. Cells contain DNA and many other elements carboxylic acid functional groups. to enable the cell to function.

Antigen: Usually a protein found on the surface of the Cellulase: An enzyme complex that breaks down cellulose virus that stimulates the immune response, especially the to beta-glucose. It is produced mainly by symbiotic production of antibodies. bacteria in the ruminating chambers of herbivores. Aside from ruminants, most animals (including humans) do not Biobased products: Fuels, chemicals, building materials, produce cellulase and are therefore unable to use most of electric power, or heat produced from biological materials. the energy contained in plant material. The term may include any energy, commercial, or industrial products, other than food or feed, that utilize Chromosomes: The self-replicating genetic structure of biological material or renewable domestic agricultural cells containing the cellular DNA. Humans have 23 pairs (plant, animal, and marine) or forestry materials. of chromosomes.

Bioinformatics: The use of applied mathematics, Collagen: The main protein of connective tissue and informatics, statistics, and computer science to study the most abundant protein in mammals. It is the main biological systems. Major research areas include sequence component of ligaments and tendons. alignment, gene finding, genome assembly, protein structure alignment, protein structure prediction, Cry1A: A protein derived from the bacterium Bacillus prediction of gene expression, and protein-protein thuringiensis that is toxic to some insects when ingested. interactions. This bacterium occurs widely in nature and has been used for decades as an insecticide, although it constitutes less Biopesticides: Certain types of pesticides derived from than two percent of the overall insecticides used. such natural materials as animals, plants, bacteria, and certain minerals. For example, canola oil and baking soda Cultivar: In botany, a plant that has been created or are considered biopesticides. selected intentionally and maintained through cultivation.

Biotechnology: A set of biological techniques developed Double helix: The twisted-ladder shape that two linear through basic research and applied to research and strands of DNA assume when complementary nucleotides product development. Biotechnology refers to the use of on opposing strands bond together. recombinant DNA, cell fusion, and new bioprocessing techniques. DNA (deoxyribonucleic acid): The genetic material of all cells and many viruses; the molecule that encodes genetic Biotechnology-derived: The use of molecular biology information. DNA is a double-stranded molecule held and/or recombinant DNA technology, or in vitro gene together by weak bonds between base pairs of nucleotides. transfer, to develop products or to impart specific The four nucleotides in DNA contain the bases adenine capabilities in plants or other living organisms. (A), guanine (G), cytosine (C), and thymine (T). In

Economic Perspectives / October 2005 38 eJOURNALOURNAL USA nature, base pairs form only between A and T and Genetically modified organism (GMO): Often, the between G and C; thus the base sequence of each single label GMO and the term “transgenic” are used to refer strand can be deduced from that of its partner. to organisms that have acquired novel genes from other organisms by laboratory gene transfer methods. Gene: The fundamental physical and functional unit of heredity. A gene is an ordered sequence of nucleotides Genetics: The study of the patterns of inheritance of located in a particular position on a particular specific traits. chromosome that encodes a specific functional product such as a protein or an RNA molecule. Genome: All the genetic material in the chromosomes of a particular organism. Gene expression: The process by which a gene’s information is converted into the structures and functions Germline: The line (sequence) of germ cells that have of a cell. genetic material that may be passed to a child.

Gene expression profiling: A method of monitoring Herbicide-tolerant crop: Crop plants that have been expression of thousands of genes simultaneously on a developed to survive application(s) of one or more glass slide called a microarray. commercially available herbicides by the incorporation of certain gene(s) via biotechnology methods such as genetic Gene flow: The transfer of genes from one population engineering, or via traditional breeding methods such as to another of the same species, as by migration or the natural, chemical, or radiation mutation. dispersal of seeds and pollen. Hybrid: Seed or plant produced as the result of Gene mapping: The process of determining where genes controlled cross-pollination as opposed to seed produced are located on individual chromosomes. as the result of natural pollination. Hybrid seeds are selected to have higher quality traits (for example, yield or Gene splicing: The isolation of a gene from one pest tolerance). organism, and then the introduction of that gene into another organism using techniques of biotechnology. Membrane protein: A protein molecule that is attached to or associated with the membrane of a cell. Gene therapy: An experimental medical technique that relies on the insertion of genes into an individual’s cells Microbial pesticides: Pesticides that consist of a and tissues to treat a disease. Typically, a defective gene microorganism, for example, a bacterium, fungus, is replaced by a normally functioning one. The normal virus, or protozoan, as the active ingredient. Microbial gene is delivered to target tissues in most cases by an pesticides can control many different kinds of pests, adenovirus that has been genetically altered to render it although each separate active ingredient is relatively harmless. specific to its target pest or pests. For example, some fungi control certain weeds, and other fungi kill specific Gene transfer: A common technique in molecular insects. The most widely used microbial pesticides are biology that refers to a genetic change brought about by subspecies and strains of Bacillus thuringiensis, or Bt. taking up and recombining DNA. Molecular machine: An assemblage of a discrete number Genetic engineering: The technique of removing, of molecular components designed to achieve a specific modifying, or adding genes to a DNA molecule in order function. Each molecular component performs a single to change the information it contains. By changing this act, while the entire supramolecular structure performs a information, genetic engineering changes the type or more complex function that results from the cooperation amount of proteins an organism is capable of producing, of the various molecular components. thus enabling it to make new substances or perform new functions. Molecular self-assembly: The assembly of molecules without guidance or management from an outside source. Self-assembly can occur spontaneously in nature,

eJOURNALOURNAL USA 39 Economic Perspectives / October 2005 for example in cells (such as the self-assembly of the Pathogen: An agent that causes disease, especially a living lipid bilayer membrane) and other biological systems, as microorganism such as a bacterium or fungus. well as in human engineered systems. Many biological systems use self-assembly to assemble various molecules Peptide: Fragments of a protein, from two or more and structures. Imitating these strategies and creating amino acids in a chain, much like beaded chain bracelets. novel molecules with the ability to self-assemble into When animal meat proteins are digested, they break supramolecular assemblies is an important technique in down first into peptides and then into their amino acid nanotechnology. constituents.

Monoclonal antibody: An antibody that is mass Pesticide resistance: A genetic change in response to produced in the laboratory from a single clone and that selection by a pesticide resulting in the development of recognizes only one antigen. Monoclonal antibodies are strains capable of surviving a dose lethal to a majority typically made by fusing a normally short-lived, antibody- of individuals in a normal population. Resistance may producing B cell to a fast-growing cell, such as a cancer develop in insects, weeds, and pathogens. cell. The resulting hybrid cell, or hybridoma, multiplies rapidly, creating a clone that produces large quantities of Plant-incorporated protectants (PIPs): Formerly the antibody. referred to as plant pesticides, substances that act like pesticides that are produced and used by a plant to Mutation: Any inheritable change in DNA sequence. protect it from pests such as insects, viruses, and fungi.

Nanomedicine: A rapidly moving scientific field Pollen: The cells that carry the male DNA of a seed in which scientists are developing a wide variety of plant. nanoparticles and nanodevices, scarcely a millionth of an inch in diameter, to improve detection of cancer, boost Polymerase chain reaction (PCR): A technique for immune responses, repair damaged tissue, and thwart copying and amplifying the complementary strands of atherosclerosis. Earlier in 2005, the U.S. Food and a target DNA molecule. It is an in vitro method that Drug Administration approved a nanoparticle bound to greatly amplifies, or makes millions of copies of, DNA the cancer drug Taxol for treatment of advanced breast sequences that otherwise could not be detected or cancer. Another nanoparticle is being tested in heart studied. patients in the United States as a way to keep their heart arteries open following angioplasty. Protein: A large molecule composed of one or more chains of amino acids in a specific order. The order is Nanometer: One billionth of a meter. determined by the base sequence of nucleotides in the gene that codes for the protein. Proteins are required Nanotechnology: Systems for transforming matter, for the structure, function, and regulation of the body’s energy, and information that are based on nanometer- cells, tissues, and organs, and each protein has unique scale components with precisely defined molecular functions. Examples are hormones, enzymes, and features. Also, techniques that produce or measure antibodies. features less than 100 nanometers in size. Proteomics: The use of technologies such as mass Natural selection: The concept developed by Charles spectrometry to detect protein biomarkers in the blood Darwin that genes that produce characteristics that are that may indicate early signs of disease, even before more favorable in a particular environment will be more symptoms appear. One such marker is C-reactive protein, abundant in the next generation. an indicator of inflammatory changes in blood vessel walls that presage atherosclerosis. Nucleotide: A cellular constituent that is one of the building blocks of ribonucleic acids (RNA) and Recombinant DNA molecules (rDNA): A combination deoxyribonucleic acid (DNA). In biological systems, of DNA molecules of different origin that are joined nucleotides are linked by enzymes in order to make long, using recombinant DNA technologies. chainlike polynucleotides of defined sequence.

Economic Perspectives / October 2005 40 eJOURNALOURNAL USA Recombinant DNA technology: A procedure used Tissue culture: A process of growing a plant in the to join together DNA segments in a cell-free system laboratory from cells rather than seeds. This technique is (an environment outside a cell or organism). Under used in traditional plant breeding, as well as when using appropriate conditions, a recombinant DNA molecule can techniques of agricultural biotechnology. enter a cell and replicate there, either autonomously or after it has become integrated into a cellular chromosome. Traditional breeding: The modification of plants and animals through selective breeding. Practices used Recombination: The process by which progeny derive a in traditional plant breeding may include aspects of combination of genes different from that of either parent. biotechnology such as tissue culture and mutation breeding. Resistance management: Strategies that can be employed to delay the onset of resistance. For insect resistance Transgenic: Containing genes altered by insertion of management, this includes the use of a “refuge” in which DNA from an unrelated organism; taking genes from one the insect will not be challenged by the pesticide used in species and inserting them into another species in order to the rest of the field. get a certain trait expressed in the offspring.

Selective breeding: Making deliberate crosses or matings Variety: Subdivision of a species for taxonomic of organisms so that the offspring will have a desired classification. Used interchangeably with the term characteristic derived from one of the parents. “cultivar” to denote a group of individuals that is distinct genetically from other groups of individuals in the species. Single nucleotide polymorphisms (SNPs): Relationships An agricultural variety is a group of similar plants that, between genes and probing populations for variations by structural features and performance, can be identified in the genetic code that may increase one’s risk for a from other varieties within the same species. particular disease or determine one’s response to a given medication. Virus: A noncellular biological entity that can reproduce only within a host cell. Viruses consist of nucleic Splicing: See Gene splicing. acid covered by protein; some animal viruses are also surrounded by a membrane. Inside the infected cell, the Stem cell: A “generic” cell that can make exact copies virus uses the synthetic capability of the host to produce a of itself indefinitely. In addition, a stem cell has the progeny virus.  ability to produce specialized cells for various tissues in the body, such as heart muscle, brain tissue, and liver tissue. Scientists are able to maintain stem cells forever, Sources: Agricultural Biotechnology: Informing the Dialogue. Cornell University College of Agriculture and Life Sciences: Ithaca, NY. 2003; developing them into specialized cells as needed. There McGraw-Hill Dictionary of Scientific and Technical Terms. 6th ed. New are two basic types of stem cells. The first type is the York and Chicago: McGraw-Hill, 2002; Nill, Kimball R. Glossary embryonic stem cell, which is obtained from either of Biotechnology Terms. 3rd ed. Boca Raton, FL: CRC Press, 2002; aborted fetuses or fertilized eggs that are left over from Wikipedia at http://en.wikipedia.org/; The McGraw-Hill Encyclopedia of Science & Technology Online at http://www.accessscience.com/ in vitro fertilization. Embryonic stem cells are useful for Encyclopedia. medical and research purposes because they can produce cells for almost every tissue in the body. The second type is the adult stem cell, which is not as versatile for research purposes because it is specific to certain cell types, such as blood, intestines, skin, and muscle.

eJOURNALOURNAL USA 41 Economic Perspectives / October 2005 BIBLIOGRAPHY Additional readings on biotechnology

Acquaah, George. Understanding Biotechnology: An Integrated Fumento, Michael. BioEvolution: How Biotechnology Is and Cyber-Based Approach. Upper Saddle River, NJ: Pearson/ Changing Our World. San Francisco, CA: Encounter Books, Prentice Hall, 2004. 2003.

Bailey, Ronald. Liberation Biology: The Scientific and Moral Goodsell, David S. Bionanotechnology: Lessons From Nature. Case for the Biotech Revolution. Amherst, NY: Prometheus Hoboken, NJ: Wiley-Liss, 2004. Books, 2005. Grace, Eric S. Biotechnology Unzipped: Promises and Realities. Barnum, Susan R. Biotechnology: An Introduction. 2nd ed. Rev. 2nd ed. Washington, DC: Joseph Henry Press, 2005. Belmont, CA: Thomson/Brooks/Cole, 2005. Huang, Jikun, Scott Rozelle, Carl Pray and Qinfang Wang. Chrispeels, Maarten J. and David E. Sadava. Plants, Genes, “Plant Biotechnology in China.” Science, vol. 295, 25 and Crop Biotechnology. 2nd ed. Boston, MA: Jones and January 2002, pp. 674-676. Bartlett, 2003. Kreuzer, Helen and Adrianne Massey. Biology and Colwell, Rita. Testimony Before the U.S. House of Biotechnology: Science, Applications, and Issues. Washington, Representatives Committee on Science Research DC: ASM Press, 2005. Subcommittee, 12 June 2003. http://www.house.gov/science/hearings/research03/jun12/ Loffler, Alicia, ed. Kellogg on Biotechnology: Thriving Through colwell.htm Integration. Evanston, IL: Northwestern University Press; London: Kogan Page, 2005. Eicher, Carl K., Karim Maredia and Idah Sithole-Niang. Biotechnology and the African Farmer. Staff Paper 2005-08. Miller, Henry I. and Gregory Conko. The Frankenfood Myth: East Lansing, MI: Michigan State University Press, 2005. How Protest and Politics Threaten the Biotech Revolution. New http://agecon.lib.umn.edu/cgi-bin/pdf_view.pl?paperid=168 York, NY: Praeger, 2004. 21&ftype=.pdf Pray, Carl, Jikun Huang, Ruifa Hu and Scott Rozelle. “Five Farm Foundation. Economics of Regulation of Agricultural Years of Bt Cotton in China: The Benefits Continue.” Plant Biotechnologies. Issue Report; August 2005. Oak Brook, IL: Journal, vol. 31, no. 4, August 2002, pp. 423-430. Farm Foundation, 2005. http://www.farmfoundation.org/Issue%20Reports/ President’s Council of Advisors on Science and documents/August2005ISSUEREPORTFINAL.pdf Technology. The National Nanotechnology Initiative at Five Years: Assessment and Recommendations of the National Fedoroff, Nina V. and Nancy M. Brown. Mendel in the Nanotechnology Advisory Panel. Washington, DC: President’s Kitchen: A Scientist’s View of Genetically Modified Foods. Council of Advisors on Science and Technology, 2005. Washington, DC: Joseph Henry Press, 2004. http://nano.gov/FINAL%5FPCAST%5FNANO%5FREPO RT.pdf Freidberg, Susanne. French Beans and Food Scares: Culture and Commerce in an Anxious Age. New York, NY: Oxford Shetty, Kalidas, ed. Food Biotechnology. 2nd ed. New York: University Press. 2004. Dekker/CRC Press, 2005.

Economic Perspectives / October 2005 42 eJOURNALOURNAL USA Shmaefsky, Brian. Biotechnology in the Farm and Factory: Wu, Felicia and William Butz. The Future of Genetically Agricultural and Industrial Applications. Philadelphia, PA: Modified Crops: Lessons From the Green Revolution. Santa Chelsea House Publishers, 2005. Monica, CA: RAND, 2004. http://www.rand.org/publications/MG/MG161/ Smith, John E. Biotechnology. 4th ed. Cambridge, NY: Cambridge University Press, 2004. Zhao, Xiaojun and Shuguang Zhang. “Fabrication of Molecular Materials Using Peptide Construction Motifs.” Winston, Mark L. Travels in the Genetically Modified Zone. Trends in Biotechnology, vol. 22, no. 9, September 2004, pp. Cambridge, MA: Harvard University, 2004. 470-476.

eJOURNALOURNAL USA 43 Economic Perspectives / October 2005 INTERNET RESOURCES Online sources for information about biotechnology

U.S. GOVERNMENT ACADEMIC AND RESEARCH INSTITUTIONS

National Library of Medicine AgBioWorld National Center for Biotechnology Information http://www.agbioworld.org http://www.ncbi.nlm.nih.gov/ Agricultural Biology Communicators National Nanotechnology Initiative U.S. Land Grant Colleges and Universities http://www.nano.gov/ http://agribiotech.info/

U.S. Department of Agriculture American Institute of Biological Sciences http://www.actionbioscience.org/index.html Animal Plant and Health Inspection Service Biotechnology Regulatory Services American Phytopathological Society http://www.aphis.usda.gov/brs/index.html http://www.apsnet.org/media/ps/

Economic Research Service Center for Global Food Issues Economic Issues in Agricultural Biotechnology http://www.cgfi.com http://www.ers.usda.gov/publications/aib762/ Cornell University United States Regulatory Oversight in http://www.nysaes.cornell.edu/agbiotech Biotechnology Responsible Agencies http://www.aphis.usda.gov/brs/usregs.html#usda Council for Agricultural Science and Technology http://www.cast-science.org U.S. Department of State Bureau of International Information Programs Donald Danforth Plant Science Center http://www.usinfo.state.gov/ei/economic_issues/ http://www.danforthcenter.org/ biotechnology.html Foresight Nanotech Institute U.S. Environmental Protection Agency http://www.foresight.org/ Toxic Substances Control Act Biotechnology Program http://www.epa.gov/opptintr/biotech/index.html Information Systems for Biotechnology http://www.isb.vt.edu U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition International Service for the Acquisition of http://www.cfsan.fda.gov/~lrd/biotechm.html Agri-biotech Applications http://www.isaaa.org/ U.S. Regulatory Agencies Unified Biotechnology Web Site Iowa State University http://usbiotechreg.nbii.gov http://www.biotech.iastate.edu/

National Agricultural Biotechnology Council http://www.cals.cornell.edu/extension/nabc

Economic Perspectives / October 2005 44 eJOURNALOURNAL USA Pew Initiative on Food and Biotechnology EUROPA http://www.pewagbiotech.org (European Commission) http://www.europa.eu.int/comm/food/food/ University of California Biotechnology Program biotechnology/index_en.htm http://ucbiotech.org/ European Food Safety Authority University of Maryland http://www.efsa.eu.int/science/gmo/catindex_en.html

Medical Biotechnology Center Food and Agriculture Organization http://www.umbi.umd.edu/~mbc/ http://www.fao.org/biotech

Agricultural Biotechnology International Food Policy Research Institute http://agnic.umd.edu/ http://www.ifpri.org/themes/biotech/biotech.htm

International Rice Research Institute INDUSTRY http://www.irri.cgiar.org

AGBIOS International Service for National Agricultural http://www.agbios.com/main.php Research http://www.isnar.cgiar.org/kb/Bio-index.htm Biotech Knowledge Center http://www.biotechknowledge.com Organization for Economic Cooperation and Development Biotechnology Industry Organization http://www.oecd.org/topic/0,2686,en_2649_37437_1_1_ http://www.bio.org/ 1_1_37437,00.html

Council for Biotechnology Information World Health Organization http://www.whybiotech.com/ http://www.who.int/foodsafety/biotech/en/

CropLife America World Intellectual Property Organization http://www.croplifeamerica.org http://www.wipo.int/tk/en/genetic/index.html

INTERNATIONAL ORGANIZATIONS The U.S. Department of State assumes no responsibility for the content and availability of the resources listed above, all of which were active as of October 2005. Consultative Group on International Agricultural Research http://www.cgiar.org

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