A Brave New World in the Life Sciences

Abstract

The breadth of biological threats is much broader than commonly thought and will continue to expand.

For thousands of years, humans have manipulated plant and animal stocks–first by accident and later selectively–to meet changing societal and environmental needs. But the discovery of the structure of DNA in 1953, followed by the invention of DNA recombinant technology two decades later, made it possible to manipulate genetic material in a directed fashion and to alter the “nature” of an organism within a single generation. Then, in 2001, scientists finished the initial draft of the human genome sequence, opening a portal to vast possibilities, such as gene therapy. This pattern of rapid, punctuated technological advancement reflects a revolutionary change in the way people attempt to understand biological systems and a growing capacity to manipulate them. As physicist and author Gregory Benford has observed, just as physics dominated and shaped the contours of the twentieth century, so too may we now be at the start of the “biological century.” 1

Everyday in laboratories around the world, bio-medical researchers are using sophisticated technologies to manipulate microorganisms and hosts in an effort to understand how microbes cause disease and to develop better preventive and therapeutic measures against infectious disease. Plant biologists are applying similar tools in an effort to improve agricultural yield and explore the potential for using plants as an inexpensive medium for manufacturing vaccines, antibodies, and other products. Similar efforts are underway with animal husbandry. Scientists and engineers in many other disciplines are relying on continuing advances in the life sciences to develop environmental remediation technologies, improve biodefense capabilities, and create new materials. Moreover, other fields not traditionally viewed as biotechnologies–such as materials science, information technology, and nanotechnology–are converging with biosciences in unforeseen ways and enabling the development of previously unimaginable technological applications.

This new knowledge holds enormous potential to improve public health and agriculture, strengthen national economies, and close the development gap between resource-rich and resource-poor countries. However, as with all technological advances, it is almost deliberately naive to think that the extraordinary growth in the life sciences might not be exploited for nefarious purposes. This is true even though, since antiquity, humans have generally reviled the use of disease and toxins for hostile purposes. In its most recent unclassified report that sought to predict the most important worldwide trends, the U.S. National Intelligence Council argued that a major bioterrorist attack will likely occur by 2020. 2 Official U.S. statements continue to cite a dozen or so countries that are pursuing or are already believed to have biological weapons capabilities. 3

It was against this background that the National Research Council (NRC) and the Institute of Medicine (IOM) in 2004 formed the ad hoc Committee on Advances in Technology and the Prevention of Their Application to Next-Generation Biowarfare Threats. The goal was to examine current trends and future objectives of research in public health and the life and biomedical sciences that contain applications relevant to the development of new types of biological weapons or agents of biological origin, with a focus on five to ten years into the future. The committee recognized that the global technology landscape is shifting so rapidly that any attempt to devise a formal risk assessment of the future threat horizon could be an exercise in futility.

But the committee's report, “Globalization, Biosecurity, and the Future of the Life Sciences,” released earlier this year, did reach a troubling, overarching conclusion: The breadth of biological threats is much broader than commonly appreciated and will continue to expand for the foreseeable future.

First strike: Experts at the Fort Detrick, Maryland, biomedical research laboratory open an anthraxlaced letter that was sent to Democratic Sen. Patrick Leahy on November 16, 2001.

OUT OF LEFT FIELD

The rapid growth of biological and other relevant technologies over the past 30 years has been driven by several simultaneous processes. For starters, there has been a quantitative increase in performance coupled with a decrease in the cost of existing technologies and instruments–as well as sudden and occasionally dramatic paradigm shifts resulting from unanticipated new inventions, discoveries, and insights. In addition to recombinant DNA technology (which sparked the biotech revolution in the 1970s), prominent new inventions and discoveries in recent history include the polymerase chain reaction (a technique by which fragments of DNA can be replicated very rapidly, without the use of a living organism) and the advent of RNA interference (RNAi) technology (which triggers a naturally occurring mechanism within cells that selectively silences and regulates specific genes). Innovations such as these are a precondition for the rapid growth of technology. They result in the capacity to reduce the development costs associated with new and potentially very useful products, such as the recombinant hepatitis B vaccine, one of the early “fruits” of the recombinant DNA era.

Equally important, however, are both public and political support for these efforts. Such support can drive the availability of government or venture capital funding required to fuel the advancement of research and development activities. Current levels of government support in the life sciences can be attributed in part to unforeseen historical events, such as the political decision to declare a “war on cancer” in the 1970s, the emergence of the HIV/AIDS pandemic in the 1980s, and the 2001 anthrax mailings. 4

This constantly changing and rapidly growing global technological landscape makes it extremely difficult, if not impossible, to predict specific future trends. Just a year before it earned the “Breakthrough of the Year” title from Science magazine, RNAi was met with doubt and criti-cism. 5 Self-assembling nano-devices, such as the DNAzyme (a device that can bind and cleave RNA molecules one by one) developed in 2004 by Purdue University researcher Chengde Mao, were unimaginable a couple of years ago. 6 About the only thing one can predict with certainty is that the life sciences will continue to advance quickly, in a variety of directions, and that new and previously unanticipated paradigm shifts are very likely to occur in the future.

Some of these shifts may come “out of left field”; they may be the consequence of technologies that have very different applications from those originally intended, or may be combined in unexpected, nontraditional configurations. Discoveries born of the merger of nanotechnology and biotechnology are one example of such a synergistic combination. For instance, in January 2005, researchers from the University of California, Los Angeles, described a nanoscale mechanism for externally controlling protein function–a technological advance that could ultimately lead to a generation of “smart” drugs that are active only when certain DNA sequences are present or a certain gene is expressed. 7 Such breakthroughs are likely to continue, particularly as nanotechnology is rapidly proliferating worldwide. The number of nanotech patent applications from China, for instance, ranks third in the world behind the United States and Japan, and Chinese papers on nanoscience and nanotech-nology in peer-reviewed international journals now outnumber those from the United States.

Such technological synergy further suggests that microbial pathogens and their toxins, which are currently a major focus of U.S. biodefense efforts, are not the only agents of biological origin to be concerned about. A growing number of experts warn that bioregulators–small, biologically active compounds (such as neurotrans-mitters) that are essential for normal physiological functioning–may pose a more serious dual-use risk than had previously been appreciated. 8 If manipulated, these compounds could cause pain, alter moods, and trigger other psychological changes. Yet bioregulators have not generally been viewed as potential threats, largely because of the lack of effective delivery technology.

But recent technological developments have made the potential dissemination of these compounds much more feasible. Previously, the dual-use risk of bioregulators was considered minimal because of their lack of suitability for aerosolization unless microencapsulated. (Microencapsulation is the envelopment of small solid particles, liquid droplets, or gas bubbles with a protective coating comprised of compounds such as organic polymers, wax, and fat.) Initially limited to the pharmaceutical industry, the applications of microencapsulation have expanded to include water treatment, food and agriculture, and the cosmetic industry. It's small wonder that, according to data provided by the Southwest Research Institute, the number of U.S. patents for encapsulation processes has increased from about 1,250 during 1976-1980 to about 8,500 during 1996-2001. 9 Future applications of microencapsulation could include the transplantation of encapsulated live cells for therapeutic purposes and teddy bears that release a scent that helps children sleep. 10 But if used in the delivery of bioregulators, the technology poses tremendous risks.

Alternatively, bioregulators or any biologically active compound could be expressed and delivered by a virus. Two robust, well-disseminated technologies make this undertaking possible. The first is reverse engineering of viruses–a technique recently used by U.S. researchers to reconstruct the 1918 Spanish Flu virus that killed as many as 50 million people. The other technology is de novo synthesis of nucleic acids, which makes it possible to create genetic sequences that specifically program cells for the expression of a given protein. By modifying a common, transmissible, human-adapted virus to express one of these potent molecules, the challenges of both agent production and delivery could be addressed.

This concern over bioregulators highlights the reality that the materials, equipment, and technology necessary for disseminating and delivering biological agents to their intended recipients are equally, if not more, important than the agents themselves. During its two years of deliberations, the ad hoc committee identified a number of other potential dual-use risks. What follows are just two, in-depth examples.

GENOMIC MEDICINE

Whereas “genetics” refers to the study of specific genes and their effects, “genomics” encompasses the study of genetic material on a large scale–the roles and interactions of all the genes and components of an entire genome (the complete genetic blueprint of an organism). The first complete genome sequence of any independent life form was published in 1995. 11 This field of research saw another major breakthrough in 2001, when the Human Genome Project, coordinated by the Energy Department, the National Institutes of Health, and Celera Genomics published the first draft sequence of all human genes, comprising 3 billion chemical bases strung in a sequence over 23 pairs of chromosomes.

Scientists have long known that genetic variation is the basis of human individuality, as well as susceptibility to disease. As such, genomics offers tremendous potential for treating disease. Pharmaceutical companies anticipate producing more effective drugs with fewer side effects. Therapies can be tailored to individual patients. People susceptible to specific disorders can engage in preventive health by altering their lifestyles.

Genomic medicine is still in its infancy. Although the Human Genome Project has identified nearly all of our genes, we still do not know what each gene does or how they work in tandem. But, as with other biomedical fields, state-of-the-art technologies are lowering the barriers and costs for genomic research. Whereas it cost roughly $800 million to complete the first map of the human genome, a team of researchers at the Harvard Medical School announced last year a method for sequencing DNA that they say could accomplish the same task for $2 million now and $20,000 in the future. And other emerging technologies may make a $1,000 human genome sequence possible within the next five years. 12

Animal pharm: Researchers at National Taiwan University succeeded in breeding three green male pigs by injecting fluorescent green protein into pig embryos. The pigs, used to study human diseases, could help researchers track changes in some developing tissues.

Understanding and harnessing genomic variation is expected to contribute significantly to improving the health of people worldwide, including the developing world. 13 Mexico, for instance, is in the process of developing one of the first genomic medicine technology sectors in Latin America, which is expected to serve as a regional model for other countries. The Mexican government and medical and biomedical research communities see a window of opportunity for investing in this emerging technology, so as to minimize the likelihood of needing to depend on foreign aid and sources in the future. With a population of 100 million people comprising 65 distinct ethnic groups, the genetic sequences unique to Mexico's inhabitants could preclude the import of genomic-tailored medicines developed abroad. “One might question the cost of developing a genomic medical platform in a country still challenged with basic needs like clean water, maternal health, and nutrition,” acknowledged a 2005 report on dual-use technologies published by the NRC and the IOM. But “many of the diseases that genomic medicine would target bear a significant economic and public health cost to Mexico. Direct costs of diabetes, for example, account for 4 to 6 percent of the total annual health budget.” 14 Likewise, genomic medicine activities in Singapore represent another national effort to gain leverage in this field. Already, high-tech manufacturing and financial services serve as the fulcrum of the Singaporean economy. Strengthening biotech capacity, including in genomic medicine, is viewed as the next step forward to accelerated economic growth. 15

But the same genomic sequences that will one day allow health care providers to develop patient-specific treatments might some day be exploited as targets for novel biological agents. Knowledge generated from genomic medicine could be used to target specific ethnic, racial, or other population characteristics. A company called DNA Print Genomics, for example, has already identified a number of genetic markers that correlate highly with racial or ethnic designations, many of them having to do with metabolizing toxins found in foods that are indigenous to certain areas. The markers identified by this firm provide quantitative measures of an individual's ancestry, according to four different “anthropological groups”–Native American, East Asian, Sub-Saharan African, and European. (“European” ancestry can be broken down into subgroups including, but not limited to, Northwestern European and Southeastern European.) 16

Genomically targeted weapons need not be hugely effective or even completely selective to cause major problems. In addition to the direct health effects of an attack, tremendous societal repercussions might be triggered–such as social tension and fragmentation–that could potentially do more damage than the immediate harm caused by the disease itself.

BIOPHARMING

The expansion of genetically modified (GM) or transgenic crops is expected to be one of the most important future agricultural trends associated with or resulting from advances in biotechnology. Potential benefits of transgenic agriculture include the development of disease-resistant crops (which obviate the need for some environmentally hazardous pesticides) and the production of better-tasting foods.

Environmental and societal benefits notwithstanding, ultimately, as with the pharmaceutical industry, economics is the bottom line. Any technology that results in lower production costs and higher profit margins will likely progress more rapidly than other, lower-yield ventures. About 45 percent of the world's crops are lost to disease, insects, and drought annually. In the United States alone, $20 billion worth of crops are lost annually (one-tenth of production)–a large margin that could be potentially reduced by advances in transgenic technology.

The recent rapid growth and global dispersion of commercialized GM crops suggests that efforts to improve and maximize agricultural productivity already serve as yet another powerful driver and distributor of advanced biotechnologies. According to a report issued in January 2005 by the International Service for the Acquisition of Agri-Biotech Applications (ISAAA), as of 2004 there were 14 biotech “mega-countries,” that is countries that grow more than 50,000 hectares of biotech crops. 17 Based on data from Cropnosis (a crop protection market research firm) and provided by ISAAA, in 2004, the global market value of biotech crops was an estimated $4.7 billion and was expected to top $5 billion in 2005.

Transgenic crops are not the only agricultural application of advancing life science knowledge. Similar technological advances are being applied to biopharming, which entails the harvesting of bioactive molecules from mass-cultured organisms and crops for use as ingredients in industrial products and pharmaceuticals. Transgenic crop plants, into which the genes for bioactive compounds from other species have been inserted, serve as horticultural manufacturing platforms. A novel advantage of biopharming is the crop-based production of vaccines and antibodies otherwise not possible or too expensive to produce using conventional methods. 18 Plant manufacturing platforms provide a potentially cost-effective means to produce vaccines, thus offering the ability to deal with some of the problems associated with global vaccine manufacture and delivery.

However, transgenic plants could be malevolently engineered to produce large quantities of bioregulators or toxic proteins, which could either be purified from plant cells or used directly as biological agents. As with legitimate production, using transgenic plants as bioreactors would eliminate the need for mechanical equipment normally associated with the process. The technology would be limited to producing protein-based agents. But because transgenic plants would be largely indistinguishable from non-transgenic crops, biopharming could potentially provide a covert means for producing large amounts of product. 19

THE PATH FORWARD

Biotechnology, nanotechnology, and information technology are converging in ways that will enable humans to do things–for good or ill–never dreamt of until now. Unfortunately, the existing proliferation control models for halting or slowing the global spread of these tools and technologies rely heavily upon the nuclear arms control paradigm. But as a recent U.N. report on counterterrorism strategies astutely noted: “Biotechnology is not like nuclear technology. Soon, tens of thousands of laboratories worldwide will be operating in a multibillion-dollar industry. Even students working in small laboratories will be able to carry out gene manipulation. The approach to fighting the abuse of biotechnology … will have more in common with measures against cybercrime than with the work to control nuclear proliferation.” 20

Past policy responses to the problem of biological weapons have either focused on strengthening the proliferation control regimes embodied by the Geneva Protocol and the Biological and Toxin Weapons Convention (BWC) or enhancing “informal” dialogues between scientists when formal governmental engagement is either strained or nonexistent. The U.S. rejection of the compliance and verification protocol for the BWC in late 2001, coupled with the war in Iraq, precipitated by concerns–flawed or otherwise–over that country's biological weapons programs, demonstrates the need to redefine conventional arms control policy and practice in light of a changing political, national security, and technology landscape.

In the face of these complexities, the NRC/IOM committee concluded that there is no silver bullet to solve the problems and threats posed by biological warfare and bioterrorism. Addressing the problem is analogous to the iterative process of software development, where in the early phases there may be multiple, not always compatible, systems that incrementally develop into a commonly accepted approach and standard. Instead of a top-down control regime to stem the flow of materials and knowledge that have applications and implications for the life sciences enterprise, the committee proposed a number of recommendations that could constitute a web of protection to reduce the likelihood that these emerging technologies will be used successfully for destructive purposes.

Grand design: A map of the human genome debuts at a February 12, 2001 news conference

One key recommendation is that scientific communications and exchanges must remain open. The committee was deeply troubled by proposals from a variety of parties to impose constraints on the flow of scientific information stemming from fundamental research on pathogens and technologies. While it is understandable that one might feel safer with rigid and far-reaching regulations on dual-use research of concern, this type of regulatory regime creates an illusion of safety. Such draconian measures do little to reduce risks or increase domestic security, since the risks associated with malevolent dual use go well beyond a list of pathogens and their toxins and encompass virtually all aspects of the life sciences. 21 In addition to being infeasible and undesirable, such restrictions are likely to have the unintended consequence of impeding the development of robust defenses against future biological threats and hampering competitiveness in the global marketplace.

An example of such undesirable restrictions can be found in a recent Commerce Department proposal to revise and “clarify” its requirements on “deemed exports.” Under this proposal, a deemed export occurs when a foreign national working in the United States gains access to technology–or information–that is export controlled. In interpreting its obligations under this clarification, at least one prominent university in the United States concluded that deemed exports could include providing, transferring, or disclosing technology and information to a foreign national within the United States via telephone conversations, facsimiles, e-mail communications, face-to-face discussions, tours of laboratories, training sessions, and sharing computer data. Fortunately, this proposed deemed export policy has been put on hold until an advisory committee reviews and provides recommendations on it to the Commerce Department. 22

We have been down this road before. The struggle to decide whether areas of scientific research and communications should be constrained in the name of national security recurred throughout the Cold War. In the early 1980s, the Reagan administration sought to restrict scientific communication in a number of fields. That controversy eventually led to a presidential directive that is still in force today. National Security Decision Directive 189 (NSDD-189) states that federally funded fundamental research, such as that conducted in universities and laboratories, should “to the maximum extent possible” be unrestricted. Where restriction is deemed necessary, the control mechanism is formal classification. NSDD-189 further states that “no restrictions may be placed upon the conduct or reporting of fundamental research that has not received national security classification, except as provided in applicable U.S. statutes.” 23 The proliferation of an ever-expanding class of information deemed by some in the federal government to be “sensitive but unclassified” may, in effect, nullify the classification regime envisioned by NSDD-189 and erode the traditional culture of openness in the global life sciences research enterprise. 24

The futile nature of attempting to predict, and therefore prepare for, the countless ways terrorists or malevolent states might choose for a biological attack led the NRC/IOM committee to its final conclusion: The best preparation is to strengthen the nation's fractured public health infrastructure and the lack of coordination that exists among the myriad federal and state agencies that would be called on during an attack. The same science and technology that poses risks is also a critical component of our nation's defense against both natural and deliberate biological threats. Of all the committee's recommendations, this one is perhaps the most obvious and important. But it is also the least novel, and therefore, unfortunately, the least likely to be heeded.

Despite considerable effort since September 11, 2001 to shore up its health system and to coordinate its response agencies, few if any experts believe that the United States has achieved even a minimal level of success in accomplishing these goals. Ironically, substantial returns from these investments are guaranteed. Even in the absence of a deliberate attack, a robust, agile public health system and a progressive biodefense strategy greatly enhance our ability to address the ever-present and constantly evolving threats to health from nature, as should be clear from the avian flu hazard. Although short on sizzle, such efforts are imperative. The costs will be high if we fail to make such investments.

Supplementary Material

Uniting Against Terrorism: Recommendations for a Global Counterterrorism Strategy

Mapping the Global Future