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Discovery, Innovation, and Policy in Human Health

by
Shirley Ann Jackson, Ph.D.
President, Rensselaer Polytechnic Institute

Keynote Symposium: “New Biologists for the New Biology”
47th Annual Meeting of the American Society for Cell Biology
Washington Convention Center, Washington, D.C.

Saturday, December 1, 2007


Good evening.

Science always has been conducted within a global context. There is a long history of scientists, in different countries, talking and working with each other. But at the outset of this millennium, new challenges and new imperatives profoundly are impacting science and how it must be done. This is prompting new thinking about the role and conduct of science — especially science in human health — and the importance of new and innovative approaches to scientific discovery and technological innovation.

My purpose, this evening, is not to tell you what you know a lot more about than I do, but to use the kinds of work you do as a context to define and to examine some of the new challenges and new imperatives.

What is different about science, today, rests upon two pillars:

  • One pillar consists of challenges science must confront which affect human health and welfare, or energy supply, or other arenas, and which travel across, or appear in, multiple countries or multiple populations. One might call them scientific challenges without geographic and population borders.
  • A second pillar consists of challenges and (related) scientific questions which require multiple disciplines to address. One might call them scientific discoveries and technological innovations without disciplinary borders.

CHALLENGES WITHOUT GEOGRAPHIC AND POPULATION BORDERS
Consider issues which have warranted recent headlines — pandemic diseases linked to viruses such as HIV-AIDS or the H5N1 virus, responsible for Avian Flu. While we have, with great effort, made progress in the treatment of HIV-AIDS, the H5N1 virus, the highly pathogenic avian influenza A epizootic which infects primarily birds, is potentially even more threatening. While the H5N1 virus does not usually infect humans, infections with these viruses have occurred sporadically from direct contact with infected birds. There is concern that the virus will mutate, cross species, and cause a global pandemic. Because of its ability to cross species and to be carried by migrating birds, this, clearly, is a challenge which crosses both geographic and population borders.

Another disease is Leishmaniasis, a parasitic infection transmitted through the bite of an infected sand fly. A deadly version — visceral Leishmaniasis (VL) (also known as kala-azar) — affects 1.5 million people around the world, killing 200,000 annually, primarily in India, Bangladesh, Sudan, Brazil, and Nepal. With approximately a half million new cases each year, it is the second most deadly parasitic disease in the world, after malaria.

Historically, there has been a focus on infectious disease, be it viral (H5N1), bacterial (Staphylococcus, Streptococcus), or parasitic (malaria, Leishmaniasis), but also, a focus on diseases involving rapid cell growth, such as cancer. Of course there are cancers of all kinds, and while there are certain genetic markers for cancers that have been discovered, there are not, yet, complete therapies to eliminate the progression of many cancers.

There have been surgical interventions to curtail the progression of disease, and, there has been vaccine or pharmaceutical intervention. In addition to these types of diseases, which remain a focus of global concern, there is an increased attention to diseases which cannot be dealt with by traditional approaches — diseases which involve cell death, or ones that result from changes in protein structure.

While I will not delve into the specific scientific questions embedded in each challenge, inherent within each are scientific concerns, technological challenges, policy issues, and even global diplomatic imperatives. Speaking broadly, these worldwide challenges must be resolved in concert, in order to develop effective solutions.

Diseases without geographic and population borders, whose treatments involve traditional and non-traditional approaches to diagnosis, mitigation, or cure, inherently draw upon new interventional strategies and techniques which derive from multiple disciplines and technologies. Examples include new sensors and detection technologies, high throughput data analysis, visualization and animation capabilities, computationally intensive modeling, and new drug delivery techniques. For example, drug therapies for infectious diseases and cancers may involve targeting selected cells for the delivery of small organic molecules, or creating anti-cancer vaccines with cell surface markers. For diseases such as Parkinson’s, Alzheimer’s, and juvenile diabetes, treatment may require cell replacement therapies, and the monitoring and understanding of protein structure and conformation.

The understanding of these diseases from the cellular, genetic, and proteomic perspective crosses biology, biochemistry, physiology, computation, data mining, visualization, and physical modeling.

Interventions will require the ability to image and to manipulate at the cellular and sub-cellular levels, and the ability to bioengineer cells to respond to certain drugs, among many approaches.

Cell replacement therapies necessarily lead to consideration of stem cell research.

DISCOVERY AND INNOVATION WITH DISCIPLINARY BORDERS
Stem Cells
From the beginning, of course, this society (the ASCB) has been a leader in the advocacy for stem cell research. The announcement in November — that research teams from Japan and the United States had created potential stem cell substitutes from human skin cells — could effectively end-run the controversial ethical issues of embryo destruction, and policy restrictions on federal funding which have impeded progress in this arena.

If the discovery holds, it gives scientists new ways of thinking about the downstream challenges of using stem cells to study and to treat disease, and to apply the knowledge gained to the development of conventional drugs. However, it is far from clear whether science can abandon embryonic stem cell research, and many feel that it should continue.

Weighing in on the challenge, engineers at Rensselaer Polytechnic Institute have developed new tools to resolve two problems which have slowed progress in stem cell research — how quickly to test stem cell response to different drugs or genes, and how to create a large supply of healthy, viable stem cells from only a few available cells.

These researchers have created methods to enable high-throughput study of stem cells on devices the size of a standard microscope slide. The techniques enable thousands of individual stem cell experiments to be carried out quickly, and in parallel, on one small device. The device will enable drug researchers to quickly screen thousands of small molecules for their impacts on the fate of stem cells.

The team developed a specialized stamping technique that can be used to quickly understand how different genetic sequences affect stem cell development. The stamp is covered with thousands of mircoscale prongs. The prongs imprint the surface of the corresponding slide, creating a microarray platform with thousands of individual cell-adhesive divots — like mircoscale Petri dishes without a clean room or sophisticated machinery.

Another Rensselaer team has transformed a polymer found in common brown seaweed into a device that can support the growth and release of stem cells at the site of a bodily injury or at the source of a disease. The findings, which are detailed in the December 2007 issue of Biomaterials, mark an important step in efforts to develop new medical therapies using stem cells.

This slide shows a cluster of proliferating neural stem cells circled in black; a separate microbead releases alginate lyase, circled in white, that will break down the outer layer of the scaffold, releasing stem cells into the body. The scaffold can degrade in the body at a controlled rate, enabling scientists to control growth of stem cells in the scaffold and to direct how, when, and where to release them in the body.

Systems Biology
The efficacy of converging multidisciplinary approaches is aptly demonstrated in systems biology. It is born of the catalog of genetic information provided by the Human Genome Project, which examines the integrated and interacting network of genes, proteins, and biochemical reactions within biological organisms or processes. Systems biology seeks to model these interactions within one system. Networks of biological components interact in highly structured but incredibly complex ways. Understanding and modeling these complex interactions and systems require a new and inherently interdisciplinary approach to a more full understanding and comprehension of life.

Experimental techniques, in systems biology, involve transcriptomics, metabolomics, proteomics, and high-throughput techniques used to collect quantitative data. Theoretical techniques employ computational modeling to construct and validate models which propose specific testable hypotheses. It, also, is seen as a strategy to integrate complex data from diverse experimental sources — made available via the Internet—about the interplays between different hierarchies of biological information and biological systems.

The data quantities are vast and require digitizing, interdisciplinary tools, and the assistance of computer scientists, mathematicians, physicists, and engineers. The U.S.-based Institute for Systems Biology employs astronomers, among others, because they are comfortable coping with huge amounts of data.

TECHNOLOGICAL INNOVATION
There are other examples where multiple fields come together to address critical science and technologically-based issues.

Energy security is one of the greatest economic and political issues of our time. Given the growing global energy demand, a comprehensive energy roadmap must be developed. In the interim, with continued fossil fuel usage, we must pursue the extraction and use of such fuels — in as efficient and environmentally benign a way as possible. Nanotechnology holds promise here.

Nanotechnology is applied science and technology directed toward the control of matter on the atomic and molecular scale. It is inherently multidisciplinary, drawing from fields which include applied physics, materials science, interface and colloid science, device physics, supramolecular chemistry, chemical engineering, mechanical engineering, and electrical engineering.

Its uses are legion, and only now being understood. My own university is exploring nanoparticle gels, polymer nanocomposites, and nanostructured biomolecule composite architectures. Each research thrust is supported by multiscale theory and modeling, as well as extensive characterization efforts.

In the oil and gas industry, an array of possibilities from nanotechnology research holds promise. Consider:

  • Designer properties” to enhance hydrophobic or hydrophilic behavior, to enhance materials for waterflood applications.
  • Lightweight, rugged materials which reduce weight requirements on offshore platforms, and more reliable and more energy-efficient transportation vessels.
  • Nano-sensors deployed in the pore space via “nano dust” to provide data on reservoir characterization, fluid flow monitoring, and fluid type recognition.
  • Small drill-hole evaluation instruments to reduce drilling costs, and to provide more environmental sensitivity due to less drill waste.

Nano-engineered materials can provide predictable responses to known stimuli. Examples include:

  • Pipelines which detect conditions under which undesirable materials might form, and respond accordingly to avert a problem (for example: non-desirable phase changes such as ice plugs).
  • Pipelines which detect leaks and perform self-healing processes.

These show that smart materials aligned with sensor technologies can facilitate intelligent exploitations of oilfield systems.

Paper Battery
The innovative impact of converging approaches is further aptly demonstrated by the development of a “paper battery” at Rensselaer Polytechnic Institute.

At Rensselaer researchers have developed an integrated energy storage device from cellulose (separator), carbon nanotubes (electrode), and a liquid salt (electrolyte). 

More than 90 percent of the device is cellulose. Researchers infused the cellulose with aligned carbon nanotubes, which act as electrodes and allow the storage device to conduct electricity.

The nano-engineered device can operate over a 400° F temperature range and can serve as both a high-energy battery and a high-power capacitor. It is completely integrated, can be printed like paper, is lightweight, flexible, and has the capability to use human body fluids to activate the battery. It is geared toward meeting the design requirements of implantable medical equipment as well as tomorrow’s electronics and transportation. Because it is primarily cellulose and contains no toxic chemicals, it is environmentally benign.

Its development resulted from a chance interaction in our new Center for Biotechnology and Interdisciplinary Studies between resident postdoctoral students with expertise in biopolymers, nanotubes, and electronics from three different Rensselaer laboratories. While each laboratory had decades of experience in their respective fields, it was the confluence of postdoctoral students from each laboratory that resulted in the creation of this extraordinary new device.

DIVERSITY-ENHANCED DISCOVERIES AND INNOVATION
As all of these examples strongly suggest, our need to mitigate critical global challenges requires the employment of diversity in its broadest sense. There are four aspects of “diversity” which we must enjoin — diversity of approach, diversity of outlook, diversity of pedagogy, and diversity in fact. We may call this diversity-enhanced scientific discovery and technological innovation.

Diversity of Approach
Diversity of Approach involves new links between and among disciplines, and between sectors, which combine to create new approaches. In the following example, the combination of experience in pharmaceuticals in the private sector, and in public policy, led to a new way of addressing a global public health issue.

Leishmaniasis
Dr. Victoria Hale, a scientist in the pharmaceutical and biotechnology industries, who, also, had been an official at the U.S. Food and Drug Administration (FDA), devised a unique, nonprofit approach to developing pharmaceuticals for diseases of the developing world. From her FDA experience, Dr. Hale knew that many promising drug-development projects — especially for diseases of the poor — are not developed to completion, nor prepared for clinical trials, because the economic framework is geared toward blockbuster drugs for diseases which affect wealthy populations.

While about 90 percent of the world’s diseases affect the populations of developing nations, only about 3 percent of all research and development is directed toward these diseases.

Dr. Hale organized the Institute for OneWorld Health, the first not-for-profit pharmaceutical company in the United States. The company identifies “orphan drugs,” negotiates for intellectual property rights, raises development funding, and asks researchers to contribute expertise to the development process.

Three years ago, OneWorld Health completed the largest-ever Phase III clinical trial of paromomycin, an off-patent, broad-spectrum aminoglycoside antibiotic with anti-parasitic activity known to be effective in treating Leishmaniasis, but which had not gone through clinical trials for approval. Another antibiotic, Amphotericin B, effectively treats Leishmaniasis, but a treatment costs $120. Clinical trials by OneWorld Health showed that a course of paromomycin was as effective as Amphotericin B, but costs only about $10.

In August of 2006, the Government of India approved Paromomycin IM Injection, to cure Visceral Leishmaniasis (VL). The approval of the once-daily, 21-day cure provides lifetime immunity, and challenges the assumption that pharmaceutical research and development is too expensive for new medicines the developing world so desperately needs.

OneWorld continues to demonstrate its commitment to expanding the reach of this drug. Just last month, OneWorld Health announced a major Phase 4 pharmacovigilance and access program for paromomycin to study the safety and effectiveness of the drug in progressively more rural areas in Bihar State in India.

OneWorld Health currently is working on drugs to treat malaria and Chagas disease, and was recently awarded a $46 million grant from the Bill and Melinda Gates Foundation to expand its research on new treatments to complement traditional approaches for fighting diarrhea, a leading cause of death in children under the age of five worldwide. This research will examine drugs for secretory diarrheal disease, particularly anti-secretory drugs that inhibit the loss of fluid in the intestine.

Cyanobacteria
In yet another example: in areas of high biodiversity, organisms which cannot flee their predators—plants or coral, for instance—are evolutionarily predisposed to develop high toxicity. Such substances may be useful in pharmaceuticals to treat human disease.

One such organism is “cyanobacteria,” also known as “blue-green algae.” You may be familiar with the work of Dr. William Gerwick at the Scripps Center for Marine Biotechnology and Biomedicine in La Jolla, California, who has studied cyanobacteria for years.

Several years ago, Dr. Gerwick, collaborated with Eduardo Ortega, a parasitologist at Panama's Institute for Advanced Scientific Investigations, to determine if cyanobacteria had the potential to be used for the development of drugs. Dr. Ortega had pioneered a new screening method to "prospect" for organisms which produce toxins that may act against malaria, dengue fever, and Leishmaniasis. The method involved tagging a parasite's DNA with fluorescent stain and incubating it with the cyanobacteria. If the toxins have no effect on the parasite, the fluorescence will increase as the parasite reproduces. If the fluorescence does not increase, researchers know that they have found cyanobacteria with drug development potential.

Dr. Gerwick and researchers at the University of Michigan have discovered a “next step,” which was published in the Nov 9th issue of Science. They have acquired a new molecular tool that can help transform toxins from cyanobacteria into a next-generation cancer drug. This cross-disciplinary team of chemists, biologists, immunologists, and oceanographers decoded a key part of the biosynthetic pathway of curacin A, a leading anti-cancer drug candidate derived from a Caribbean coral reef cyanobacterium called L. majuscula. They found that a GNAT enzyme — one of a family of proteins long known to play roles in gene regulation, hormone synthesis, and antibiotic resistance—helps to initiate the chain-building process that forms curacin A.
From a policy and legal standpoint, this raises interesting questions about who should profit from patents based on biodiversity in developing countries.

Indeed, in October, 50 least-developed countries expressed support for a proposal to amend the World Trade Organization rules on intellectual property rights. The amendment would require disclosure of the origin of genetic resources in patent applications to combat what some view as “biopiracy.” The amendment would support obligations arising from the Convention on Biological Diversity — a treaty adopted in 1992 to “establish sovereign national rights over biological resources.” The United States and Japan are opposed to mandatory disclosure. Members plan to continue discussion of this issue at the next meeting of the World Trade Organization Council for Trade-related Aspects of Intellectual Property Rights (known by its acronym: The TRIPS Council), tentatively scheduled for February 2008.

Sometimes the issue arises closer to home. The state legislature in Hawaii recently convened an Advisory Commission on Bioprospecting to help balance native Hawaiian interests with those of the companies seeking to use its natural resources for commercial profit.

Researchers studying bacterial mats at Yellowstone National Park recently discovered a new bacterium — called chloracidobacterium thermophilum, which has a DNA sequence similarity to cyanobacteria. It uses chlorophyll to convert solar energy into chemical energy. Its ability to boost the growth rate of other bacteria, such as those used to make ethanol, ultimately may help to increase the production rate of biofuels.

The National Park Service is reviewing an Environmental Impact Statement on Benefits-Sharing, with the goal of creating a national policy. A decision document is expected to be forthcoming next year.

Diversity of Outlook
Addressing global challenges requires not only Diversity of Approach, but Diversity of Outlook, as well. This concept references the “perspective” with which one comes at a challenge. Interdisciplinarity and multidisciplinarity inherently bring diversity of outlook to bear on the challenge at hand. But, reaching beyond a purely discipline-based approach into other sectors is critical, as well.

Dr. Hale, for instance, had experiences which gave her a unique perspective. A personal, ethical concern for “orphan” disease victims, enlarged and expanded by experience with pharmaceuticals development in both the private and the regulatory sectors, enabled her to offer a new perspective to address the issue.

Diversity of Pedagogy
In order for a new generation of scientists to develop the knowledge, skills, and mind-sets of diversity of approach and outlook, we need, i.e. to become “new biologists for the new biology,” we must engage Diversity of Pedagogy.

Speaking as a university president, the kind of education we need, and the kind we are offering at Rensselaer, is “diversity-enhanced education.” Diversity of Pedagogy provides this education through the utilization of a variety of new media and tools. New technologies — such as simulation of physical phenomena, gaming technology, tele-presence, and tele-immersion (which allow collaboration in real time across geographies) — all are tools that can help us to teach today’s students in a different way and to extend their reach.

In addition, we are building challenging, engaging, and highly relevant academic programs which combine grounding in fundamentals and theory with experiential learning. We are working to assure that the vast percentage of our undergraduate students have research experience before they graduate. And, we are securing opportunities for every undergraduate to study abroad. We have made biology a requirement for an engineering degree, and are considering making an international experience a requirement, as well.

DIVERSITY IN FACT
Of course, diversity-enhanced education, as well as diversity-enhanced scientific discovery and technological innovation, fundamentally require investment in human capital. Thus, the fourth aspect of diversity — Diversity in Fact — refers to investment in people and the importance of inclusiveness. This means that all of our young people, of diverse ethnicities and backgrounds, must be encouraged and inspired to achieve at the highest levels.

As a university president, and as a theoretical physicist, I have deep concerns that our national capacity for discovery and innovation are in jeopardy. Converging forces have created what I call the “Quiet Crisis,” eroding the production of the scientists, mathematicians, engineers, and technologists we need. The scientists and engineers who came of age in the post-Sputnik era, are beginning to retire. At the same time, we are no longer producing sufficient numbers of new graduates to replace them.

The rate of growth in the number of talented international scientists, engineers, and graduate students coming to the United States has slowed — down 27 percent since 2003. Other nations are investing in their own education and research enterprises, offering new opportunities for their scientists and engineers to study and to work at home. And, with globalization, they, also, can find employment elsewhere, not necessarily in the U.S.

Our demographics have shifted. The "new majority" in the United States now comprises young women and the racial and ethnic groups which, traditionally, have been underrepresented in our advanced science and engineering schools. It is to these “nontraditional” young people to whom we, also, must look for our future scientists and engineers, while we spur the interest in science and engineering among all of our young people.

We cannot overlook one half to two-thirds of our population of young people, yet argue that we are tapping the best talent without tapping the complete talent pool. Early-career researchers in biomedical sciences, especially, now face twice the length of time to becoming first-time winners of grants from the National Institutes of Health (NIH) than did scientists who are their teachers and mentors. The average age of a person receiving their first NIH RO1 grant is more than 42 years old. Convincing young people to invest in a science career, but to wait decades for success, is challenging.

This “Quiet Crisis” is "quiet" because the true impact unfolds gradually over time — it takes decades to educate a biomolecular researcher or a nuclear engineer. It is a "crisis" because our national innovative capacity rests solely upon their talents, and upon our ability to interest and to excite all of our youth to the marvels of science and engineering — to the wonders of discovery and innovation. By the time the crisis is fully upon us, we will not be in a position to respond in real time.

There has been a parallel decline of investment in U.S. basic research, especially in the physical sciences and engineering. Federal investment in scientific research has been shrinking, driven by concern over “big government,” limits on federal spending, concern for federal deficit growth, and confidence in market-driven private sector research. The American Association for the Advancement of Science (AAAS) estimates that, overall, federal science research spending has declined by half since 1970, as a percentage of Gross Domestic Product (GDP). NIH, the second largest supporter of federal research and development, has seen its budget flatten in the past four years, which, of course, amounts to an actual decline.

Due to the efforts of many, from multiple sectors, we have a new law — the America COMPETES Act, which authorized new spending levels for a host of research and education programs at the National Science Foundation, Department of Energy, National Institutes of Standards and Technology, National Oceanic and Atmospheric Administration, National Aeronautics and Space Administration and Department of Education. While this bill did not include NIH it will, if properly funded, enhance and increase programs supporting the study of science—by students from all backgrounds.

CONCLUSION
We know only a small fraction of what we need to know for real progress in human health. And yet, we may be hampered by our own success. The swift progress of the last 60 years possibly has given our legislators and the general public a faulty understanding of what science knows — and a lack of comprehension of what science may yet reveal. As a result, there is a lack of understanding of the continuing need for fundamental research into biological systems, and for engineering, physical, and computational sciences, and their relation to human health.

Science has always been done within a global context. But how will scientists operate within a globalized world? — the “flattening” world brought about by the convergence of burgeoning communication and information technologies. This is impacting science in ways similar to its impact on the corporate sector and even nations. The new global environment has created global challenges without geographic borders and scientific discoveries and technological innovations without disciplinary borders.

Operating within this environment will require diversity in its very broadest sense—diversity-enhanced scientific discovery and technological innovation, and diversity-enhanced education. Making progress in human health, and in other arenas, will require sustained and attentive leadership toward employment of diversity among scientists of every stripe.


Source citations are available from the division of Strategic Communications and External Relations, Rensselaer Polytechnic Institute. Statistical data contained herein were factually accurate at the time it was delivered. Rensselaer Polytechnic Institute assumes no duty to change it to reflect new developments.

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