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The JPMorgan Chase Health Award
Leilani M. Miller
Imagine you live in Botswana. You have a 39% chance of being infected with HIV.
Imagine you have just been diagnosed with colon cancer. Which drugs your doctor decides to give you depends on how far your cancer has progressed.
Imagine that you are blind and that even blink-ing your eyes brings excruciating pain.
Imagine that you or a loved one is bleeding to death from an ectopic pregnancy in a country with no blood banks.
Imagine that you have high blood pressure and the first three drugs your doctor prescribes for you cause extremely unpleasant side effects (and don’t even help your blood pressure).
Imagine you have diabetes, heart disease, can-cer, or any of a number of human diseases.
Now, imagine we have the technology to help you.
This year’s 59 applications explored wide-ranging approaches to the use of technology for the benefit of humanity. Some endeavored to deliver medi-cal instruments or technological training to resource-poor regions. Others used the Internet to distribute health information and connect people using Web sites, databases, message boards, and chat rooms. Many were instrumental in developing innovative new tech-nologies to address complex health issues, while oth-ers successfully adapted existing technologies to new uses. Finally, several applicants developed simple, yet appropriate, technologies to address specific local problems.
Our panel employed the following criteria for select-ing the Laureates. The technology itself did not have to be completely new; an innovative application of an existing technology to health issues was acceptable. Most importantly, the technology should address a serious problem or challenge of broad significance. To quote one of our panelists: “Is this technology noble and global?” We favored technologies that showed the most promise to be the greatest benefit to the greatest number of people. The impact of the tech-nology on the problem addressed must be clear and measurable. Ideally, there would be valid evidence of the effect of the technology on the problem. The ap-plicant must also indicate an awareness of potential negative effects of their technology. Finally, the tech-nology should serve as a model for others to emulate.
Andreas Pluckthun, University of Zurich, Zurich, Switzerland
Antibodies are proteins created by our im-mune systems to bind and attack foreign intruders. Normally, cells in our immune system recombine dif-ferent gene modules to create more than a billion dif-ferent antibody molecules so that they can defend against a huge variety of pathogens. Antibodies have become an integral part of modern biological research. They are used in the search for new pharmaceuticals and, in some cases, are used as therapeutics themselves for diseases ranging from cancer to cardiovascular disease. Their usefulness as therapeutics is due to their unique ability to recognize particular targets with ex-quisite specificity. This property can help rid the body of undesirable disease-causing proteins, or it can tar-get cancer cells for selective destruction with toxic “magic bullets.”
Conventional methods to generate antibod-ies that react to particular substances involve inject-ing (immunizing) an animal with the substance. The animal’s immune system responds by making antibod-ies to the injected substance. The antibodies can be obtained by collecting blood from the immunized ani-mal or by growing antibody-producing cells derived from the animal in the laboratory. Recombinant anti-bodies can be created without immunizing an animal. Functional human antibody fragments can be engi-neered, expressed in bacteria (or mice), screened for desired properties, and isolated.
Arguably, the most important contribution that recombinant antibodies are making to medicine is the ability to make fully human antibodies. For example, the first generation of monoclonal antibody therapeutics used antibodies derived from mice. These antibodies can be very effective in treating disease; however, the human body recognizes them as foreign and mounts an immune response against them. In some cases, these antibodies can continue to be used only when the patient is also taking strong immuno-suppressant drugs, which can have serious side effects. A second generation of antibody therapeutics has been made possible by various technologies developed to express fully human antibodies in mice or bacteria. These antibodies will have a much cleaner safety pro-file because the human body will not recognize them as foreign and react against them. Production of re-combinant antibodies is much faster and they can be more easily optimized for tighter binding to their tar-gets, allowing lower doses to be administered to pa-tients. Furthermore, super-stable antibodies are now possible to engineer, which could allow the develop-ment of drugs that will not require refrigeration. In general, recombinant techniques give the researcher full control over the structure of the drug—the poten-tial uses are limitless.
Dr. Andreas Pluckthun at the University of Zurich (http://www.unizh.ch/~pluckth) is a pioneer and one of the leading investigators in the field of recombinant antibodies. His research over the past 15 years has resulted in a series of discoveries that have not only laid the foundation for this field, but continue to extend and improve it. Dr. Pluckthun’s work expressing human antibodies in bacteria and his development of extraordinarily stable antibodies rep-resent groundbreaking and unique contributions to the field of immunology and immune therapy. Through Dr. Pluckthun’s efforts, along with the ef-forts of other scientists, antibody engineering is emerg-ing as one of the principle routes to new pharmaco-logical agents. In 1992, Dr. Pluckthun co-founded the Munich biotech company MorphoSys (http:// www.morphosys.de/) to develop and commercialize his recombinant antibody technology for medical use. Investigators throughout the world are now using Dr. Pluckthun’s technology in the development of new antibodies for diagnostic and therapeutic medicine.
Debbie Glencross, South African National Health Laboratories, Johannesburg, South Africa
Globally, 40 million adults and children were living with HIV/AIDS at the end of 2001 (http:// www.unaids.org/). Although the global adult HIV prevalence rate is 1.2 percent, this disease has reached alarmingly high incidence rates of up to 39% in cer-tain regions of sub-Saharan Africa. In fact, sub-Sa-haran Africa had 70% of the global total of HIV in-fected individuals and over 2.2 million deaths in the year 2001. (Report on the Global HIV/AIDS Epi-demic 2002 - UNAIDS).
With so many people in the developing world infected with HIV, spread of this disease can only be avoided through education of the entire population and successful treatment of those carrying the virus. Current treatment strategies rely upon anti-retroviral drug cocktails that inhibit the HIV life cycle. Although these expensive drugs have been offered for distribution in developing countries at reduced prices, effective treatment of HIV/AIDS is only possible if these drugs are accompanied by both accessible and affordable monitoring of CD4+ cells.
CD4+ cells are a type of white blood cell that plays an important role in the immune system. These cells help to identify, attack, and destroy bacteria, fungi, and even cancer cells. Unfortunately, these cells are a primary target for HIV, and the number of CD4+ cells in the blood gradually declines as HIV disease progresses. This loss of such critical cells incapacitates the immune system, thus allowing opportunistic infections and AIDS-related malignancies. A CD4+ cell count measures the number of CD4+ cells in a blood sample and is a marker of the strength of a person’s immune system. Normal levels range from 500-1200 CD4+ cells per cubic millimeter. CD4+ counts are used for (1) AIDS surveillance (according to criteria established by the Centers for Disease Control and Prevention, HIV-infected persons with CD4+ counts below 200/mm3 are considered to have AIDS, regardless of whether they are sick or well), (2) monitoring rate of progression of AIDS to determine when to begin anti-retroviral therapy (ART), (3) to determine when therapy is required to prevent opportunistic infection (certain opportunistic infections or conditions tend to occur at particular CD4+ levels), and (4) to monitor the effects of ART. For people on ART, CD4+ cell counts are recommended every 3 months. Unfortunately, current CD4+ monitoring methods are prohibitively expensive for resource-poor settings, where a majority of the people infected with HIV reside.
As part of the international Afford CD4 Project (http://www.affordcd4.com/), Dr. Debbie Glencross of the South African National Health Laboratories has developed a new, less expensive test using flow cytometry to monitor CD4+ cell counts during HIV therapy. Flow cytometry counts cells as they “flow” past a detector. In this case, whole blood is mixed with monoclonal antibodies that adhere only to CD4+ cells. These antibodies fluoresce a particular color when exposed to certain wavelengths of light. As the cells flow past a detector, the number of fluorescing cells are counted and compared to the total number of cells, which are also counted.
Dr. Glencross’ innovative application of flow cytometric technologies uses a different reference cell when counting CD4+ cells. This difference allows more consistent testing at a fraction of the cost (less than 1/6 the cost of current tests). Through the Centers for Disease Control and Prevention (CDC), Dr. Glencross’ CD4+ test has already been implemented in several laboratories in Uganda and is currently being developed for several other CDC collaborative sites internationally. The increased availability of a reliable gold standard for measuring CD4+ will improve monitoring of immune status and allow the development of appropriate therapeutic strategies in resource-poor settings.
Perry Rosenthal, Boston Foundation for Sight, Chestnut Hill, Massachusetts
For some unlucky people (between 10,000 and 50,000 worldwide per year), a trip to the pharmacy can be the beginning of a nightmare. Adverse drug reactions (to both prescription and over-the-counter drugs) in some people can trigger a painful and debilitating disease called Stevens-Johnson Syndrome. In addition to fever and blisters over the entire body, many people with this disease develop severe eye disorders, characterized by excruciating sensitivity to light and a vulnerability to ulcers that resist healing and can lead to blindness. Until recently, not much could be done for these patients to relieve their pain and/or restore their sight.
Through a series of elegant technological innovations, Dr. Perry Rosenthal, President of Boston Foundation for Sight (http://www.bostonsight.org/) developed a contact lens that could help these patients. Dr. Rosenthal addressed this problem by redesigning an older, failed contact lens design. This previous scleral lens was very large (about the size of a quarter) and was entirely supported by the tough, insensitive, white tissue of the eye called the sclera, thus avoiding contact with the damaged cornea. The Boston Scleral Lens combines the elements of advanced polymer chemistry, digital lens design and state-of-the-art computerized manufacturing technology. Unlike conventional contact lenses, this device rests on the sclera and creates a space over the cornea that is filled with artificial tears. It is made of oxygen-porous plastic, invented by Dr. Rosenthal, which allows the cornea to breathe while covered by the lens. These lenses function by filling in the surface irregularities of the cornea to restore vision, protecting it from exposure to air and the rubbing effects of blinking, and providing a reservoir of oxygen that allows the eye to heal. While Stevens-Johnson victims are the most dramatic beneficiaries of the Boston Scleral Lenses, patients with severe dry eyes and many different corneal disorders may also benefit.
The Boston Foundation’s innovative surface-generating design technology has increased the success rate of the Boston Scleral Lens from 40% in 1990 to its current 80%. The Federal Drug Administration approved this technology in 1994 as a therapeutic and vision-restoring device, and it has been shown to be effective in restoring the sight of otherwise blind individuals (American Journal of Ophthalmology 130, 2000, 25-41).
Stephen Fodor, Affymetrix,
Monitoring gene expression lies at the heart of a wide variety of medical and biological research projects, including understanding disease, studying basic biological processes, and identifying new drug targets. Until recently, comparing gene expression levels in different tissues or cells was limited to tracking one or a few genes at a time. Using DNA micro-ar-rays, it is now possible to simultaneously monitor the activities of thousands of genes.
Micro-arrays are ordered arrays of tiny spots of DNA affixed to a substrate (e.g., a glass slide) and then exposed to target molecules (RNA or DNA) to determine gene expression patterns or DNA sequence. For example, to determine what genes are turned “on” (expressed) or “off” in a particular tissue, RNA molecules (the products of a gene turned “on”) are allowed to react with the DNA probes on the glass slide (sometimes called a “chip”). The RNA molecules will bind to DNA from their corresponding genes and, because the RNAs are tagged with a fluorescent molecule, the positions on the chip to which they attach can be detected. The intensity of the fluorescence also gives a quantitative measure of the amount a particular RNA has been expressed from its corresponding gene. Because the DNA has been placed on each chip in a particular pattern, the ocation of the fluorescence identifies the gene or genes that produced significant amounts of RNA in the sample. This allows the researcher to compare gene expression in different tissues, under different conditions, or during different stages of development or disease progression. For example, DNA micro-arrays can be used to identify which genes are turned on or off specifically in cancer cells. Since this could be as many as 20,000 genes, this type of whole genome analysis would be impossible without DNA micro-arrays.
This technology finds itself at center stage thanks to the recent successful decoding of the human genome as part of the Human Genome Project. Mi-cro-array technology has revolutionized biomedical research. The results are perhaps clearest in cancer research. Rather than studying one gene at a time, micro-arrays can be used to obtain a global picture of gene expression in a tumor cell. In addition, by looking at gene expression patterns in diseased tissue, researchers are identifying potential targets for new drugs. When DNA, rather than RNA, is used as a target molecule to bind to the immobilized DNA probes on a chip, other types of analyses are possible. For example, micro-arrays are also being used to map inherited disease susceptibilities and to minimize adverse drug reactions and optimize drug efficacy.
In 1989, Dr. Stephen Fodor and colleagues at Affymax Research Institute combined technologies adapted from the semiconductor industry (photolithography masking techniques) with solid-phase chemistry to create an entirely new method for synthesizing ordered arrays of biomolecules (Fodor et. al., Science 251, 1991, 767). In 1993, Dr. Fodor co-founded Affymetrix (http://www.affymetrix.com/), where he continued development of GeneChip® micro-arrays, containing hundreds of thousands of DNA probes packed at extremely high densities. Affymetrix refers to their glass slides as “chips” in reference to the silicon chips of the semiconductor industry, from which their micro-array technology is derived. Affymetrix high-density oligonucleotide arrays differ from other micro-array formats in that the probe is generated directly on the chip rather than created separately and then spotted onto the surface. This method involves adding one nucleotide at a time to sequentially create oligonucleotides (short DNA fragments). Specific oligonucleotides can be placed at specific locations by the use of protective chemistry and lithographic masks. Using this process, DNA can be placed on chips at extremely high density, with as many as 60 million individual probes on a chip only five inches square!
Whether providing tools for discovery or helping establish the foundations for future clinical tests, Dr. Fodor’s GeneChip® micro-arrays are enabling researchers to exploit the information and opportunities provided by the Human Genome Project. As one eminent scientist has stated, Dr. Fodor is “creating and nurturing massively parallel cutting-edge technologies that are profoundly altering medicine to enhance life.”
Oviemo Ovadje, EATSET Blood, Lagos, Nigeria
A woman suffering an ectopic pregnancy in a developing country without adequate blood resources is likely to bleed to death, as the blood leaks out into her own body cavity. In developed countries, this can be avoided through surgery and transfusion of many units of blood. Developing countries have limited functional blood banks and inadequate blood transfusion services. This scarcity of blood resources is further compounded by the prevalence of the HIV virus in many of these developing countries.
Dr. Oviemo Ovadje addressed the problem of blood salvage from body cavities by creating the Emergency Auto Transfusion Set (EATSET) device to replace and improve the primitive gauze filtration tech
nique currently practiced in most developing countries (http://www.eatset.com/). The EATSET device is a low cost, appropriate technology that addresses the needs of developing countries. It can be adapted for use with a vacuum pump or, in areas without electricity, a manual pump can be used to generate the vacuum. This type of device allows blood that has collected within a body cavity to be filtered and transfused back into the patient and is particularly attractive in developing countries where blood resources are extremely scarce or likely to be infected with HIV. Patients who benefit from this technology not only include women with ectopic pregnancies, but also accident victims with internal bleeding and people with ruptured aneurysms. In just a few years of use, more than 84 patients have benefited from the use of the EATSET device.
This year’s group of applicants again shows a diversity of new ways technology is benefiting human health. These approaches illustrate the resourcefulness of those working to increase the health of all the inhabitants of this world. It is particularly reassuring that many of the applicants have targeted the most vulnerable of our global community, those living in developing countries with limited health resources. It is also encouraging to see different groups of people, whether they be individual researchers, not-for-profit institutions, or for-profit companies, each with different interests and approaches, all striving to unleash the potential of technology to create a healthier world. •
Leilani Miller, Chair, Associate Professor of Biology, Santa Clara University
Marie Barry, Retired, ALZA Corporation
Wm. David Burns, Senior Policy Director, Principal Investigator, and National Director of the Program for Health/Higher Education, Association of American Colleges and Universities
Neil Quinn, Senior Lecturer in Computer Engineering, and Senior Fellow, Center for Science, Technology, and Society
Jon Showstack, Adjunct Professor of Medicine and Health Policy, Institute for Health Policy Studies, University of California, San Francisco
Craig Stephens, Associate Professor of Biology, and Director, Biotechnology Program, Santa Clara University