New Developments in Medical Research: NIH and Patient Groups
Harold Varmus, M.D.
Director, National Institutes of Health
Department of Health and Human Services
House Commerce Subcommittee on Health and Environment
March 26, 1998
Mr. Chairman and Members of the Subcommittee:
I am Harold Varmus, Director of the National Institutes of Health. Through the conduct and support of outstanding biomedical research, NIH seeks to expand fundamental knowledge about the nature and behavior of living systems, and to apply that knowledge to reduce the burdens of disease and disability. Today, I would like to provide an overview of how science works, and how the support of basic research across many disciplines has created remarkable opportunities for future research that will lead to improved health for humanity.
Medical progress rarely occurs without the pursuit over many years of both basic research and disease-specific research. Because the benefits of research are unpredictable, work on a broad range of topics is necessary. Although basic research projects initially may appear to be unrelated to any specific disease, findings from this research ultimately may prove to be a critical turning point in a long chain of discoveries leading to improved health. In addition, discoveries from research in one specific disease area often are related to other diseases. I will discuss two areas of research, Friedreich's ataxia and pain, as examples of research areas that further illustrate these points.
The story of Friedreich's ataxia illustrates how many areas of clinical and basic research can come together in unexpected ways. In this rare disorder, research involving neuroscience, genetics, clinical medicine, molecular biology, and even biology of yeast and bacteria are converging. The findings offer insights to basic biology and to many other disorders, and illustrate the importance of understanding the mechanism of disease in order to devise treatments.
Friedreich's ataxia is a multi-system disease: Friedreich's ataxia is a progressive disease that affects the nervous system, the heart, and the pancreas. The disease strikes about 1 in 50,000 persons, or several thousand in the U.S. Ataxia refers to loss of coordination, an unsteady walk, slurred speech, and other symptoms which usually appear between the ages of 5 and 15 years. These symptoms reflect the death of cells in certain parts of the nervous system. Eventually most affected children experience an enlargement of the heart and progressive loss of muscle control leading to motor incapacitation and the need for use of a wheel chair. At least 10 to 20% develop diabetes mellitus or carbohydrate intolerance. Blindness and deafness are also common. Most young people afflicted with this disease die in early adulthood.
Genetics: Friedreich's ataxia is inherited recessively; that is, a person gets the disease only when he or she inherits defective genes from both parents. About 1 in 90 people of European ancestry carry the disease gene and most of them do not know it. In 1996, an international group of scientists, with the cooperation of patients and families with Friedreich's and their physicians, identified the gene, cloned it, and decoded its sequence. The gene (called X25) carried the instructions for making a protein that was not previously known. The protein was named frataxin.
Triplet repeats: The nature of the defect in the gene for frataxin was a surprise. Just in the last few years, a new type of genetic defect, called a triplet repeat expansion, has been discovered in several brain diseases. The genetic defect in Friedreich's ataxia is a new twist on this theme. The four possible code letters of DNA specify the 20 amino acid building blocks of proteins by using three-letter "words," that is, three letter sequences of DNA code for each amino acid. In triplet repeat expansions, one of these triplets is abnormally repeated many times in the gene--for example, CAG, CAG, CAG. In most known triplet repeat diseases, like Huntington's disease and several hereditary ataxias, this repetition produces proteins with long runs of the same amino acid, glutamine. These abnormal proteins harm cells--we are just beginning to learn how--so these diseases are usually dominantly inherited, that is, one defective gene from either parent is enough to cause disease. There is converging evidence that abnormal protein aggregation may contribute to not only Huntington's disease and other glutamine repeat diseases, but also to more common neurological disorders like Parkinson's disease and Alzheimer's disease.
Friedreich's ataxia is the first known case of a recessive disease caused by a triplet repeat. In Friedreich's, the repeated part of the gene (GAA) is not in the blueprint for the protein itself, but in a "non-coding" region of the gene called an intron. The very long triplet repeats somehow cause too little of the protein to be made. This finding opens the possibility that other recessive diseases-and there are hundreds that remain unexplained-might be caused by a similar triplet repeat mechanism.
Clues from yeast: Knowing the gene and protein is just the beginning in understanding a disease, especially when the function of the protein, like frataxin, is completely unknown. Scientists found an important clue by using the computer to compare the frataxin protein to other proteins in large databases. They found that frataxin was very similar to certain proteins in yeast, the simplest organisms with cells like ours, and even in certain types of bacteria. Similarities like these often indicate that the proteins carry out cell functions so fundamental that they have been conserved across evolution.
Scientists studying yeast, which is much more efficient than working with human tissue, found that the yeast frataxin-like protein acts within mitochondria, the energy factories of the cell. There the protein controls levels of iron, an essential-but potentially dangerous-element in energy metabolism. When too little of the protein is present in cells, iron builds up to toxic levels in the mitochondria. The iron, in turn, reacts with oxygen to produce free radicals, highly reactive substances that can damage and kill cells. The presence of frataxin-like proteins in bacteria also fits this scenario, because our mitochondria probably evolved eons ago from free-living ancestors of these bacteria which took up residence in cells.
Back to patients: Circumstantial evidence had suggested that mitochondria might play a role in Friedreich's ataxia. Now, returning to patient studies armed with clues from the work in yeast, clinical researchers have confirmed that frataxin is a mitochondrial protein in mice and in humans, and that this protein is normally present in the tissues affected by the disease. New studies in human tissue, also guided by the yeast findings, suggest that defects in iron metabolism really are important in the disease. The susceptibility of the nervous system, heart, and pancreas may reflect the fact that the relevant cells in these tissues do not divide in adults (and so cannot be replaced). Nerve and muscle cells also have metabolic needs that make them especially vulnerable to free radical damage.
This rapid flow, in Friedreich's and many other diseases, from the laboratory to the patient and back again, with each exciting new finding provoking new lines of investigation, energizes clinical and basic researchers.
Implications for Friedreich's and other disorders: In the immediate future, the new understanding of the genetic basis of Friedreich's ataxia will be important for diagnosis and counseling. With new understanding about iron and free radicals, we can finally begin to think about treatment, but it will not be simple. Recent evidence suggests that the direct approach of trying to chelate -- bind up -- excess iron could be harmful and even exacerbate the problems of Friedreich's patients, so more basic research to understand the disease is critically needed. The leading investigators in the field are in agreement that clinical studies must be grounded in a better understanding of the disease process.
Friedreich's ataxia now joins a growing list of degenerative disorders, such as Parkinson's disease, in which free radicals have been implicated. As with progress in many rare diseases, what we discover about cellular changes and therapeutic approaches in Friedreich's ataxia may lead us to important insights about more common disorders.
A Collaborative Approach to Pain: Many health problems we study at NIH concern all the Institutes and invite an interdisciplinary approach to research. A good example is pain. Pain is the symptom that drives most people to see a physician or dentist, and from there, perhaps, a rheumatologist, a cardiologist, a neurologist or even an acupuncturist. As Americans live longer, we can expect to see an increase in the numbers of people living with chronic painful conditions-people with arthritis, osteoporosis, heart disease, diabetes, cancer. There are others with less common painful conditions like trigeminal neuralgia, fibromyalgia or phantom pain. This is why the NIH capitalizes on its diversity of talents and approaches to address the needs of these patients. That is one of the principal reasons that I established the NIH Pain Research Consortium in 1996. By bringing all the NIH components that support pain research into the Consortium, we are signaling our intent to coordinate and enhance pain research, not only across NIH, but also beyond, to other agencies, the academic community and the private sector.
That intent was underscored by a Consortium-sponsored symposium we held last fall that brought scientists from many fields together -- along with representatives from pharmaceutical companies and patient groups -- for two days of discussions and science reviews. Imaging specialists demonstrated advanced techniques for visualizing areas of the brain affected by pain. Geneticists described methods for tracking genes that could determine sensitivity to analgesics. They also discussed the latest findings on sex differences in response to drugs. Molecular and cell biologists detailed the many molecules that control the traffic along the pathways carrying the news of pain to the brain. Most importantly, these scientists emphasized that pain messages stamp an impression on the brain. If the barrage of pain signals continues unabated, that impression can become indelible, causing harmful changes in the nervous system that include making a bad pain worse: the sensation of pain can spread over a wider area and sensitivity increases so that even a light touch is extremely painful.
But the investigators were hopeful, too: the identification of so many types of cells, receptors, transmitters, genes, growth factors, inflammatory mediators and hormones that figure in our experience of pain, is creating an enormous playing field of targets for therapeutic interventions.
Three weeks ago, at the NIH appropriations hearings, I remarked that we are at the dawn of the golden age of neuroscience. The energy, enthusiasm and excitement of the investigators at the Consortium symposium bear witness to that optimism. But equally important have been the innovations in technology that have made brain imaging possible, refined our microscopic and analytic tools, and led to the development of high-speed computer-based systems of data collection and storage. Twenty-first century bioscience will depend as much on the integration of high technology and other scientific disciplines into biology as on the traditional life sciences themselves.
Of Frogs and Snails and Rodent Tails: I can illustrate the critical importance of integrating all these elements into research with two examples of drug development to combat pain. The first concerns a species of Ecuadorian frog collected by John Daly, a chemist in the NIH intramural program in 1974. This was not the investigator's first trip to South America. In the 1960s, he had made forays into Colombia to collect the frogs that were the source of poison that Native peoples used on their blow darts. The work of extracting and analyzing the poison from thousands of frog skins was tedious at the time, based on methods available before the advent of powerful mass spectrometry techniques. The extracts were identified as alkaloids, toxic to the sodium ion channels in nerve cells essential to muscle movement.
The work on frog skins might have ended there except for the interest of an American Museum of Natural History herpetologist who read about the dart poison and proposed further collaborations. The two scientists went on to collect thousands of specimens of South American frogs whose skin glands contained a wide variety of alkaloid toxins, including a rare extract from the Ecuadorian frog, Epipedobates tricolor. What was unusual was the behavior of mice when injected with the extract: their tails would rise and arch over their backs, exactly as they do in response to an opioid drug. Not only was the extract an analgesic, it proved to be 200 times more powerful than morphine. Subsequent tests showed that it did not act on opiate receptors. Unfortunately, the extract had side effects that precluded its use in human subjects. Again, attempts to analyze the venom structure in search of less toxic derivatives were thwarted by technological shortcomings. Even the effort to collect more skins to augment stores of the compound was frustrated because, by this time, frogs had become endangered species. Breeding the species in the lab was also fruitless because the lab-grown frogs failed to produce the extract. The presumption is that the frogs obtain their potent defense weapon against predators from dietary sources in their native habitats.
By the early 90s, however, nuclear magnetic resonance spectrometry had advanced to the point where the minute sample still available could be analyzed and the compound synthesized. The extract, called Epibatidine, is similar to nicotine and acts at a type of nicotinic receptor in the brain. Because of its toxicity, it remained on the shelf until scientists at Abbott Laboratories began to explore the use of nicotine-like drugs to treat Alzheimer's disease. Instead of therapy for dementia, they found that one of 500 variants of the compound they made, ABT-594, was an excellent analgesic useful against a variety of pains, including the notoriously hard-to-treat neuropathic pain that can follow nerve injury. The good news is that the drug has none of the sedating and constipating effects of opiates. ABT-594 is now being tested in Phase I clinical trials.
My second pain story is also about poisons: a toxin found in very beautiful but deadly marine cone snails that live in warm ocean reefs. These snails kill marine organisms by injecting a venom composed of small proteins in a family of "conopeptides." These compounds block calcium channels in nerve cells that are also essential in generating nerve signals. Neurex, a biotechnology firm in Menlo Park, California, is testing a conopeptide derivative called SNX-111. The feature that makes the new drug so attractive is that it targets a type of calcium channel found only in the nervous system. Other calcium channel blockers can control pain, but pose a risk to the heart because they can react with calcium channels in heart muscle as well. The new drug is currently being tested on patients with neuropathic pain resistant to all other medications tried.
Like the frog story, the cone snail saga is also one that spans decades of research and daunting technology, beginning with the observations of snail behavior by a Filipino scientist now in the United States, and the subsequent chemical analyses of the venom. Most importantly, drug development would have stalled without the work of another NIH intramural scientist who developed an animal model of neuropathic pain by compressing nerves exiting from the spinal cord of a rat. The method has been adopted by pain researchers worldwide, not only allowing in vivo testing of new analgesics, but also the study of the complex events that follow nerve injury.
We are in the midst of a revolutionary phase of biological research, when genes, cells, and complex phenomena are being understood at an unprecedented rate. Never before have we had such powerful research tools to develop clear understandings of fundamental biological and genetic processes to study and treat diseases. As we have seen, it is never known with certainty which scientific areas will produce the greatest returns soonest. At any given time, moreover, some fields are more likely to repay the investment in them by yielding great discoveries that advance knowledge.
Assessing scientific opportunities requires expertise in various scientific fields, breadth of vision across many disciplines, and judgment to determine the likely yield from making investments in particular areas of research. Scientific opportunities may arise from many sources, from a single technological development, or from a scientific "breakthrough." Often the breakthrough or even the knowledge accumulated is in an area that appears only remotely related to the area where it will have its greatest impact. Recognition of these scientific opportunities allows investigators to approach previously unanswered questions in new ways.
Mr. Chairman, I am grateful to you for providing a forum for the discussion of these issues, and I would be pleased to answer any questions you or Members of the Subcommittee may have.