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.
Friedreich's Ataxia
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.
Pain Research
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.
Conclusion
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.