Testimony of Francis S. Collins, M.D., Ph.D.

Testimony of Francis S. Collins, M.D., Ph.D.

Director, National Human Genome Research Institute
National Institutes of Health

Before the Appropriations Subcommittee on Labor, Health and Human Services and Education
United States Senate

July 11, 2001

Mr. Chairman, and members of the subcommittee, it is a pleasure to be here today to discuss the recent scientific advances in genetics that will lead to improved health, and the development of therapies to treat various illnesses. First I would like to thank the subcommittee, and especially you Mr. Chairman and Ranking Member Specter, for your commitment and determination to invest in the Human Genome Project and other areas of basic biomedical research at the National Institutes of Health (NIH). Today I would like to focus my remarks on the recent developments in genetics in order to give you a sense of the great promise this field of research holds for all of us and why I think this research requires continued investment. Today you will also hear from patients and advocates who are fighting to find a cure for genetic diseases. All of us have gained a powerful new set of tools from the recent advances in human genetic research. But as a physician who has taken care of patients, and as a medical geneticist who has devoted the last decade to the Human Genome Project, I know it is critical that we move the great promise of basic research into the clinic as quickly as possible, in order to make significant progress towards treating or preventing these devastating illnesses.

Human Genome Sequence

Last year, Human Genome Project scientists capped their achievements of the last decade with a historic milestone -- the complete initial reading of the text of our genetic instruction book. This book is written in an elegant digital language, using a simple four-letter alphabet where each letter is a chemical base, abbreviated A, C, G or T. At present, more than 95 percent of the 3.1 billion bases of the human genome are freely available in public databases. This is an awesome step toward a comprehensive view of the essential elements of human life, a perspective that inaugurates a new era in medicine where we will have a more profound understanding of the biological basis of disease and develop more effective ways to diagnose, treat and prevent illness.

Between March 1999 and June 2000 the international collaborators in the Human Genome Project sequenced DNA at a rate of 1000 bases per second, seven days a week, 24 hours a day. After completing the working draft of the human genome sequence in June of 2000, Human Genome Project scientists and computational experts scoured the sequence for insights. They reported the first key discoveries in the February 15, 2001 issue of the journal Nature. Among the findings were the following:

• Humans are likely to have only 30,000 to 40,000 genes, just twice as many as a fruit fly, and far fewer than the 80,000 to 150,000 that had been widely predicted.
• Genes are unevenly distributed across the genomic landscape; they are crowded in some regions and spread out widely in others.
• Individual human genes are commonly able to produce several different proteins.
• The repetitive DNA sequences that make up much of our genome, and commonly regarded as "junk," have been important for evolutionary flexibility, allowing genes to be shuffled and new ones to be created. The repetitive DNA may also perform other important functions, and provides fascinating insights into history.

Finishing the Human Genome Sequence

Because of the enormous value of DNA sequence information to researchers around the world, in academia and industry, the public Human Genome Project (HGP) has always been committed to the principle of free, rapid access to genomic information through well-organized, annotated databases. Databases housing the human genome sequence are being visited by tens of thousands of users a day. Over the coming two years, the HGP will increase the usefulness of the human genome sequence to the world's researchers by finishing the sequencing to match the project's long-standing goals for completeness and stringent accuracy. More than 40 percent of the draft sequence, including two of our 24 chromosomes, has already been finished into a highly accurate form -- containing no more than one error per 10,000 bases. Finished sequence for the entire genome is expected by 2003.

Human Genetic Variation

While the DNA sequence between any two individuals is 99.9 percent identical, that still leaves millions of differences. For understanding the basis of common diseases with complex origins, like heart disease, Alzheimer's disease, and diabetes, it is important to catalog genetic variations and how they correlate with disease risk. Most of these are single letter differences referred to as Single Nucleotide Polymorphisms (SNPs). With a draft of the human genome sequence in hand, the pace of SNP discovery has increased dramatically. In FY 1999, NHGRI organized the DNA Polymorphism Discovery Resource consisting of 450 DNA samples collected from anonymous American donors with diverse ethnic backgrounds. NHGRI has funded studies looking for SNPs in these samples. The non-profit SNP Consortium came into being in April 1999, with the goal of developing a high-quality SNP map of the human genome and of releasing the information freely. Consortium members now include the Wellcome Trust, a dozen companies (mostly pharmaceutical companies), three academic centers and the National Institutes of Health (NIH). This has been remarkably successful, with five times more SNPs being contributed to the public domain than the consortium originally planned. As of June 22, the public database that serves as a central repository for SNPs has received 2,972,764 SNP submissions.

With the increased knowledge about human variation, the genetic underpinnings of various diseases, including diabetes, are being discovered. The recent discovery of a gene, calpain-10, whose disruption contributes to diabetes, resulted from studies linking diabetes with genetic variations across the whole genome and then in a specific part of chromosome 2. The newly discovered gene variant suggests that a previously unknown biochemical process is involved in the regulation of blood sugar levels.

Gene Expression

The newfound abundance of genomic information and technology is propelling scientists out of the pattern of studying individual genes and into studying thousands at a time. Large-scale analyses of when genes are on or off (gene expression) can be used, for example, to study the molecular changes in tumor cells. This exciting new approach combines recombinant DNA and computer chip technologies to produce microarrays or DNA chips. Classifying cancer on a molecular level offers the possibility of more accurate and precise diagnosis and treatment. Intramural researchers at NHGRI have used large-scale expression studies to discover genetic signatures that can distinguish the danger from different skin cancers, and that can distinguish between hereditary and sporadic forms of breast cancer.

Protein Structure, Function and Interaction

We must remember that we are at the beginning of the genomics era, not the end. With a global view of human genes now possible, scientists are eager to obtain a similarly comprehensive view of human proteins, a field called "proteomics." Researchers want to know the functions of proteins and how the proteins work together in cells. Only a subset of all possible proteins are present in any given cells at any given time. To study protein function on a wide scale, various groups of researchers plan to identify the locations of proteins, their levels in different cells, their structures, the interactions among different proteins, and how they are modified. NHGRI is contributing to this field by developing technologies for efficient, large-scale analyses, particularly for determining protein interactions and measuring protein abundance in different cells.

Promise for Treatments and Prevention

With the availability of a comprehensive view of our genes, genetic testing will become increasingly important for assessing individual risk of disease and prompting programs of prevention. An example of how this may work involves the disease hereditary hemochromatosis (HH), a disorder of iron metabolism affecting about one in 200 to 400 Americans. Those with the condition accumulate too much iron in their bodies, leading to problems like heart and liver disease, and diabetes. The gene causing the condition has been identified, allowing early identification of those in whom HH may develop. Once people at risk are identified by genetic testing they can easily be treated by periodically removing some blood. The NHGRI and NHLBI are engaged in a large-scale project to determine the feasibility of screening the adult population for this very preventable disorder.

Genetic testing is also being used to tailor medicines to fit individual genetic profiles, since drugs that are effective in some people are less effective in others and, in some, cause severe side effects. These differences in drug response are genetically determined. Customizing medicine to a patient's likely response is a promising new field known as pharmacogenomics. For example, a recent publication in the journal Hypertension showed how pharmacogenomics applies to high blood pressure. Researchers found a variation in a particular gene that affects how patients respond to a commonly used high blood pressure drug, hydrochlorothiazide. Other recent studies reveal that doctors should avoid using high doses of a common chemotherapy treatment (6-mercaptopurine) in a small proportion of children with leukemia. Children with a particular form of a gene (TPMT) suffer serious, sometimes fatal, side effects from the drug.

Genomics is also fueling the development of new medicines. Several drugs now showing promising results in clinical trials are "gene-based" therapies, where an exact appreciation of the molecular foundations of disease guides treatment design. One of the first examples is Gleevec (previously called STI571), produced by Novartis for treating chronic myelogenous leukemia (CML), a form of leukemia that mostly affects adults. CML is caused by a specific genetic flaw -- an unusual joining of chromosomes 9 and 22 producing an abnormal fusion gene that codes for an abnormal protein. The abnormal fusion protein spurs uncontrolled growth of white blood cells. Novartis designed a small molecule that specifically inactivates that protein. In phase I clinical trials, this drug caused dramatically favorable responses in patients, while side effects were minimal. By targeting the fundamental biochemical abnormality associated with this form of cancer, rather than killing dividing cells indiscriminately as most chemotherapy does, the drug offers better treatment results and fewer toxic effects on normal cells. Just a month ago, in the record time of just 2 1/2 months, the FDA approved widespread use of Gleevec. Meanwhile, Bayer and Millennium announced the development of another cancer drug born of genomics in January 2001. GlaxoSmithKline is testing a new genomics-derived heart disease drug that targets a protein involved in fat metabolism. Johnson&Johnson is testing a drug targeting a brain receptor identified through genomics, and involved with memory and attention. Human Genome Sciences has four clinical trials in progress to test gene-based drug candidates.

Ethical, Legal and Social Implications

From its inception, NHGRI recognized its responsibility to address the broader implications of having access to genetic information and technology. Since the inception of the Human Genome Project Congress has provided funds for research to study the ethical, legal and social implications (ELSI) of genome research. To that end one of the greatest areas of concern has been in the area of genetic discrimination. Recently President Bush addressed this issue in his Saturday radio address of June 23. In that address the President said, "Just a few months ago, scientists completed the mapping of the human genome. With this information come enormous possibilities for doing good. As with any other power, however, this knowledge of the code of life has the potential to be abused. Genetic discrimination is unfair to workers and their families. It is unjustified -- among other reasons, because it involves little more than medical speculation. ... To deny employment or insurance to a healthy person based only on a predisposition violates our country's belief in equal treatment and individual merit. ... Just as we have addressed discrimination based on race, gender and age, we must now prevent discrimination based on genetic information. My administration is working now to shape the legislation that will make genetic discrimination illegal. I look forward to working with members of Congress to pass a law that is fair, reasonable and consistent with existing discrimination statutes."

Predictions for the Future

We must not ignore the ethical, legal, social, and the commercial issues that genetic research raises, but the bottom line is that the promise of this research is so great for alleviating human suffering that the most unethical thing we can do is to slow down the research. If research continues to proceed vigorously, we can expect medicine to be transformed dramatically in the coming decades.

We can predict that by the year 2010, predictive genetic tests will exist for many common conditions where interventions can alleviate inherited risk; successful gene therapy will be available for a small set of conditions; and primary care providers will be practicing genetic medicine on a daily basis. By the year 2020, gene-based designer drugs are likely to be available for conditions like diabetes, Alzheimer's disease, hypertension and many other disorders; cancer treatment will precisely target the molecular fingerprints of particular tumors; genetic information will be used routinely to give patients appropriate drug therapy; and the diagnosis and treatment of mental illness will be transformed. By the year 2030, we predict that comprehensive, genomics-based health care will become the norm, with individualized preventive medicine and early detection of illnesses by molecular surveillance; gene therapy and gene-based therapy will be available for many diseases; and a full computer model of human cells will replace many laboratory experiments. These advances will require continued investments in basic research if we are going to realize these goals.

Thank you Mr. Chairman. I would be happy to answer any questions.