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Francis S. Collins, M.D., Ph.D.
Director, National Human Genome Research Institute
National Institutes of Health
Health, Education, Labor and Pensions Committee
United States Senate
July 25, 2001
Mr. Chairman, and Members of the Committee, 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 and prevent devastating diseases. First, I would like to thank the Committee, and especially you Mr. Chairman, for your strong support of the Human Genome Project and your commitment to ensure that advances in our understanding are used to improve the health of our citizens and not for harm. Today I would like to focus my remarks on the great promise genetics research holds for all of us and the potential obstacle that genetic discrimination poses to the realization of this promise.
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% 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, 7 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% of the draft sequence, including two of our 24 chromosomes, have already been finished into a highly accurate form – containing no more than 1 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% identical, that still leaves millions of differences. For understanding the basis of common diseases with complex origins, like heart disease, Alzheimer 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 included the Wellcome Trust, a dozen companies (mostly pharmaceutical companies), three academic centers, and NIH. This has been remarkably successful, with 5 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.
Just last week, we held a landmark workshop to discuss taking the study of human variation to the next step ¾
deciphering patterns of variation across large regions of DNA (called haplotypes) which will greatly accelerate the ability to identify the hereditary factors in common disease.
With this 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.
The new-found abundance of genomic information and technology is propelling scientists to go beyond 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 dangers from different skin cancers, and that can distinguish between hereditary and sporadic forms of breast cancer.
Promise for new 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 National Human Genome Research Institute (NGHRI) and National Heart, Lung and Blood Institute (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. In May 2001, FDA approved Gleevec for the treatment of Chronic Myeloid Leukemia after a review time of less than three months. 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.
The Future of Genetic Medicine
As I recently wrote in the February 2001 issue of the Journal of the American Medical Association, 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, I 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.
Genetic information can be enormously valuable to patients and providers as it can guide early detection, intervention and prevention. But as President Bush recently noted, "this knowledge of the code of life has the potential to be abused. Employers could be tempted to deny a job based on a person's genetic profile. Insurance companies might use that information to deny an application for coverage, or charge excessive premiums."
Individuals in a preliminary NIH colon cancer study were provided education and counseling before being offered the genetic test. When asked what factors might lead them to take the test, the overwhelming majority stated they wished to learn about their children's health risks and to obtain information to help guide their own cancer screening. When asked what factors might lead them not to take the test, 10% indicated their greatest concern was handling the information emotionally and 28% were concerned about the effect on family members. These are reasonable and very personal issues of concern. But, the number-one concern cited by 39% was losing insurance. In a similar study involving genetic testing for increased risk of breast and ovarian cancer, fully one third of the individuals who opted not to participate said that they did so because of their concern about genetic discrimination.
In a survey of genetic counselors, published in the June 2001 edition of the Journal of Clinical Oncology, an overwhelming majority indicated that they would take a genetic test based on high-risk family history for colon or breast/ovarian cancer (91% and 85% respectively). These professionals clearly know the value of the information. But, 68% said they would pay out of pocket for the testing rather than bill their insurer because of fear of discrimination. Twenty six percent said they would use an alias.
In conclusion, I would like to again quote President Bush, who got it exactly right when he said, "Genetic discrimination is unfair to workers and their families. It is unjustified. 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. In the past, other forms of discrimination have been used to withhold rights and opportunities that belong to all Americans. Just as we have addressed discrimination based on race, gender and age, we must now prevent discrimination based on genetic information."
Thank you Mr. Chairman. I would be happy to answer any questions.