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Human Genome News, September-December 1995; 7(3-4):3

Evolution of a Vision -- Part II

by Francis S. Collins, Director of NIH NCHGR

(Ed. note: Part I of this article was written by David Smith, Director of the DOE Human Genome Program.)

FY 1996 marks the end of the first 5 years and the beginning of a new era in the Human Genome Project. It is very rewarding to note that we have met or exceeded most of our ambitious goals some ahead of time and all under budget. The genetic map is complete, the chromosome physical maps are within 18 months of completion, and pilot programs to begin sequencing the entire human genome are under consideration.

Fortunately, we do not have to wait until the end of the project to reap its benefits; information generated by the Human Genome Project is quickly disseminated through public electronic databases and used by researchers across the United States and the rest of the world. Already this information is changing the way biomedical research and the practice of medicine are being conducted. The benefits are widely apparent, as significant discoveries of the genetic basis of a vast number of genetic diseases from polycystic kidney disease and Alzheimer's to breast cancer, colon cancer, and diabetes are happening at a staggering pace.

New Maps Aid Gene Hunters
Detailed maps coming out of the Human Genome Project are critical to understanding the basis of many common diseases complex disorders resulting from the effects of multiple genes and environmental influences. Not long ago, for example, a researcher used genetic maps to discover at least five different chromosome regions that appear to play a role in insulin-dependent (type 1) diabetes. This kind of genome scan would not have been possible without high-resolution genome maps. The maps will be invaluable in teasing apart the contributions of genes to other complex disorders, including heart disease, asthma, cancers, and psychiatric disorders. In conjunction with the detailed maps, genome technologies also played a key role in the isolation of 13 disease genes in FY 1995, including the BRCA1 gene for hereditary breast cancer.

Meeting Sequencing Challenges
Having met or exceeded our original goals for genetic mapping, we now turn our vision for the next phase of the Human Genome Project to the most challenging technological undertaking of all: determining the sequence of DNA bases in the entire 3-billion base-pair length of human DNA. Knowing the order of DNA bases tells an investigator where genes are located, as well as what instructions are carried in a piece of DNA. This information is critical to understanding the function of genes and how they cause disease. Technology development for this work primarily has been carried out experimentally on the DNA of important model organisms. Researchers sequencing the genome of the roundworm have amassed almost 28 million bases of DNA from that organism over one-quarter of the animal's genome and have increased their annual production rate from 2 million to 14 million DNA bases. These investigators expect to complete the sequence of the roundworm genome by the end of 1998.

Thus far, technology development in sequencing DNA has aimed at reducing cost and increasing rate. This past year, NCHGR began a new initiative to reduce the scale of sequencing instrumentation and increase sequencing speed. We will also explore new strategies for minimizing time-consuming bottlenecks by developing integrated, matched components throughout the sequencing process. The urgency of pushing these advances now is considerable because reducing the cost by only $.01 per base pair will save $30 million in the production phase of human DNA sequencing.

NCHGR recently solicited proposals for pilot projects to test strategies for full-scale production sequencing of mammalian DNA. Applicants must expect to sequence at least one million bases of contiguous DNA over the 3-year period; they must also explain how their approach will help improve sequencing technology and capability to achieve the complete, accurate, finished human DNA sequence by 2005. This proposal request is justified by the technological progress and project-management experience already achieved and by the need to gain more experience in large-scale human DNA sequencing, which scientists anticipate will present different issues from those encountered in sequencing nonhuman DNA.

Impact of Genome Research
Our knowledge about gene function will continue to grow as researchers analyze the genetic causes of disease at the molecular level and associate specific gene alterations with an individual's risk for disease. An immediate spin-off of disease-gene discovery is the development of genetic tests that may indicate an individual's predisposition to disease. With the ability to test for disease genes, we can design medical programs for individuals that include lifestyle, diet, and medical surveillance to alleviate or prevent disease. Eventually, new treatments will be developed for many diseases that result from gene malfunctions, but there will be a lag time between our ability to offer a genetic test and the ability to understand the disease sufficiently to develop new treatments and therapies.

Genetic testing also can be potentially harmful if other people use test results to deny jobs or take away insurance. All of us carry probably four or five really fouled-up genes and another couple of dozen that are not so great and place us at some risk for something. People don't get to pick their genes, so their genes shouldn't be held against them.

Using personal genetic information to discriminate would severely limit the anticipated medical benefits of human genetic research. In addition to justified concerns over health insurance and jobs, the fear of such misuse will make people unwilling to impart this information to doctors or even family members. As new preventive and treatment methods arise, protecting individuals from discrimination and stigmatization based on their genetic makeup will become increasingly important.

Transformation of Medicine
Beyond the development of new genetic tests and treatment strategies, my long-term dream is for scientists to figure out how diseases work and cure them in advance. In two or three decades, we hope to be able to find out what genetic disease a person is at risk for and fix it by putting in a gene that has the appropriate sequence. This dream has already started to come true in the case of cystic fibrosis. Finding the CF gene enabled researchers to identify people with two copies of the mutated gene and to begin gene-therapy trials soon after.

Unfortunately, medical training in genetics is lagging far behind these scientific advances. Most medical schools are not yet emphasizing the genetics courses so vital to medical education, and many physicians in practice today have had no genetics training at all. This situation will have to change dramatically if medical science is to keep up with and make use of the rapid and extremely valuable discoveries that can affect so many lives.

Genetics is going through a golden era right now. A century from now, people will look back and talk about how exciting it must have been to work in this field at a time when everything was breaking wide open. It's also very gratifying because science is moving so fast to help people suffering from disease. That's what I'm excited about the chance to do something about diseases that have been completely untreatable in the past and now are beginning to yield their secrets.

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Human Genome Program, U.S. Department of Energy, Human Genome News (v7n3).

Human Genome Project 1990–2003

The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.

Human Genome News

Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.