1. The Human Genome Project Eric Lander PhD Director Whitehead Center for Genome Research Cambridge, MA Eric Topol MD Provost and Chief Academic Officer Chairman and Professor Department of Cardiology Cleveland Clinic Cleveland, OH

2. The Human Genome Project has been underway for 15 years. 1997-2001 were dedicated to sequencing with a final intensive push over the last 18 months. February, 2001: dual publication of the genome maps, with some 94% of the human genome now freely available on the web. Human Genome Project History

3. Ahead of schedule Every milestone in the project was met ahead of schedule. The schedule was a shot in the dark; when the project started, no one knew how long it would take. Human Genome Project

4. Incomplete Human Genome Project Despite the headlines, the sequence is still incomplete. The project will be finished when: every last gap closed in the sequence errors are at a rate of <1 in 10,000 Expect most of the gaps to be filled by summer, 2001; another 18 months to tidy up the sequence The target date to have everything pristine is April 23, 2003

5. Similarity of man and mouse There is a difference of only a few hundred genes between man and mouse. We shouldn’t be very surprised since man and mouse show great homology in physical systems. While the large physiological systems are similar, the details in physiology and drug reaction are not; small variations in proteins have large consequences. Human Genome Project

6. Two distinct effects are likely: more sophisticated population studies to find causative genes will be possible availability of the genome sequence will allow the detection of gene expression and proteomic analyses New insights for coronary disease Human Genome Project

7. A substantial fraction of cardiovascular disease is heritable, but finding the responsible genes has been difficult. We already have identified 1.5 million (out of 4 million) sites of genetic variation in the genome. When we have all major genetic variants, we can test each variant for correlation with CVD. Finding causative genes Human Genome Project

8. DNA arrays and proteomic analyses will become available. Researchers will look at diseased and healthy tissue in different circumstances to examine the RNA and proteins expressed. This will lead to an explosion of ideas and hypotheses on the pathophysiology and treatment of disease. Pathophysiological insight Human Genome Project

9. “I think it is going to change medicine the same way the periodic table changed chemistry.” -Eric Lander Systematic approach Human Genome Project

10. The human population is 5000 generations removed from a small founding population. Variants in the genome tend to group together in ancestral segments up and down the chromosome, making analysis easier. The number of segments is probably between 30 and 40,000. Studies will probably end up only involving some 100,000 genetic variants. Too many variants? Human Genome Project

11. Within the next 3 years, everything should be in place to begin large studies. 2 or 3 years after that should start netting us many of the important genes. A decade out we will have a pretty solid understanding of etiology, pathophysiology and an explosion of treatment ideas, not unlike what has been happening in cancer already. When will see a major impact? Human Genome Project

12. A lot of progress has been made recently in understanding the genetics and treatment of certain types of cancers. It may be more difficult to find therapies for CVD because in cancer, you just have to kill a diseased/aberrent cell while CVD requires more subtlety, since it deals with normal cells and normal responses. Cancer treatment vs CV treatment Human Genome Project

13. “I am extremely optimistic that the ground work is set now for a real molecular understanding that I think will then translate into the clinic.” -Eric Lander Optimism for the future Human Genome Project