The doctor of the future

In the future, Dr. Ronald Crystal believes, physicians will be genetic medicine doctors.

The Human Genome Project (HGP) was a 13-year project coordinated by the US Department of Energy and the National Institutes of Health. Although completed in 2003, analyses of the data will continue for many years. Generations of biologists and researchers will benefit from the detailed DNA information that the HGP provided. “The Human Genome Project is to the biologist and the biomedical scientist what the periodic table was to the chemist,” says Dr. Ronald Crystal, Chairman of the Department of Genetic Medicine at Weill Cornell Medical College. Awe inspired, he continues: “The sequence of the genome is the bible of all work relating to the genetic basis of human disease. What we now understand is that all humans are basically identical, that is 99.9 percent of their genetic sequences. Only 0.1 percent makes us different. Not only different as individuals, but also different in terms of our susceptibility to disease.”

The amount of new information from the HGP is enormous. It has caused scientists to reinvestigate the role of genetics and other risk factors involved in the development of disease. Virtually all human diseases are the result of the interaction of factors relating to genetic susceptibility and modifiable environmental factors. Crystal: “We are all exposed to very complex environments that are changing throughout our life. It’s that interaction with the environment and what our genes produce that makes us either susceptible to or protects us from various diseases. So the sequencing of the human genome was a monumental event in terms of biology that has revolutionized the whole approach to human disease.”

DNA Microarrays

Ultimately, Crystal would like to be able to sequence an individual’s whole genome. The technology, however, is not quite there yet; it is also a timely procedure and far from being cost-effective. A useful tool to study the whole genome is a single nucleotide polymorphism (SNP) array. An SNP is a variation at a single site in DNA. There are an estimated five to 10 million SNPs in the human genome, which makes it the most frequent type of variation in the genome. “You can fit 500,000 SNP probes on a single chip, which you can hold on the palm of your hand. If you analyze this it will tell you the difference between individuals,” explains Crystal.

SNPs are highly conserved throughout evolution and within populations, which makes an SNP map an excellent genotypic marker for research. To describe the common patterns of human DNA sequence variation, the international HapMap Project has developed the haplotype map (HapMap). Members of the project, a collaboration among scientists in Japan, the UK, Canada, China, Nigeria, and the US, are hopeful that the map will be a key resource for researchers to find genes affecting health, disease, and responses to drugs and environmental factors. “The map was created by sequencing the entire human genome of 270 individuals around the world, including Africans, Japanese, Chinese and Caucasian Europeans living in the US. The differences among those populations are now available,” says Crystal.

Microarray technology is advancing rapidly and Crystal is hopeful that soon one million SNP probes can be placed on a single DNA microarray to obtain even finer maps of the differences amongst human genomes. “This will improve our ability to identify multiple abnormalities of complex disorders where many different genes are contributing to whether you are more susceptible or protected from a disease”, explains Crystal, adding: “Not only will this give us the ability to determine who is at risk and who isn’t, but it will also identify new targets for drugs. As new drugs are developed they can be developed against these genes or gene products that appear to increase the risk of getting a disease.”

Progress in this area could help cure such complex disorders as diabetes and cardiovascular disease – also known as the new epidemic and killer number one. Crystal’s major interest, currently the fourth killer in the US, is chronic obstructive lung disease, mostly caused by a gruesome mix of cigarette smoke, secondary smoke and air pollution. “We have drugs that treat heart disease or diabetes, but we have no drugs that change the mortality of chronic obstructive lung disease. We have drugs that can alleviate symptoms and make people feel better but we can’t change the rate at which people die from this disease. Chronic obstructive lung disease is increasing in the US so much so that by the year 2020 it will be the third largest killer in our country.” To prevent this, Crystal is trying to identify the genes that allow individuals to smoke without ever developing any problems. Identifying who is at risk and who is not will help Crystal to recategorize the disease on a biological level. Eventually, he hopes to be able to identify targets for the development of new drugs that will not only alleviate symptoms but prolong the life of people who develop the disease.

Personalized medicine

Pharmacogenomics correlates SNPs with a drug's efficacy and toxicity. It aims at optimizing drug therapy with respect to the patients' genotype to ensure maximum efficacy with minimal side effects. This holds the promise of personalized medicine: drugs that are tailor-made for individuals and adapted to each person's own genetic makeup. Although advances in this field have been made for example in the development of lung cancer treatment, there is a long list of challenges that hold up progress. “The biggest challenge,” says Crystal, “is phenotypes. In terms of lung disease this means are you categorized as someone with emphysema or are you categorized as bronchitis? If we identify the wrong phenotype, correlating this with the genes won’t help very much. So we need to be very accurate, using the appropriate medical tests.” Another major issue is cost. Research and technology are expensive. Funding is restricted and competition for the biomedical research dollar is tough.

A third problem, and probably the most complex to resolve, is the social aspect and the ethical considerations associated with genetic privacy. “Eventually, we will be able to determine who is at risk for getting a specific disease and who is not. That’s in conflict with the way we fund our medical system. If the insurance companies know who is at risk, they might change their rates,” says Crystal, and pauses – after a pensive moment, he adds: “The technology of genetics is far ahead of the treatments we have. As we develop the power of this technology, we can identify who is at risk and who isn’t. What are the consequences of telling somebody that they are at risk of developing a disease? What will be their subsequent behavior if we can’t treat them? Do you really want to know that you are going to get Alzheimer’s when you are 55 if we don’t have the drugs that can treat it? This is a society challenge.”

Not surprisingly, society is concerned and voices its apprehensiveness: who owns and controls genetic information? Who should have access to personal genetic information, and how will it be used? How will it affect an individual and society's perceptions of that individual? There are several responses. Crystal’s is education: “It is our obligation as physicians and biomedical scientists to help educate the population. The more people understand, the more comfortable they will become with it. The technology is very powerful and evolving. The important thing is not to be frightened by it. It has great potential to alleviate suffering and prolong our lives and that of our families. We all want that.”

Crystal is determined that the discoveries of the HGP are a revolution in medical care. “It’s not one that is going to happen over night because the biology underlying it and the medical aspects are very complex. But in my lectures to young doctors in training I always point out that genetic medicine is their future. They are going to be genetic medicine doctors.”

Ronald Crystal: “A pioneer in genomics, gene therapy and genetic medicine, Dr. Ronald Crystal trained in internal medicine at Massachusetts General Hospital. After 23 years at the National Institutes of Health, he came to Weill Medical College of Cornell University in 1993. He is Chief of Critical Care Medicine and Chairman of the Department of Genetic Medicine.”

Ronald Crystal: “Eventually, we will be able to determine who is at risk for getting a specific disease and who is not.”