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BREAKTHROUGHS SUMMARY ARTICLE The Full-length version of this article is also available, published online as http://www.fasebj.org/cgi/content/full/17/8/787e.< /FONT> |
On nearly a daily basis, newspaper headlines tout the discovery of a new gene related to human disease. Compare this with April 1953, when the news of James Watson and Francis Crick’s elucidation of DNA structure barely attracted the interest of journalists. In the 50 years since this discovery, basic genetic research has made great strides, spawning new fields, such as genomics, and leading to applications in human medicine.
The founding father of genetics, Gregor Mendel, could hardly have guessed that his experiments with pea plants would be followed by a twisted path of discovery resulting in sequencing of the human genome. A series of elegant, fundamental experiments connected Mendel’s theories of inheritance to our current ability to understand and treat disease at the level of the gene. Hermann Joe Muller introduced the concept of genetic mutation, clearing the way for Linus Pauling to link a defective gene with the crippled hemoglobin protein that causes sickle cell anemia. By 1944, Oswald Avery, Maclyn McCarty, and Colin MacLeod had identified DNA as the genetic material of an organism. This led to the race to elucidate the molecular structure of DNA, culminating in Watson and Crick’s construction of the double helical model, based largely on the X-ray crystallography images of Rosalind Franklin. For their model of DNA structure, Watson and Crick shared the 1962 Nobel prize with Franklin’s partner, Maurice Wilkins. Franklin herself had died before the prize was awarded.
In 1985, a collaboration of international researchers resolved to sequence the entirety of the human genome. The Human Genome Project received private and public funding from the National Institutes of Health and the Department of Energy. The ‘first draft’ of the genome was published in early 2001, and the ‘final draft’ will be published in April 2003, exactly 50 years after publication of Watson and Crick’s pivotal paper. As more genes are discovered and connected with basic biological functions and disease conditions, better animal models of human genetic conditions are being developed and knowledge of gene function is increasing.
Perhaps the area in which application of basic genetic research has had the greatest impact is that of genetic testing. Genetic tests act not only as diagnostic tools, but can also be used to aid in risk assessment, allowing for early intervention and, in certain cases, prevention of a disease. The model example of genetic testing leading to disease prevention is that of phenylketonuria, or PKU, which strikes 1 in 20,000 infants. Basic research led to discovery in the 1980s of the defective gene that causes PKU, and leads to severe retardation. Careful regulation of the diet to avoid phenylalanine can prevent disease symptoms from occurring, and testing of newborns for PKU is now mandatory in all 50 states.
Cystic fibrosis (CF) is the most common recessive genetic disease in Caucasians, affecting 1 in 3,300 children in the United States each year. CF is caused by any of 1,000 known mutations in a gene called CFTR; the prognosis for the patients is quite variable: some patients experience mild symptoms with a long life-span, others have debilitating symptoms leading to an early death. Although testing a child for CF does not predict prognosis or determine a course of treatment, testing parents to identify carriers of the recessive gene may influence their reproductive decisions. Physicians, genetic counselors, and potential parents can work together to assess the risk of passing on the disease and the potential prognosis for offspring. More complicated is the use of genetic testing to predict late onset conditions. The series of genetic mutations leading to the hereditary and sporadic forms of colon cancer have been well-elucidated by researchers. While detecting the occurrence of any one of these mutations will not necessarily predict whether an individual will develop colon cancer, it may help determine the extent of their risk.
The future of medical application of genetics research lies in targeted drug development and personalized medicine. An early example of pharmacogenetics is the introduction of Gleevec, a drug used to treat chronic myelogenous leukemia, which occurs when a mutated gene produces an oncogenic protein. Discovery of this gene and the resulting protein allowed scientists to design Gleevec, which specifically blocks the action of the malformed protein. Haplotype mapping, which categorizes minute differences in the genetic makeup of individuals, can contribute to individualized treatments based on how a person’s genetic makeup will respond to a particular drug or intervention. Researchers have discovered that patients suffering from breast cancer whose tumor cells carry a mutation known as HER2 will be receptive to the drug Herceptin. If no such mutation is present, Herceptin is an inappropriate form of chemotherapy and the physician will need to focus elsewhere on treating the patient. As basic genetic research continues, an increased depth of knowledge will allow for design of similar treatments, tailored to the individual needs and sensitivities of the patient.
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