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Human Genetics: From Medical Discipline to Medical Tool
Q: In the last several years, we have witnessed a revolution in human genetics. Given that you trained in the field of medical genetics, how has it evolved in the context of this larger revolution from your graduate days at the University of Illinois in Urbana to your current directorship at HPCGG?
A: Medical genetics was in its infancy back then. If a child was born with an abnormality, the doctors would say, "something is wrong, and you need to have a geneticist take a look." It wasn't until people actually began to identify that genes were involved in some diseases, that you could test the children and in some cases do prenatal diagnosis through amniocentesis. At that point, the two groups that used medical genetics most extensively were obstetricians and pediatricians.
Q: Was this before the Human Genome Project (HGP) took shape?
A: Yes. What's happening now, because of the HGP, is recognition that genetics plays an important role in most diseases: cancer, obesity, diabetes, cardiovascular, neurologic and psychiatric diseases. All of medicine.
No Such Thing as a Single Gene Disorder
Q: If I went out on the street today and asked whomever I came across, "What do you think of when I say, 'genetics' and 'disease'?" he or she might answer, "Tay-Sachs or cystic fibrosis," where we've learned that defects in one gene cause one disease. Is this thinking correct?
A: There is no such thing as a truly single gene disorder. If you take two kids with cystic fibrosis who have identical mutations in the same gene and ask, "What does the disease in those two kids look like?" it is not exactly the same. Why? Even though they both have a problem with the same gene, CFTR, they also have differences in a whole bunch of other genes that modulate the effects of CFTR.
Lung Cancer is Not Lung Cancer is Not Lung Cancer
Q: So what does this multi-genetic concept mean for an average U.S. adult, who is more likely to get lung cancer than cystic fibrosis?
A: Today we know that lung cancer is not lung cancer is not lung cancer; it is two or three or five diseases based on all the genes that contribute to its onset and progression. Therefore, some patients with "lung cancer" will respond to one drug and some to another drug.
Q: How do we figure out which person will respond to which drug?
A: The first step is to identify the genes involved in the disease. That was the whole basis for the HGP, in which I participated. Now we are identifying these genes at a rapid pace. The next step is to understand how those genes cause the disease. Then, in some cases, you can use this understanding to come up with tests to predict who is susceptible to develop a disease or in some cases who will respond favorably to certain drugs.
Q: Researchers at Partners already did that, right? They discovered that a gene, epidermal growth factor receptor (EGFR), is involved in the response of certain lung cancer patients to an anticancer drug called gefitinib.
A: Yes. A subset of patients with non-small cell lung cancer, 10 percent, bears mutations in that gene. They respond dramatically to a drug that targets EGFR.
We now have developed a genetic test that tells which lung cancer patients might benefit most from the drug. This is personalized medicine in action.
Where We Can Make a Difference Today
Q: Is the EGFR story the paradigm for personalized medicine in the near future?
A: EGFR is an excellent example of how we can use the genetic information to make decisions about appropriate treatments for patients, in this case, lung cancer patients.
Q: Why aren't there more of these personalized medicine success stories thus far?
A: For any drug treatment to be accepted in common practice, you need to show that the outcomes are positive. And the way you show that is through clinical trials. We need to conduct similar types of trials with genetic testing.
Q: Why aren't such trials conducted?
A: Clinical trials are expensive and hard to do. Right now, they are the bottleneck.
Q: So then how can we ever realize personalized medicine on a global scale?
A: We need to have many different things come together to make it on a global scale. Pharmaceutical companies have to recognize that finding more personalized medicines will be valuable for them. The physicians should recognize that incorporating genetics into their treatment programs will benefit their patients. The patients will have to be knowledgeable about the availability of such testing. Insurance companies will have to recognize that reimbursing for these tests would save lives and money. Last, the government has to pass laws to make sure that there are no privacy concerns with the genetic information being made available to the patients and their caregivers. All of these different things have to happen to fully make it global.
Q: And what is HPCGG doing in the meantime to advance this effort?
A: We are looking for how we can make a difference with drugs that are already out there on the market. We are starting with a blood thinner called warfarin. It is prescribed each year for 24 million people in the U.S. Too high a dose, and you can bleed to death; too little and you get blood clots. Right now doctors have to guess the right dose.
Q: Based on statistics?
A: No. A physician's experience and best guess. That's all we've got. Yet, you could do a couple of genetic tests that would help about 30 percent of the population to determine the right dose.
Q: So why not test patients now?
A: We have to show that conducting a genetic test and using the results to make decisions would indeed be helpful. We also have to dramatically change the way we do diagnostics. Right now, a genetic test may take more than 2 weeks to get the answer. We have to be able to get the answer from the test before 48 hours, because patients can't wait longer than that.
Q: Do you think that you can do this?
A: If you put a challenge in front of bright people, they will make it happen.
Q: And then what?
A: We do a small trial of 1500 people to make sure the test works. Then move to a larger trial.
Q: And what will this mean to the larger concept of personalized medicine?
A: Doing one trial is not going to be sufficient. But it will certainly demonstrate the feasibility of using genetics to change the way that we take care of one group of patients. In the future, we need to do these types of trials in many more indications. At HPCGG, we are looking at many possible clinical trials including those that might help us determine the right dose of antidepressants, pain medications like codeine, and cancer chemotherapy.
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