Michael Wigler
Genetics Professor, Cold Spring Harbor Laboratory

A Routine Checkup for Cancer?

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New technology fueled by genomic research could soon make a simple blood test for cancer a part of ordinary visits to the doctor.

Michael Wigler

Dr. Michael Wigler has made wide-ranging contributions to biomedical research in genetics, cancer, and cognitive disorders. Dr. Wigler attended Princeton University as an undergraduate, majoring in Mathematics, and Columbia University for graduate studies in Microbiology. After receiving his Ph.D., he began his scientific studies at Cold Spring Harbor Laboratory, where he continues his work to this day as an American Cancer Society Research Professor.

Early in his career, Dr. Wigler developed methods for engineering animal cells with his collaborators at Columbia University, Richard Axel and Saul Silverstein. These methods are the basis for many discoveries in genetics, and the means for producing medicines used to treat heart disease, cancer, and strokes. Dr. Wigler continued his genetic explorations, and in the early 1980s isolated the first human cancer genes. In the mid 80s, Dr. Wigler and his collaborators demonstrated conservation of cellular pathways in humans and yeast, thereby providing deep insights into the function of the cancer genes.

In the early 1990s, Drs. Wigler and Clark Still developed a method for building vast chemically indexed libraries of compounds, an approach that is still in use for drug discovery. During the same period, Wigler’s group developed the concept and applications of representational analysis, RDA, which led to identifying new cancer genes and viruses. He later enhanced this concept through use of microarrays, a method now widely used commercially for genetic typing.

Dr. Wigler’s research is presently focused on the genomics of cancer and genetic disorders. He expects this work will eventually improve the targeting of cancer treatment and lead to early detection tests for cancer. His studies in human genetics led to the discovery of a vast source of genetic variability known as copy number variation (CNV), and to the breakthrough that spontaneous germline mutation is likely to be a contributing factor in autism. His genetic theories and methods suggest to new approaches to understand many other cognitive and physical abnormalities.

For his fundamental contributions to biomedical research, Dr. Wigler is a recipient of numerous awards and honors and is a member of the National Academy of Science and the American Academy of Arts and Sciences.

Question: What has your research revealed about the genetic causes of cancer?

Michael Wigler: Yeah.  Well, the first observation was that there was a very strong correlation between the extent to which the genome in a cancer cell has changed and the lethality of the cancer.  So that, if one’s looking at cancer and there’s lots of changes in the genome, that patient is less likely to survive than a patient whose genome has just begun to evolve.  That was the first major observation. 

There were a lot of particular details that emerged from those studies, that is, we found the locations of genes that are called uncA genes and tumor suppressor genes.  The individual genes at these places, many of the changes are what we call recurrent.  They happen over and over again in different people with the same cancer, and there are genes in those regions that one can show functionally alter the capacity of the cancer cell to grow, divide, or spread in the individual.  So this has been an engine also for the discovery of new cancer genes. 

We weren’t the first ones to do this.  People have been using these techniques for a while, including ourselves, for a period of 10 years or more.  Sometimes particular drugs that are given to a patient are determined by whether that patient has a particular gene amplification in their cancer.  The most well-known example of that is patients with amplification of the HER2 gene will likely respond to Herceptin.  So, our review has been that specific amplifications will correlate with drug sensitivity, we’re in the middle of exploring that, and we’ve also begun to look at single cells within cancer.  So that we can now actually look at the genome of an individual cell within the cancer and that’s giving us a much more detailed picture of how the cancer has evolved. 

So, we think we’ll be able to identify, for example, the earliest cells, the earliest mutations in a cancer that will tell us how the cancer began to grow in the first place.  It will also tell us what you might call the tribal, or population structure of the cancer, and that tells us about how the cancer is... how the individual cancer cells are interacting with each other, interacting with the host, and migrating through the cancer, and possibly migrating throughout the patient.  So that we think that by looking at the individual cells of the cancer, we’ll be able to improve clinical staging and drug treatment enormously.  But this is a long-term project.  This will take us five years, 10 years.

Question: How might this research impact clinical cancer treatments?

Michael Wigler: Well, I can give you two ways—there are many ways this research could impact the clinic.  I can give you two very concrete examples.  If a new drug is being tested in a population with a particular type of cancer, one might look for correlations between response to the drug and the genome profile.  That could tell you which patients are likely to respond to a drug so that patients don’t have to take a drug that’s not going to benefit them and don’t have to suffer the side effects of a drug that’s not going to benefit them.  And that will ultimately lead to the design of better drugs.  

A second way—and this next way is not quite science fiction, but we’re looking a little bit into the future—when we can examine the genome of individual cells, and can do that cheaply, we can develop early detection tests for cancer that are based on blood.  So, it’s now being appreciated widely that even cancers that perhaps have not yet metastasized release their cells into the bloodstream and do so in fairly large numbers so that you can collect cells from the blood and identify them as a kind of cell that shouldn’t be in the blood.  But people haven’t yet been able to look at the genomes of these individual cells.  So, some of the methodology that we are developing will enable us to do that.  So you can imagine that at some time in the future, you can draw blood in the doctor’s office and just like the doctors now do what’s called a blood count to determine how many white blood cells you have, whether it’s likely that you’ve got a fever, they’ll be able to sort out from the blood this small proportion of cells that might be being spun off by a cancer somewhere undetected in the body.  And by looking at the genome of those cells, and possibly by also looking at the RNA that those cells are making, I'll be able to say "This person has malignant bone cancer," and then you can look for that. 

So, this technology can ultimately lead to early detection for cancer.

Recorded April 12, 2010