Sequencing the Genome “Changed Everything”
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 does your research consist\r\n of on a day-to-day\r\nbasis?\r\n\r\n
Michael Wigler: Our lab studies the genome \r\nof organisms and\r\nalso the genome of cancer cells. \r\nAnd we work on two kinds of problems: the evolution and outcome \r\nof\r\ncancers, and also on genetic disorders of a spontaneous sort, that is,\r\nnon-heritable genetic disorders. \r\nAnd those are two very—it sounds like two very different things, \r\nbut\r\nthey’re related by our methodology, which is genomic analysis.\r\n\r\n
What we do is called difference analysis, for \r\nexample, if\r\nwe’re looking at a cancer, we’ll want to see where that cancer has \r\nmutated\r\nrelative to the genome of the person who gave rise to that cancer. That’s differential genomic\r\nanalysis. And it tells us where\r\nthe cancer has mutated. And from\r\nthe types of mutations, the number of mutations, we can infer a lot \r\nabout\r\ncancer etiology.\r\n\r\n
Question: Is biology becoming a more \r\nquantitative than\r\nqualitative science?\r\n\r\n
Michael Wigler: Well, biology has always \r\nbeen influenced\r\nstrongly by quantitative types. \r\nMany physicists in the late ‘30s, early ‘40s, ‘50s, came into \r\nbiology,\r\nstrongly influenced it. There was\r\na period, I would say, from the time I was a graduate student in the \r\nmid-‘70s\r\nuntil the mid- to late-‘90s, where it was not particularly quantitative,\r\n and that was\r\nlargely because of the revolution in recombinant DNA. So,\r\n really all you needed to be a good biologist was a good\r\nsense of logic and a good imagination. \r\nAnd mathematical and statistical skills weren’t really that \r\nnecessary\r\nfor much of biology. And I was in\r\nthat group actually. I had studied\r\nearlier on as a mathematician but I used almost none of those \r\nmathematical\r\ntools when doing biological research. \r\nOf course, the logic comes in handy, but the tools were not very\r\nvaluable. There was no place for\r\nthem because the kind of data that we were getting was very individual \r\ndata and\r\nI actually had a rule of thumb. I actually disliked statistics early on \r\nin my\r\nlife and I felt that if I needed to do statistics to see what I was \r\nobserving,\r\nthen I wasn’t really observing anything.\r\n\r\n
But that changed with the advent of the sequencing \r\nof the\r\nhuman genome. That changed\r\neverything. And the development of\r\nnew high throughput methods of extracting data, it forced biologists to\r\nreconsider the value of statistics and mathematics in the analysis of \r\ntheir\r\nsubject. So, a number of\r\nbiologists moved in that direction. \r\nNot a lot, but quite a number did. \r\nAnd I was one of those who moved in that direction.\r\n\r\n
Question: How has the sequencing of the \r\ngenome “changed\r\neverything”?\r\n\r\n
Michael Wigler: You know, we are so close, \r\nhistorically, to\r\nthat period, and the data that’s coming out of that effort is still \r\nbeing\r\ngenerated. I think it’s very hard\r\nfor any of us to really judge the impact that it has had. \r\n It was a huge revolution in terms of\r\nthe kinds of experiments one can conceive of doing. The\r\n only thing comparable in my lifetime was the recombinant\r\nDNA revolution which changed entirely the kinds of experiments people \r\ndid.\r\n\r\n
Since sequencing methods are changing so fast, the \r\ncost of\r\nsequencing has dropped enormously. \r\nAnd with each drop in the cost, it changes entirely how you think\r\n of\r\nattacking the problem. So, in a\r\nfew years from now we’ll be in a position to have DNA sequence of a very\r\n high\r\nquality for a million people and know the medical history of these \r\nmillion\r\npeople. And there’ll be—I don’t\r\neven think our computers are yet to a stage where they will be able to \r\nhandle\r\ndata of that type and the kind of analysis tools that will be needed to \r\nanalyze\r\nthat haven’t been developed yet. \r\nSo, we’re in a really a strange point in the history of biology \r\nwhere\r\nthings are changing so rapidly, we can’t quite see the shape of the \r\nfuture\r\nyet.
Recorded April 12, 2010
The revolution sparked by the Human Genome Project will soon produce more genetic information than our computers can currently handle.
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If you want to know what makes a Canadian lynx a Canadian lynx a team of DNA sequencers has figured that out.
- A team at UMass Amherst recently sequenced the genome of the Canadian lynx.
- It's part of a project intending to sequence the genome of every vertebrate in the world.
- Conservationists interested in the Canadian lynx have a new tool to work with.
If you want to know what makes a Canadian lynx a Canadian lynx, I can now—as of this month—point you directly to the DNA of a Canadian lynx, and say, "That's what makes a lynx a lynx." The genome was sequenced by a team at UMass Amherst, and it's one of 15 animals whose genomes have been sequenced by the Vertebrate Genomes Project, whose stated goal is to sequence the genome of all 66,000 vertebrate species in the world.
Sequencing the genome of a particular species of an animal is important in terms of preserving genetic diversity. Future generations don't necessarily have to worry about our memory of the Canadian Lynx warping the way hearsay warped perception a long time ago.
Artwork: Guillaume le Clerc / Wikimedia Commons
13th-century fantastical depiction of an elephant.
It is easy to see how one can look at 66,000 genomic sequences stored away as being the analogous equivalent of the Svalbard Global Seed Vault. It is a potential tool for future conservationists.
But what are the practicalities of sequencing the genome of a lynx beyond engaging with broad bioethical questions? As the animal's habitat shrinks and Earth warms, the Canadian lynx is demonstrating less genetic diversity. Cross-breeding with bobcats in some portions of the lynx's habitat also represents a challenge to the lynx's genetic makeup. The two themselves are also linked: warming climates could drive Canadian lynxes to cross-breed with bobcats.
John Organ, chief of the U.S. Geological Survey's Cooperative Fish and Wildlife units, said to MassLive that the results of the sequencing "can help us look at land conservation strategies to help maintain lynx on the landscape."
What does DNA have to do with land conservation strategies? Consider the fact that the food found in a landscape, the toxins found in a landscape, or the exposure to drugs can have an impact on genetic activity. That potential change can be transmitted down the generative line. If you know exactly how a lynx's DNA is impacted by something, then the environment they occupy can be fine-tuned to meet the needs of the lynx and any other creature that happens to inhabit that particular portion of the earth.
Given that the Trump administration is considering withdrawing protection for the Canadian lynx, a move that caught scientists by surprise, it is worth having as much information on hand as possible for those who have an interest in preserving the health of this creature—all the way down to the building blocks of a lynx's life.
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