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Vol. LXIV, No. 4
February 17, 2012
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Botstein’s ’Bots
Evolution in Yeast Yields Clues to Tumor Development

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Dr. David Botstein delivers 2nd Nirenberg Lecture.
Dr. David Botstein delivers 2nd Nirenberg Lecture.
Much of what science has learned about genetics in recent decades has yeast to thank for the insights, and few people in American science are putting yeast through a more rigorous curriculum than Princeton University’s Dr. David Botstein, who gave the second annual Marshall Nirenberg Lecture at NIH on Jan. 4.

In a lecture titled “Evolution and Cancer,” Botstein showed reams of data gleaned from some 600 cultures of yeast that are being put through hundreds of generations of growth by his collaborators Greg Lang and Michael Desai, using robots for the scut work. By watching evolution at work, they hope to understand the processes that engender out-of-control cell growth, or cancer.

Continued...

In a lecture titled “Evolution and Cancer,” Botstein showed reams of data gleaned from some 600 cultures of yeast that are being put through hundreds of generations of growth by his collaborators Greg Lang and Michael Desai, using robots for the scut work. By watching evolution at work, they hope to understand the processes that engender out-of-control cell growth, or cancer.

“We can reason from one organism [yeast] to the other [human], much of the time,” he assured. From an abstract of his talk: “These ideas motivated a comparison between results of molecular genetic studies of experimental evolution in yeast and the molecular genetic phenomena associated with tumorigenesis and tumor progression. We find some very striking similarities, including recurring genomic rearrangements, alterations of the regulation of specific growth-promoting genes, population- genetic features that affect the fitness trajectories of growth rate variants in evolving populations and physiological and metabolic similarities derived from the conservation of the basic plan of growth and cell multiplication among all eukaryotes.”

“What can we learn about the process of evolution from yeast?” he asked, adding that yeast is the source of most of the genetic annotation known to science. Using an advanced version of the chemostat invented in 1950 by Jacques Monod and Leo Szilard, Botstein and his colleagues are interrogating successive generations of yeast—kind of an accelerated version of natural evolution, with its mutations and selection preferences—in search of the underlying causes of cancer.

Botstein answers questions from the audience as NIH director Dr. Francis Collins looks on.

Botstein answers questions from the audience as NIH director Dr. Francis Collins looks on. Botstein said that hearing Dr. Marshall Nirenberg speak at Harvard in 1962 “was one of the great events of my scientific lecture-going.”

Photos: Bill Branson

Again from his abstract: “It is hoped that some of the insights from yeast will aid the interpretation of sequence changes found in tumors, especially in the urgent necessity to distinguish ‘driver’ from ‘passenger’ mutations.”

A renowned pot-stirrer in U.S. science and the originator—according to NIH director Dr. Francis Collins, who introduced him—of the strategy behind the Human Genome Project, Botstein used the occasion to ally himself firmly with Nirenbergian science and to speak critically of the rush to embrace “translational science.”

This was ironic given that, only 2½ hours prior to Botstein’s talk, the same venue (Masur Auditorium) played host to an upbeat town-hall meeting of NIH’s new center for translational sciences.

“I did not know Marshall Nirenberg very well,” Botstein said at the outset of his lecture, “but I do remember the first time I heard him talk, in 1962 at Harvard.” This was when the world was just learning of Nirenberg’s eventual Nobel Prize-winning work deciphering the genetic code.

“It was a transformative thing for me,” Botstein continued. “I had just decided not to be a physicist… The coding problem prompted me to study genetics. It was one of the great events of my scientific lecture-going, I have to say.”

He recounted that his NIH hosts had preferred the topic of translation to the lecture title he proposed, but Botstein insisted on a basic science emphasis in honor of the occasion, declaring, “There are two senses of the word ‘translation’: one of these [mRNA to protein] I don’t work on, and I don’t agree with the enthusiasm for the other.”

Later in his talk, in a segment he labeled “A Message for the Sponsor,” he touted Nirenberg as a scientist “as basic as they come…For him, the pursuit of understanding was paramount.” Botstein declared, “Understanding is what we do…If we starve basic science, there will be nothing left to translate.”

In his view, “we spend way too much time looking at the weeds and not enough time looking at the forest. That’s our modern dilemma.”

Thanking NIGMS for providing the robotic technology used in his studies, Botstein also lamented a common problem plaguing researchers in an era of ever-faster sequencing machines and interpretive skills that can’t keep pace.

“We are standing at the bottom of the Grand Coulee dam here, and will be fully underwater by mid-semester,” he predicted. A “tsunami of data” outstrips science’s capacity to analyze.

Collins assured his guest that NIH continues to embrace basic science heartily. “We recognize that it is our seed corn…Rest assured, there’s no crisis here at NIH.”

The full talk is archived at http://videocast.nih.gov/summary.asp?Live=10493.NIHRecord Icon


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