Faculty Research in the News

Tilghman reflects on DNA study

By Meredith Wright | The Daily Princetonian

President Shirley Tilghman and biology professor David Botstein recounted tales of their involvement as young scientists in the Human Genome Project and gave their opinions on hot topics in molecular biology in a talk Tuesday afternoon.

The talk, titled “Speaking of Genetics ... Five Years Later” was led by author Jane Gitschier, a professor at the Institute of Human Genetics at the University of California San Francisco, who first interviewed Tilghman and Botstein separately in 2006 for the journal PLoS Genetics. Gitschier also incorporated interviews with them into her own book published in 2010 called “Speaking of Genetics: A Collection of Interviews.”

Tilghman and Botstein said in the interview that they first met in Phillip Leder’s laboratory at the National Institutes of Health in Washington, D.C., in the mid- 1970s. At the time, Tilghman was working as a postdoctoral student with molecular biology professor Lynn Enquist on cloning a single gene from the mouse genome coding for a piece of the hemoglobin protein, which transports oxygen in red blood cells.

Botstein and Tilghman met again as the youngest members of the Alberts Committee, a committee of scientists arranged by the National Academy of Sciences and Bruce Alberts to weigh the pros and cons of sequencing the human genome. Both recalled initial concerns about moving forward with the Human Genome Project, which completed sequencing in 2006.

“What many of us who worked with model organisms were concerned about was going ahead and focusing on only sequencing the human genome,” Tilghman said. “My concern in the beginning was the narrow thinking about the project,” she added.

Tilghman explained that at the time of the committee, the difficulty of sequencing DNA by hand led to concerns about not addressing the genomes of model organisms such as E. coli and C. elegans, which are commonly used in biological research.

“One of the amusing things about [the Human Genome Project report] is that I ended up writing the sequencing chapter. As it turned out, I was the only one who actually knew how to sequence DNA. The others hadn’t got their hands dirty in years,” Tilghman said.

Botstein also noted the difficulty of sequencing DNA and the funding problems that the project encountered.

“My concern was that [sequencing the human genome] would do to biology the same thing the space shuttle did to planetary astronomy, which would be to eat up all the funds and siphon money away from other projects,” Botstein said.

Tilghman and Botstein explained that their largest contribution to the committee was raising the importance of sequencing not only human genomes, but those of model organisms as well. They explained that it would be impossible to fully understand the human genome sequence without information on other organisms. Tilghman added that she had held initial concerns about the sequenced data being incomprehensible to scientists for many years, but that research and interdisciplinary cooperation has been motivated by the large source of data.

“Those data are an immense motivator to develop tools for analysis, and that’s exactly what happened with the genome,” Tilghman said. “As sequences began to pour in, the motivation in the field to attract computer scientists and mathematicians to help us was immensely important.”

Gitschier questioned Botstein and Tilghman on the repercussions of the Human Genome Project. Botstein elaborated on the impact of genome sequencing for the study of evolution.

“Evolution, which before really had only been a theory, now became a fully quantitative thing because you could take these genomes, look at the sequences, compare them and show which animals have close sequences to us.” Botstein said. “You build a tree completely automatically by mathematics just by the sequences — you get a tree essentially congruent to the tree that Darwin and others over the years constructed,” he explained.

Tilghman added that the Human Genome Project has shown that genomes are organized differently than the field had previously believed.

“The last 10 years have been an absolute explosion in all those preconceived notions,” Tilghman said. “This of course is why being a molecular biologist is so much fun, because we’re basically rewriting the story of how organisms organize their genomes and how those genomes are expressed and coordinated.”

Although Tilghman expressed disappointment in the amount of time it has taken to impact human health with data from the Human Genome Project, Botstein said that the clinical repercussions of the sequencing of the human genome have been valuable in treating and understanding cancer.

“A great deal of good has been done,” Botstein said. “This has played out nicely in cancer genetics and diagnostics, where the world is really actually different than it was 10 years ago for at least some kinds of cancer. It’s all going to happen but it’s harder than it looked.”

The discussion also included both scientists reflecting on the difficulty and surprising results of their early work, as well as addressing views on teaching and publishing in the field of molecular biology.

“Molecular biology and genetics were insurgent sciences when we were students,” Botstein said. “They are an establishment today. I think that fundamentally it’s the same question of why do startups beat the pants off IBM. There’s something about human organization, about power — that spirit doesn’t exist.”

Botstein and Tilghman then responded to questions from the audience, which ranged from questions about 17th century germ theory to the issue of lack of transparency in scientific journal articles. The first question from the audience came from a woman curious about the allegations made against the University last year concerning inhumane treatment of primates used for research in Green Hall. The woman compared the University’s conduct to that of Nazis who performed experiments on individuals in concentration camps without anesthesia.

“It seems to me the University is using the same barbaric methods of doing research on animals without treating them as anything living,” the woman said.

“We were accused by a former employee of mistreating animals in Green Hall,” Tilghman said. “We conducted a completely thorough investigation of all of these claims and we could not find evidence to support them at all. If you go on the USDA website, you will see they have completely given us a clean slate.” When the woman continued to argue that the University has mistreated animals, the audience hushed the woman until she left the lecture hall.

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