Princeton University - Council of Science & Technology

POPE PRIZE

Essay 1
The Collaborator
Shoshana R. Leffler

Essay 2
A Maverick Paleontologist in Pursuit of the Truth: Gerta Keller
Alice Lloyd George

Essay 3
Leave the Web its Dark Alleys
Jonathan R. Mayer

The Collaborator

lThe year is 1978. Two young scientists drive up the densely forested mountain ridges that loom over the medieval college town of Heidelberg, Germany. Day after day they repeat this trip. Arriving at their destination, the European Molecular Biology Organization laboratory (EMBL), they continue through a maze of closely packed laboratories until they reach an approximately 10 x 20 foot room resembling a storage closet. Upon opening the door, they are greeted by a jumble of test tubes, microscopes, dissecting needles, and row upon row of vials, containing tiny frenetic fruit flies: 40,000 fruit fly families will pass through their laboratory during the course of their year-long experiments. They are alone. Down the hall they can hear a scientist boasting about his recent experiment and another cutting him off and in turn bragging about his own laboratory find. Scientists throughout this brand new inter-governmental center for the study of molecular biology are aggressively competing. Who will get the next publication? Who will win the next award? Surely not these two young scientists. The day before, a renowned fruit fly expert told EMBL’s director, the Nobel Laureate Sir John C. Kendrew: “We need some really good fly geneticists, not these two.”

But the two scientists, Eric Wieschaus and Christiane Nüsslein-Volhard, ignore the clatter, the boasting, the derogatory remarks in the hallway. Instead, they shut themselves up in their silent room and examine flies. Quickly, they each take a set of Petri dishes containing fly embryos that they had carefully laid out on a shelf at midnight the night before. They move over to a lab bench, taking their usual spots across from each other. Simultaneously, they peer into a dual microscope that has been fitted with an eyepiece for each of them. Then together, as if a spell has been broken, they begin observing the fruit fly embryos in an assembly line fashion. If they can sort through these flies quickly enough, then they can get to the next ones!

These fruit fly embryos did not come from normal mothers. The two scientists had used UV light and toxic chemicals to create a huge number of random mutations in the fruit flies’ DNA, and then they had bred entire fruit fly families from the original mutated flies. So when they looked into the microscope they saw some embryos that had brain cells in place of skin. Others had not developed head regions. The sheer number and types of mutations made their heads spin. Wieschaus and Nüsslein-Volhard were the only two humans in the world privy to this large-scale roll of the dice. They had mutated a total of 14,000 fruit fly genes and only certain mutations produced recognizable defects in development. They only had each other to group and categorize these mutations into a recognizable pattern that could explain what types of genetic mutations give rise to problems in development. Was there a pattern? Perhaps there was none. They felt it was their destiny to find out.

Seventeen years later these two scientists, Eric Wieschaus, currently the Squibb Professor in Molecular Biology at Princeton University, and Christiane Nüsslein-Volhard, presently director of an independent division at the Max-Planck-Institut für Entwicklungsbiologie, shared the 1995 Nobel Prize in Physiology or Medicine for their 1978 research. The process of development was already known long before Wieschaus and Nüsslein-Volhard embarked on their experiments. After a female egg joins with a male sperm, the newly blended cell divides many times into smaller cells. In a structure called an embryo, some of these cells begin to look different from others. In addition, groups of similar looking cells rearrange themselves into special configurations that eventually give rise to tissues and organs. However, in 1978 little was known about the mechanisms or kinds of information encoded in a single cell that determined whether an embryo develops into a fly or a chick. And how do cells develop into different types such as muscle or nerve?

In the 1970’s biological researchers believed that molecular biology, probing the tiny molecules of a living organism with the chemist’s tools was the answer to all remaining questions in biology. With this viewpoint in mind, the European Molecular Biology Organization laboratory (EMBL), where Wieschaus and Nüsslein-Volhard conducted their research, opened in the 1970’s after four years of negotiation and another four years of actual construction. It was a serious enterprise bringing together some of the best molecular biologists from eleven nations. The center was modeled after the European Organization for Nuclear Research (CERN), the world’s largest particle physics laboratory. Molecular biologists had similar visions for EMBL.
Wieschaus and Nüsslein-Volhard, however, ignored the hype in the scientific community. They believed that genetics, which was considered established and old-fashioned to cutting-edge biologists in the 1970s, was the key to unlocking the mechanisms of embryo development. Genetics is the study of how traits are passed on between generations through segments of DNA called genes. Wieschaus and Nüsslein-Volhard wanted to apply established genetic techniques for decoding inheritance to embryo development.

But this was an onerous task. A fruit fly, the genetic experimental animal of choice for geneticists, has 14,000 genes. No one had ever imagined that out of the vast array of fruit fly genes, it would be possible to find a relatively small specific set that was responsible for development. However, Wieschaus and Nüsslein-Volhard made just this kind of imaginative leap. In 1978, they sorted through every gene by mutating them and observing the corresponding defects in the development of fruit flies. They narrowed down the ones necessary for development to 5,000 genes. In addition, they determined that an even smaller number, 139 of the 14,000 genes, played special roles in controlling the overall shape of the embryo and function of specific cells. When corresponding genes were discovered in humans,

work took on profound implications for understanding miscarriages and birth defects in humans. According to Bjorn Vennstrom, a professor at Karolinska Institute and a member of the Nobel Prize award committee, the human equivalents of the genes that Wieschaus and Nüsslein-Volhard discovered may be responsible for many miscarriages and the forty percent of birth defects with no known cause.
But Eric Wieschaus’ Nobel Prize-winning research is also remarkable because of what it tells us about his character. Wieschaus has a strong desire to seek out intellectual partners. His Nobel Prize work in the late 1970’s is just one in a long history of collaborations which continue up to the present.
For Wieschaus, to collaborate is not just a convenient means to do interesting research. Ever since Wieschaus was young boy in Birmingham, Alabama, in the 1950’s, deep intellectual connections have given him the most joy in life. It may have been his father that taught him the importance of valuing and sharing another’s intellectual efforts. Wieschaus’ father left the Catholic Church because his wife had almost died in childbirth and he wanted her to have the option of birth control in the future. However, Wieschaus’ father listened carefully to his children’s arguments of why he should return to the Church. Wieschaus recounted many years later: “He took every one of our arguments seriously, as though he was hearing it for the first time. Taking into consideration other people’s views came very heavily from that time.”
On an academic level, in high school, Wieschaus was very shy and removed from his peers until he attended a summer science program in Lawrence, Kansas, funded by the National Science Foundation: “For the first time in my life I was with kids who were smarter than I, who cared about science, and who talked about books and art. I felt as though I had finally found a group to which I belonged.” After completing his undergraduate degree at the University of Notre Dame, Wieschaus attended graduate school in biology at Yale. There, he was the only student of a young assistant professor, Walter Gehring. Gehring later became an established geneticist and embryologist in Basel, Switzerland. But at this time he was just starting his own laboratory. Wieschaus had the opportunity to work closely with an extremely knowledgeable scientist before Gehring’s lab exploded in size. He sat side-by-side with Gehring at the lab bench to learn techniques for culturing embryos in vivo. Of those times, Wieschaus recalled: “Quite remarkable. Cut up little pieces of flies. And would transplant them around. And would be a two person thing. He would cut and I would transplant. And I would cut and he would transplant.” This intimate working atmosphere was strikingly similar to the one he adopted with Christiane Nüsslein-Volhard for their Nobel Prize work.
Wieschaus later moved to Basel, Switzerland where Gehring had established a large lab. Soon after Nüsslein-Volhard joined Gehring’s lab as well. Wieschaus recognized an intellectual partner in Nüsslein-Volhard. Gehring’s lab was moving towards molecular biology and away from genetics. Wieschaus and Nusslein-Volhard were the only ones in Gehring’s lab who resisted going in this direction because they were excited by development, fruit flies, and genetics. Eventually, Gehring and Wieschaus became estranged because of their differing views.
However, the connection with Nüsslein-Volhard continued long after Wieschaus finished his work in Basel: “Even after I had left for my postdoctoral work in Zurich, I would come back to Basel, in part to finish experiments, but also always to have dinner with her. We would talk science and plan experiments we eventually wanted to do together.”
Finally, in 1978 they seized the chance to conduct the experiments they had only dreamed about. Both of them obtained positions as independent researchers at the European Molecular Biology Laboratory in Heidelberg. There, for the first time, they had their own small labs, enough funding, and the freedom to carve out their own research. They combined forces, and as a two-person team they began the experiments that would eventually win them the Nobel Prize.

Wieschaus compares that period to being on a life boat during a storm after a cruise ship sinks: “Yanni [Nüsslein-Volhard’s nickname] and I were on the same boat. Just the two of us together in the boat trying to get to shore.” He said that although they would spend a lot of time arguing about the best strategy, “we had to take each other’s opinions seriously. Each saw the other as smart. Our opinions were relevant to each other.” Despite the fact that they were young and relatively inexperienced, Wieschaus recollects that “they talked only to each other, but not anyone else. We didn’t have too many people’s opinions.” Although they could have inadvertently been doing things that were wrong, Wieschaus insists that, “Reliance on yourself is the better strategy. You don’t need 100 opinions unless you want to find the average. Talking to a lot of people won’t give you the extreme.” Therefore, Wieschaus saw Nüsslein-Volhard as someone with whom he could shoot for the extreme. He was convinced that his intellect combined with Christiane’s was enough to “get them to the shore.”

Today, Wieschaus is again pushing the limits of science by forging strong ties with other researchers. According to an article in the Princeton Weekly Bulletin, five years ago Wieschaus interrupted a conversation here at Princeton between the distinguished theoretical physicist William Bialek and the experimental biophysicist David Tank. Wieschaus said to them with a smile: “Bill, I don’t know exactly what you guys want to do, but let me tell you why you should do it with fruit flies.” This comment sparked a collaboration that continues to the present and has resulted in a model of how specific molecules within an embryo, called signal molecules, provide highly quantitative instructions for embryo development.
Wieschaus has very little training in mathematics and has even forgotten most of what he learned. However, he respects those who have the power to describe quantitatively the inner workings of cells during development: “Textbooks basically have a cartoon of the process, with little arrows on it that show generally how the embryo develops. But if you look at those cartoons with people who understand the world from a different perspective, you get different reactions. And maybe you get a strategy to look at things that might not have been available to you.”

Specifically, Wieschaus wanted to talk with his more mathematically-inclined colleagues about a protein found in the developing embryo. One of the genes that he discovered in 1978 with Nüsslein-Volhard encodes for this protein Bicoid. Bicoid spreads unevenly throughout the developing embryo’s cells. The cells that obtain the highest concentration of Bicoid are clustered in the front of the embryo and are destined to become part of the fruit fly’s head. The ability for a cell to determine whether it will become part of the head or not is due to the concentration of Bicoid that it detects. Wieschaus wanted to better understand what it means for a cell to detect a protein level.
With Professor Bialek’s abilities in mathematical modeling and Professor Tank’s expertise in microscopy, the three have been able to quantify the level of Bicoid in each cell, and model the resulting fate of that cell. They discovered that only a few molecules of Bicoid is enough to change the future of a cell from being included in the head to being excluded. Wieschaus was surprised by this discovery, because he had always believed that biology was a messy process, and that a few molecules of a protein should not irreversibly dictate the outcome of development. Without Wieschaus’ ability to reach out to others whose mathematical abilities he respects, Bicoid’s role in development would still only be understood as a cartoon arrow rather than as an intricate process.

For Wieschaus, collaboration, such as with Gehring and Nüsslein-Volhard and his colleagues at Princeton, is a deeply interactive experience. His philosophy on collaboration is that “I can only collaborate well if I am physically next to people. I don’t believe you can be creative if you’re not interacting with someone. I don’t believe you can communicate deeply by e-mail. You have to look at the same slides together and decide which slides you want to keep and which slides you don’t. That’s collaboration. You change plans and change experiments everyday to a certain extent.” Wieschaus did not just send his experimental results to Bialek to model. Instead, they sat across from one another and tutored each other in the basics of developmental biology and math. By actively interchanging ideas, they fed each other’s imaginations. For Bialek, “It was exciting because I was thinking about types of biology I’d never thought of before.” For Wieschaus: “Math is the basic tool for understanding biology at this level, but I’ve forgotten most of my calculus. And computers have transformed calculation to the point where it’s nearly beyond me. I got to run like a dog through the neighborhood with these other dogs who are doing this stuff. It was exhilarating.”

Wieschaus’ respect for other scientists’ mental power has sparked great discoveries that none of them could have uncovered on their own. Perhaps Wieschaus’ greatest discovery then is that respect for knowledge is more important and can be more productive than having raw knowledge by itself.