Profile of Clifford Tabin Rom the Outside, the Human Body Said, ‘‘If You Use Them As a Vector, You Can Is a Study in Symmetry

PROFILE Profile of Clifford Tabin rom the outside, the human body said, ‘‘if you use them as a vector, you can is a study in symmetry. But not add a new gene to the chromosome.’’ everything is symmetrical inside. Tabin was the first researcher to construct The heart, a baroque lump of a retroviral vector at the Massachusetts Fmuscle and plumbing, sits on the left side Institute of Technology. of the body. The stomach is lopsided. The Turning a retrovirus into a vector in- intestines are a snarl of counterclockwise volved duplicating this inserting of a de- coils. But the embryo begins as a small fined piece of DNA into the virus. ‘‘It was sphere of identical cells. How does this obvious how to do it,’’ he said, ‘‘just cut broken symmetry develop? the guts of the virus out and stick in a Clifford (Cliff) Tabin, who was elected new gene and package it up.’’ to the National Academy of Sciences in In the second phase of his doctoral 2007, has spent significant effort during project, Tabin followed up on Weinberg’s the course of his career working on that discovery of RAS, the first known human question. In 1995, he and colleagues oncogene, which, once mutated, triggers found the first clue: they identified a mo- the cellular cascade that leads to cancer. lecular cascade that determines asymme- Starting with a version of RAS from a try in the vertebrate embryo (1). One of bladder carcinoma, Tabin identified a sin- 3 key genes in this cascade, they reported, gle mutated amino acid that switched on was Sonic hedgehog, which encodes a the oncogene. To tie his dissertation to- ‘‘morphogen’’ that diffuses across the em- Clifford Tabin gether, Tabin inserted mutant RAS into bryo. The concentration of Sonic hedgehog his retrovirus and demonstrated that it determines how other molecules cooper- could cause cancer in mice. ate to build organs and limbs. Since its Tabin explored other fields that might ‘‘But we didn’t know anything about discovery by a collaboration between capitalize on his physics background. He what RAS did,’’ he said. ‘‘We didn’t know Tabin and 2 other labs, Sonic hedgehog learned that biologists were beginning to that it was involved in signaling between has been widely implicated in human use X-ray crystallography to peer into the cells, and we didn’t know that the muta- development. structure of protein molecules. So before tion kept RAS in an active state. Years Tabin has been at the cutting edge of earning his undergraduate degree in 1976, later, people working in flies and worms much of that developmental biology re- he hedged his bets and applied to gradu- gained the key insights into its cellular search in the past decade. In his Inaugural ate programs in both physics and biology. function.’’ Article (2), published in the June 24, 2008 ‘‘I got into a number of excellent phys- Forced Independence issue of PNAS, he adds to the under- ics programs,’’ he said. ‘‘I also got turned standing of how asymmetry develops in an down by physics programs. But every- Tabin received his doctorate in 1984, pro- embryo with a study demonstrating why where I applied in biology took me. I ficient in cutting-edge recombinant DNA the intestines coil in a specific direction. suspect they liked the idea of having techniques and with an interest in both someone with a physics background.’’ evolution and embryonic development. Keen on Physics Morphology, the study of how genes de- Tabin’s career in genetics was originally From X-Rays to DNA termine body shape, seemed like the per- inspired by physics. During World War II Tabin chose the biology department at the fect way to combine these interests. his father, physicist Julius Tabin, worked Massachusetts of Technology (Cambridge, Doug Melton’s lab at Harvard was one on the Manhattan Project in Enrico MA) for his graduate work, in part be- of the only groups studying development Fermi’s group. Julius was one of the vol- cause he wanted to work with a particular in vertebrates. So Tabin joined the group unteers who rode in a lead-lined tank to crystallographer. But his interests shifted as a postdoc with the intention of studying ground zero at Alamogordo, New Mexico, soon after he arrived on campus, when a the newly-discovered homeobox (Hox) minutes after the first atomic bomb test. group of researchers there began working genes in Xenopus embryos by injecting He whipped open a tiny trap door and with the newly discovered capacity to cre- extra copies of the genes into eggs and dug a core sample of earth for analysis. In ate recombinant DNA. then looking for any characteristic changes those few seconds, Julius received half of ‘‘It was clear that this new technology in the frog that would help determine the lethal dose of radiation. ‘‘It was a bit was going to allow us to do things that no what Hox genes did. foolhardy,’’ Cliff Tabin said, ‘‘but you one had ever done before and understand ‘‘All of the decisions within the embryo have to think about it as a war. He viewed things in a totally new way,’’ he recalled. that have to do with where you are along it as being patriotic.’’ ‘‘At the time, there were only a few places that axis from the head to the tail come Motivated by his father, Tabin launched in the country that it was possible to do from homeobox genes,’’ Tabin said. himself on a career in physics, attending recombinant DNA.’’ One of these hap- ‘‘Since homeobox genes establish differ- the University of Chicago. ‘‘I loved being pened to be on the fifth floor of the Mas- ences between body segments in flies, I a physics major,’’ he said. ‘‘The problem sachusetts Institute of Technology Cancer wanted to try and see if these genes was that the physics that I found interest- Center, which housed the laboratories of played any sort of role in distinguishing ing at the time was trying to understand Bob Weinberg, David Baltimore, Phil between an arm and a leg in vertebrates. elementary particles. It was being done on Sharp, and David Housman. Doug thought that was a very good idea. very large machines. And you didn’t de- Tabin joined Weinberg’s lab, which was sign your own experiments until you were focused at the time on mouse retroviruses, a full professor. I felt like I was getting RNA viruses that insert themselves into This is a Biography of a recently elected member of the National Academy of Sciences to accompany the member’s into physics too late for the style of sci- the host genome, instead of just replicat- Inaugural Article on pages 8499–8506 in issue 25 of volume ence that I wanted to do.’’ ing inside cells. ‘‘Because of that,’’ Tabin 105. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903946106 PNAS ͉ May 26, 2009 ͉ vol. 106 ͉ no. 21 ͉ 8407–8409 Downloaded by guest on September 25, 2021 But he also thought it was a very good but each person said ‘I want to be on the want to know, but I want to be up front idea not to do it in his lab, because Xeno- chick side.’ So in no time at all, we had with you. You should know that I’m also pus is the wrong species.’’ abandoned the newt.’’ trying to clone vertebrate hedgehog.’ And Because tadpoles develop legs very Andy was sitting right next to Phil and he slowly, researchers did their experiments A Flirtation with Fish looked in surprise at Phil and said, ‘You on limb growth and regeneration on The lab had abandoned the newt for the are? I’m actually cloning vertebrate hedge- chicks and newts. ‘‘At the time there was chick, but it was a side interest in fish that hog, too.’ There was a moment when I no lab to go to as a postdoc that was set led Tabin to a collaboration that would wondered whether everyone in the dining up to use modern molecular approaches bring about his greatest discovery. room was cloning hedgehog genes. But it and expertise in the classical fields of ei- In 1992 several groups were trying to was just a coincidence, it was really just ther chick limb development or newt limb develop the zebrafish as a model organ- the 3 of us, and we quickly realized we regeneration,’’ Tabin said. ism. Tabin had always been interested in had quite different interests.’’ Luckily, an independent postdoc posi- evolution and thought that because fins tion at Massachusetts General Hospital were the precursors of limbs, any discov- All for One and One for All (Boston) had become available. Tabin and eries about fish fins could translate into Tabin, Ingham, and McMahon decided Melton thought it might provide enough knowledge about limbs. ‘‘I hoped that if they could be a powerful team if they freedom and support for such exploration, we participated in this process,’’ he said, worked together. ‘‘We became very so Tabin moved to Mass General. ‘‘we could, in return, get our hands on open,’’ Tabin said. ‘‘It was the most fun Soon afterward, he learned that Jeremy whatever fin mutants came out of these collaboration I’ve ever been with. Because Brockes in London was also studying limb screens.’’ we were all very excited about this regeneration at the molecular level. Tabin project, we were in nearly daily communi- sent him a letter and Brockes invited him cation, sharing extremely preliminary re- for a 3-week visit to share wisdom.

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