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 into a vector in- intestines are a snarl of counterclockwise volved duplicating this inserting of a de- coils. But the 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 , 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 , which encodes a the oncogene. To tie his dissertation to- ‘‘’’ 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 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.’’ and . Keen on Physics Morphology, the study of how genes de- Tabin’s career in 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 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 (Hox) minutes after the first atomic bomb test. group of researchers there began working genes in Xenopus 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 . ‘‘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, , 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 , 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. ‘‘It was ‘‘It was clear that this sults and rethinking plans together as we very useful,’’ Tabin said. ‘‘I showed him went along. Each of the 3 labs contributed the approaches I was trying to use to new [recombinant DNA] a major step in the process.’’ move DNA into newts cells with retroviral Although they thought there was proba- vectors.’’ technology was going to bly some version of hedgehog in verte- Brockes showed Tabin how to amputate brates, they were not sure, and it was a newt limbs properly so they would grow allow us to understand relief when McMahon reported he had back. ‘‘If you just amputate a leg, the soft found a homolog in mice. Tabin and Ing- tissues dry out, and that leaves an over- things in a totally ham quickly pulled out the fish and chick hang of skin that folds over, and the area equivalents. ‘‘That was relatively easy,’’ where the wound epidermis forms is really new way.’’ Tabin said. But a snag appeared. small,’’ Tabin said. ‘‘But if you trim the McMahon’s lab ran tests to see where skin back with surgical scissors below the the mouse gene was active and found that plane of amputation, then it won’t flop Because of this passing flirtation with the only spot was in the testes. ‘‘This was over. Little tricks like that were not obvi- fish, Tabin was invited to a conference not something we wanted to hear,’’ Tabin ous to me from reading the literature.’’ held at Ringberg Castle in Germany’s said. ‘‘The testes are not particularly well- Black Forest to discuss how to proceed studied organs. We were interested in the Abandoning the Newt with the zebrafish model. There, Tabin limb, but more importantly for us, to get During his postdoctoral fellowship, Tabin was excited to find 2 scientists whose work testes you need to get roosters. And we built the nucleus of a lab. ‘‘I had a post- he knew, but whom he had never met: get chick eggs sent to us from farms. We doc in my lab—a postdoc of a postdoc— Andy McMahon, a developmental biolo- don’t have roosters running around. This and I had a technician,’’ he said. That gist who worked with mice, and Phil Ing- was a disaster.’’ It looked like the most afforded him a quick start when Harvard ham, a geneticist whose analysis had led that would come out of the effort would Medical School offered him a faculty posi- to important insights into how a gene be a single paper. tion in 1989. Within a year, he had 5 post- called hedgehog operated in Drosophila. docs and began to accumulate students. Because hedgehog, a gene expressed in Forget the Testes Soon his lab was large enough that he the wing disc of the fly, appeared to influ- Tabin’s lab decided to look at whether considered splitting his group in 2, so that ence wing organization in a manner simi- there might be additional hedgehog genes half would focus on limb regeneration in lar to a region in the chick limb bud in the vertebrate genome. Riddle found newts, and the other half would focus on dubbed the ‘‘zone of polarizing activity,’’ that in vertebrates hedgehog was not a sin- limb development in chicken embryos. one of Tabin’s postdocs, Bob Riddle, was gle gene but a gene family with 3 variants. But the technical details of gene transfer intrigued by its potential relationship to Ingham immediately looked to see where in newts were formidable. limb development. Before the Ringberg the other 2 hedgehog-related genes were ‘‘I was able to adapt retroviruses to in- meeting, Riddle and Tabin had already active in zebrafish. ‘‘Forget the testes,’’ he fect newt cells,’’ he said. ‘‘I could put for- decided to try to clone hedgehog in the told Tabin. Ingham sent pictures that eign DNA into a few cells in the regener- chicken embryo to identify a vertebrate made it clear that one of the other hedge- ating limb, but I couldn’t make the whole homolog to the gene. hog genes was expressed in 2 stripes down limb transgenic. In contrast, much more Sitting with McMahon and Ingham at the middle of the embryo: the floor plate efficient retroviral vectors had been devel- dinner one day, Tabin introduced himself. of the neural tube and the notochord. oped for chicks. We worked out protocols ‘‘And I said, ‘Phil, I’d like to ask you a ‘‘These 2 structures were known to be such that if you inject 100 chick limbs, few questions about your work on hedge- extremely important in organizing whether every one of them will be completely hog because my laboratory is trying to you make muscle versus bone in your transgenic. Plus the chick limb develops in clone some vertebrate homologs.’ It was trunk, for organizing the different types of a week whereas the newt takes a month. an awkward moment,’’ recalled Tabin. neurons in the spinal cord,’’ Tabin said. Everyone in the lab agreed it was a great ‘‘Phil’s a great guy, very solid person, ‘‘This was immediately much more inter- idea to work on both systems in parallel, and he said, ‘I’ll tell you whatever you esting to us than testes expression.’’

8408 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0903946106 Mossman Downloaded by guest on September 25, 2021 Riddle christened this version of the other land birds, it diversified and learned guide their molecular experiments, Tabin’s hedgehog gene ‘‘Sonic hedgehog’’ because to eat lots of different types of food. So team found that the coiling begins when his 6-year-old daughter had been sent a there are finches with parrot-like beaks the primitive gut tube, initially suspended comic book from a friend in England, that eat fruit, finches with woodpecker- down the midline, tilts to the left. This featuring the Sega video game cartoon like beaks that drill holes in cactus and happens because the cells of the dorsal character Sonic the Hedgehog. Riddle, pull out grubs. There are birds with mesentery, which suspend the gut, shrink Tabin, and colleagues showed that Sonic tweezer-like beaks for picking up insects, on the left and expand on the right. hedgehog was the active factor in the zone and those with strong, thick beaks for The key insight in the Inaugural Article of polarizing activity that played a major cracking nuts.’’ is that the deformation of the dorsal mes- role in laying down the blueprint for wing Tabin was interested in the genetic ba- entery is caused by asymmetric changes in development in the chick. Cells expressing sis of finch beak evolution, so he sent stu- the extracellular matrix in conjunction Sonic hedgehog are responsible for estab- dents to collect data from finches in the with unilateral expression of the adhesion molecule N-cadherin. lishing the number of digits in the hand Galapagos. Based on their analysis, his and the morphological differences be- group conducted experiments with chick Outside the Lab tween them, Tabin said. embryos and found 2 genes whose expres- Along with his research, Tabin has found Several other labs were also trying to sion determines differences in beak size ways to contribute to others outside of his find vertebrate hedgehog genes and subse- between species. Variations in 1 gene lab. Recently, his brother Geoff, an oph- quently reported their independent find- (Bmp4) influences width (6), and the thmalogist and mountaineer who has ings. But ‘‘the 3 of us got there first be- other, the gene for the protein calmodu- climbed Everest and worked extensively in cause we were working together,’’ Tabin lin, controls length (7). Nepal, got him involved in developing a said. Tabin, Ingham, and McMahon pub- Along with the study in the Galapagos, new medical school in Kathmandu, Nepal. lished their findings in back-to-back pa- Tabin has sent students to Puerto Rico, ‘‘One day, out of the blue, I got an e- pers in Cell (3–5). Mexico, and the Gobi Desert to collect mail from a Dr. Arjun Karki,’’ Tabin said. In the following years, research into organisms for his evolutionary studies, but ‘‘I knew it was from Nepal because of the Sonic hedgehog exploded as it became he has never been to those places himself. e-mail address, but it started by saying, clear how important the signaling pathway ‘‘I enjoy the photographs and live vicari- ‘Dear Professor Tabin, I wanted to start was for proper embryonic development. ously,’’ he said. by thanking you for your enormous com- Another of Tabin’s achievements followed The students sent to the Sierra Madre passion for the people of Nepal and tell- directly from Sonic hedgehog’s discovery. Oriental mountain range in central Mex- ing you how much admiration I have for Researchers in his lab were the first to ico, for example, were on a mission to your willingness to shoulder the burden of discover genes involved in establishing the collect blind fish from caves. ‘‘Caves pro- establishing a medical curriculum.’’’ difference between the left and right sides vide a unique environment [for evolu- ‘‘I’ve never been to Nepal!’’ said Tabin, who suspected a practical joke. However, of the body (1). tion],’’ Tabin said. ‘‘They are dark, they’re ‘‘We were lucky that in the chick—it’s a call to Geoff confirmed the appeal was humid, they have few predators, which is not true in the mouse or fish—Sonic genuine. He had volunteered Cliff’s good. No one’s going to eat you. The bad hedgehog is expressed in a very small do- services. news is there’s nothing for you to eat.’’ main on the left side, and not the right Athough he had not sought out this The team is investigating the genetic side, of a particular structure [Hensen’s philanthropic opportunity, Tabin felt a changes that enable these fish to adapt to node] in the early embryo,’’ Tabin said. moral responsibility to follow through on cave life. The fish grow taste buds all over ‘‘It was a marker far earlier than when the his brother’s offer. The Nepalese school their heads, are much more sensitive to organs formed. We found a series of aspires to provide a Western-quality medi- genes linked together in a pathway that pressure differences, and no longer swim cal education and specifically to train stu- ultimately determined which way the in schools. Tabin’s lab now breeds these dents to serve the acute needs of the rural heart would rotate. That was the first time blind fish for experiments. poor. Tabin helped develop the basic sci- anything was known about why the heart’s Tabin’s Inaugural Article (2) does not ence curriculum and assists in finding vol- on the left and not the right.’’ involve beaks or tastebuds. Rather, it con- unteers to teach preclinical subjects for tinues his interest in left–right asymmetry. which the expertise is lacking in Nepal. Beaks and Taste Buds He and colleagues Natasza Kurpios and ‘‘I’m privileged to be a professor at Tabin is far from a 1-hit wonder, and Nikki Davis looked for a cellular explana- ,’’ Tabin said. Sonic hedgehog occupies only part of his tion for why the intestines start to coil in ‘‘There’s no place in the world that has research portfolio. His lab has made con- a particular direction in the embryo. better labs, better students, better post- tributions to understanding the develop- ‘‘We picked the coiling of the gut be- docs, better colleagues, more money. We ment of a wide variety of tissues in the cause it’s simple,’’ Tabin said. ‘‘It reduces have so much. I don’t go out looking for embryo, including the forming skeleton. the problem of left–right asymmetric mor- ways to give back to the world. I’m not In 2003 Darwin’s finches, residents of phogenesis to the question of how you devoting my life to service, but when the Galapagos Islands that were described take a garden hose and coil it around a something falls into your lap, where you in the Origin of Species, captured Tabin’s spool counterclockwise instead of actually can give back, given how much we have, it’s almost a moral responsibility to interest. ‘‘Darwin correctly deduced that clockwise.’’ do it.’’ an ancestral bird made it down to the Ga- Using a computer simulation designed lapagos,’’ he said. ‘‘In the absence of any by computer modeler Marta Iban˜es to Kaspar Mossman, Science Writer

1. Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C (1995) hedgehog mediates the polarizing activity of the ZPA. polarity gene hh is expressed in tissues with polarizing A molecular pathway determining left–right asymme- Cell 75:1401–1416. activity in zebrafish embryos. Cell 75:1431–1444. try in chick embryogenesis. Cell 82:803–814. 4. Echelard Y, et al. (1993) Sonic hedgehog, a member 6. Abzhanov A, Protas M, Grant BR, Grant PR, Tabin CJ 2. Kurpios NA, et al. (2008) The direction of gut looping is of a family of putative signaling molecules, is impli- (2004) Bmp4 and morphological variation of beaks in established by changes in the extracellular matrix and cated in the regulation of CNS polarity. Cell 75:1417– Darwin’s finches. Science 305:1462–1465. in cell:cell adhesion. Proc Natl Acad Sci USA 105:8499– 1430. 7. Abzhanov A, et al. (2006) The calmodulin pathway and 8506. 5. Krauss S, Concordet J-P, Ingham PW (1993) A function- evolution of elongated beak morphology in Darwin’s 3. Riddle RD, Johnson RL, Laufer E, Tabin C (1993) Sonic ally conserved homolog of the Drosophila segment finches. Nature 442:563–567.

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