Winter 2013 - Baldwin School

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allowed people to set up as independent investigators, as long as they could find a department to accommodate them. There was a Clinical Biochemistry Department, where several groups were working on the kinds of problems I was interested in, and one department member in particular, Paul Luzio, was very enthusiastic about my joining them. So with Paul as my “sponsor,” I managed to get a Senior Fellowship, and in 1989 I started working in Clinical Biochemistry, in spite of not being clinical or even really a biochemist. I thought that this move would mean that instead of being a small fish in a big pond, I would become a bigger fish in a smaller pond. However, most people (Paul was a notable exception) still saw me as a small fish, mainly because all of the other senior members of the department were men. My work continued to go well, and I even managed to get a paper into Cell, the most prestigious of all the biomedical journals. Still, I remember thinking that even if I won a Nobel Prize, the department would probably still see me as Paul’s sidekick. Eventually, of course, it all worked out. I was given a lab of my own and started to take on graduate students and postdocs. I’ve recruited some exceptionally talented individuals over the years, and they have become the lifeblood of the lab. In the meantime, other cell biologists (including several women) joined Clinical Biochemistry with Wellcome Senior Fellowships, and in 1998 we all moved to a new building, where Paul is the director. So I am now in the enviable position of 16 TOP FIVE TECHNOLOGICAL ADVANCES IN CELL BIOLOGY, AS TOLD BY SCOTTIE being able to do work that I love, in a very supportive environment, and surrounded by the best colleagues imaginable. And surprisingly enough, I am still working on coated vesicles. They have turned out to be even more fascinating than I supposed when I first fell in love with them 35 years ago. I’d been drawn to them partly because they’re so beautiful (the clathrin coat forms a network of hexagons and pentagons over the surface of the vesicle) and partly because it seemed that they might hold the key to what at the time was called The Sorting Problem. The gist of this problem is that every cell contains numerous membrane-bound compartments, each with its own set of proteins, and somehow all of these proteins manage to get to the right place and stay there. There was evidence from work by Nobel Prize winners Brown and Goldstein that coated vesicles can select proteins from a particular compartment, package them as cargo, and ferry them to a different compartment. But how does a coated vesicle know which proteins to include and which ones to leave out? My work in Barbara’s lab led to the discovery of the adaptins: components of the coat that physically interact with membrane proteins and can discriminate between proteins that need to be taken somewhere else and proteins that need to stay put. When I set up my own lab, we went on to find other adaptins associated with other types of coated vesicles. Some of the adaptins turn out to be mutated in patients with particular genetic disorders; and by using a technique called RNA interference, we were able to show that HIV can hijack adaptins in order to wreak MICROSCOPY Although electron microscopy of biological specimens has been around since the 1950s, this technique can now be combined with different types of labeling (e.g., using antibodies coupled to colloidal gold particles), to show the exact location of individual molecules. The advantage of electron microscopy over optical microscopy is that it is possible to get 1,000 times the magnification without losing resolution. However, only optical microscopes can be used to look at living cells, because electron microscopes bombard the specimen with a powerful electron beam in a high vacuum. Advances in optical microscopy include many new methods for doing live cell imaging (e.g., using green fluorescent protein fused to a protein of interest). Outside the Royal Society headquarters with husband and Royal Society Fellow John Kilmartin, and daughter Claire. havoc with the immune system. In fact, adaptins are so important that it is now speculated that they may have played a key role in the evolution of eukaryotes like ourselves (i.e., organisms with compartmentalized cells), as distinct from prokaryotes (e.g., bacteria), some 2 billion years ago. But although I’m still working on coated vesicles, I’m now using approaches that weren’t even conceivable when I was a student. Probably the most important technological breakthrough for my own work has been the Human Genome Project. We now know the sequences of every single one of our genes, and although I said in my graduate school interviews that I didn’t want to work on DNA, nowadays every cell biologist works on DNA, as a way of getting at the proteins we’re interested in. For instance, we can attach the gene encoding a green fluorescent jellyfish protein to a clathrin or adaptin gene, and then watch the coated vesicles in living cells as they bop around delivering cargo proteins to different destinations. DNA MANIPULATION The technology for piecing together different bits of DNA, to make recombinant DNA, is now 40 years old. It is used, for instance, to attach the green fluorescent protein gene to a gene encoding a protein of interest. Recombinant DNA technology led to other technological advances in the late 1970s and early 1980s, such as DNA sequencing and polymerase chain reaction (a method that amplifies as little as a single molecule of DNA into millions of molecules). These advances in turn facilitated the Human Genome Project and other genome projects. To date, over a thousand human genomes, from individuals all over the world, have been sequenced; and the genomes of over a hundred other organisms have been sequenced.
The Robinson lab at the Orchard Tea Garden in Grantchester. One of the lab members couldn't make it so he was pasted in, wearing his lab coat and hat. David Hasselhoff takes a break from his schedule to serve tea. Some playful teasing among her students resulted in Scottie amassing a decent collection of Hasselhoff memorabilia in her office. We can also now identify proteins from tiny amounts of material, partly because of our knowledge of the human genome, and partly because of advances in a technique called mass spectrometry, which can be used to identify proteins definitively. I have recently revisited my first experiment on coated vesicles, but instead of just looking for tubulin, our aim was to make a complete list of coated vesicle proteins. We were able not only to identify over a thousand different proteins, but also to tell which ones were contaminants, because these proteins didn’t go away when we silenced the clathrin gene by RNA interference. And once again we found tubulin, five different versions of it, and they all behaved like contaminants. But we also found over a hundred genuine coated vesicle components, most of which were previously unknown. It’s not easy to keep up with this fast-moving field, but I was educated to be a “thinking girl,” and I enjoy the challenge. Baldwin also gave me self-belief, which I think goes much deeper than self-confidence. I know of several women who ran into difficulties similar to mine and became so discouraged that they left science. But when I was having problems as a graduate student, or when I was unable to find a job as an independent investigator, it never occurred to me to do anything other than hang in there. Baldwin also gave me many, many examples of really excellent teaching, which I try to follow now that I’m the teacher. Classes at Baldwin were not only instructive and inspiring, they were also a lot of fun, and I try to work that element into my teaching as much as I can. I like to think of our lab as an enjoyable place to work, not only for the science but also because of all the lab outings, lab traditions (which usually involve food, especially chocolate), and lab jokes (which often feature David Hasselhoff). When I found out last spring that I had been elected a Fellow of the Royal Society, it was really the icing on the cake. I already felt that I had the best job in the world, and to join a society whose members included people like Isaac Newton, Charles Darwin and Albert Einstein was an unbelievable honor. I was allowed to bring four guests to the signing ceremony, so both of my sisters (Mary B. Robinson ’71 and Lolly Robinson) were able to fly over from the States, to join John and our daughter Claire for a wonderful day. The Royal Society Charter Book is already 350 years old and is expected to last several centuries more, to be signed by 44 new Fellows every year. My signature will always be there, ink blot and all. There is a joke that “FRS” stands not only for “Fellow of the Royal Society,” but also for “Further Research Suspended,” because some Fellows feel that they have now reached the pinnacle of their careers, and there is nowhere to go but down. But Baldwin did too good a job with me, and I intend to keep on learning. Margaret Scott “Scottie” Robinson ’69 is Professor of Molecular Cell Biology at the Cambridge Institute for Medical Research at the University of Cambridge. In April 2012 Scottie was elected a lifetime Fellow of the Royal Society by a peer review process based on excellence in science. Only 5 percent of Fellows of the Royal Society are women. She is considered the leading expert on adaptins, proteins that facilitate a process that allows other proteins to be transported between various organelles of the cell. Her research has made significant contributions to the understanding of how these processes affect health and to the identification of potential targets for new therapies for diseases such as HIV. Scottie’s research has been widely published in peer-reviewed journals, and she is a frequent speaker at major scientific and medical conferences. Scottie is married to cell biologist John Kilmartin, who is also a Fellow of the Royal Society, and has a 16-year-old daughter, Claire, who is an avid soccer player. RNA INTERFERENCE Knowing the sequence of the human genome doesn’t tell us what each individual gene actually does. However, RNA interference (RNAi), a naturally occurring process first described in 1998, can now be used to silence individual genes and give us information about the functions of the proteins they encode (but in order to do this, you first need to know the sequences of the genes). Our lab recently completed a human genome-wide RNAi screen on HeLa cells (a widely used type of cell that came from a woman named Henrietta Lacks, who died over 60 years ago). The screen involved silencing over 21,000 different genes in turn, in order to find new genes that contribute to coated vesicle function. Psst: Search “HeLa” on our blog for a post by Dr. Dorfman on her AP Biology HeLa cells lab. MASS SPECTROMETRY Mass spectrometry measures the mass of individual molecules with extraordinary accuracy. For studies on proteins, the protein is first broken into fragments with an enzyme. These fragments are then ionized (i.e., given a positive electric charge) and further fragmented, then the mass-to-charge ratio of each fragment is determined. Because every single one of our more than 21,000 proteins is different, this information can be fed into a database and used to determine protein identities, even from very complex mixtures. Mass spectrometry is also extraordinarily sensitive. For instance, from 20 micrograms (0.0000007 ounces) of HeLa cell coated vesicles, we were able to identify and quantify over a thousand proteins. BIOINFORMATICS There is now so much data about genes and proteins that modern information technology is essential. Numerous databases are available on the Internet, which can be mined to analyze protein and DNA sequences. These databases are used to identify proteins detected by mass spectrometry. They can also be used to predict the structures of new proteins, and to search for evolutionary relationships between genes, and therefore between organisms. For instance, we now know that humans are surprisingly closely related to fungi, and not all that distant from amoebae, when compared with, say, plants. (And all of us – humans, fungi, amoebae, and plants alike – have coated vesicles!) WINTER 2013 ECHOES 17
Page 1 and 2: BALDWINECHOES THE MAGAZINE FOR ALUM
Page 3 and 4: FEATURES Technology and Tenacity: F
Page 5 and 6: BROTHERLY LOVE Baldwin girls and th
Page 7 and 8: ALUMNAENEWSMAKERS Julie E. Wollman
Page 9 and 10: TREKKING ON Computer Science Coordi
Page 11 and 12: FLYING HIGH Vicky Gold, Baldwin’s
Page 13 and 14: MAKE YOUR MARK: ATHLETICS HALL OF F
Page 15 and 16: Baldwin mom, Heather Andrews. Varsi
Page 17: Electron microscope image of coated
Page 21 and 22: Unveiled at the start of the academ
Page 23 and 24: FACULTYFOOTNOTES Each year faculty
Page 25 and 26: Because of Baldwin… A Baldwin gir

Winter 2013 - Baldwin School

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