Profile of Martin Chalfie

PROFILE Profile of Martin Chalfie espite having a bad reputa- tion, cholesterol is an essen- tial component of the plasma membranes of animal cells, Dwhere it is thought to modulate the properties of the lipid bilayer. Choles- terol can also bind directly to proteins in the membrane. In his Inaugural Article published in 2006, Martin Chalfie, the William R. Kenan, Jr., Professor of Bio- logical Sciences at Columbia University (New York), in collaboration with Thomas Benzing (University of Cologne, Germany), identified a new class of cholesterol-binding proteins among the prohibitin (PHB)-domain protein family (1). PHB-domain proteins appear to regulate a variety of membrane functions, from cell signaling to mechanosensation. Studying two members of the family, MEC-2 and Podocin, Chalfie, Benzing, and their colleagues found that cholesterol is crucial for the activity of two different classes of channel proteins to which the PHB-domain proteins bind. They suggest that the binding of cholesterol by the PHB-proteins alters the lo- cal lipid environment of associated membrane proteins and changes their activity. Questioning Research Chalfie, born in 1947 and elected to the National Academy of Sciences in 2004, grew up in Chicago. As a child, all ele- Martin Chalﬁe ments of science interested him, but he feels his early activities were somewhat Hastings provided Chalfie with one of Chalfie took a series of short-term jobs, mundane. ‘‘Unfortunately, I did not have including a stint selling dresses for his that real indicator of a career in science his fondest memories of Harvard. ‘‘I parents’ dress manufacturing business in that many of my friends have. I did not never seemed to be able to get to the Chicago. In 1970 he began teaching high make explosives and almost destroy my biology library when it was open, so I school at Hamden Hall Country Day home,’’ he says. As a child, he cut out asked Woody for permission to get a School (Hamden, CT). newspaper comics about nature for library key for late night reading,’’ he Chalfie took the advice of a fellow a scrapbook and, in high school, partici- recalls. ‘‘Most of my professors seemed teacher and applied to work in the labo- pated in a weekly science club after very distant, so I was amazed when he ratory of Jose Zadunaisky at Yale Uni- school. ‘‘I was fairly good at science in got up from his desk, walked down four versity (New Haven, CT) during the school,’’ he recalls. ‘‘That was the positive flights of stairs to the library office, and summer of 1971. During the initial in- reinforcement to keep me going.’’ Chalfie said, ‘Give this boy a key.’ I’ve since terview, Zadunaisky told Chalfie about entered Harvard University (Cambridge, learned that this kindness was character- MA) in 1965 and thought that he would istic of him.’’ his work measuring chloride transport in major in math. He soon switched gears. Chalfie spent the summer after his the frog cornea by using an Ussing ‘‘I was attracted to biochemistry because junior year working in the laboratory chamber. ‘‘I thought about the paper I I could do a little bit of everything: chem- of Klaus Weber at Harvard. Chalfie set had written for Woody Hastings, and istry, math, and biology,’’ he explains. out to study the active site of aspartate forgetting that that research involved ‘‘The subject also seemed new and transcarbamylase, but ‘‘although I kept sodium, not chloride, transport, toad exciting.’’ trying to do the experiments, I failed and not frog, and bladder and not During his junior year, Chalfie took miserably all summer,’’ Chalfie says. ‘‘I cornea—although it did measure trans- a cell physiology class with Woody Hast- decided I shouldn’t be in science.’’ So port with a Ussing chamber—I tried to ings, but Chalfie could not register for for his senior year, Chalfie took the last impress Jose by asking if cAMP was in- the laboratory portion and wrote a pa- required course for the biochemistry volved,’’ Chalfie recalls. ‘‘He liked the per instead. The subject, the role of cy- major and then other courses that interested him, including law, theater, and clic AMP (cAMP) in sodium transport This is a Proﬁle of a recently elected member of the National in the toad bladder, would later spark Russian literature. Academy of Sciences to accompany the member’s Inaugural an idea that led to Chalfie’s first pub- After graduating in 1969 and still un- Article on page 17079 in issue 46 of volume 103. lished research article. In the meantime, convinced about a career in research, © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0704615105 PNAS ͉ February 5, 2008 ͉ vol. 105 ͉ no. 5 ͉ 1393–1395 Downloaded by guest on October 2, 2021 question but assigned me a completely was not sure what exactly to watch. At a mechanosensory current could have oc- different project. Jose then left to do loss, he decided to count the number of curred for many reasons, but the alter- research for the summer in France.’’ microtubules in each section. Instead of ation of the properties of the current Chalfie recalls, ‘‘Enamored with my own decreasing the further from the cell suggests that the channel proteins were idea and left on my own, I didn’t do the body (as would be expected if microtu- directly involved in transduction,’’ he assigned project but tried to see if in- bules started in the cell body), the count explains. Chalfie is not done with his creasing cAMP affected the current. ‘‘fluctuated all over the place.’’ Nichol studies of mechanosensation. ‘‘Now that Fortunately, it did so dramatically, and Thomson helped Chalfie acquire more we have good evidence that we have Jose was very supportive when he found sections, and Chalfie soon showed that, identified the transduction complex, the out what I had done at the end of the contrary to prevailing theory, the micro- biggest problem lies ahead: How does summer.’’ This research would garner tubules did not span the entire length of this complex translate touch into an Chalfie his first publication (2) and give the nerve process but started and electrical response?’’ him the confidence to consider a career stopped along the way (6). in biology. Chalfie relished his time at the labo- An Enjoyable Collaboration ratory. ‘‘My time as a postdoc made me For his Inaugural Article (1), Chalfie stud- Insensitive Worms the scientist I am today,’’ he says. ‘‘The ied MEC-2, a protein associated with the For his doctoral work, Chalfie entered complete freedom, terrific colleagues, transduction complex needed for touch Harvard University’s physiology depart- and extensive material support that were sensitivity. Chalfie’s laboratory had found ment in 1972, where he chose Robert characteristic of the LMB were very that MEC-2, which is associated with the Perlman, ‘‘who still remains a terrific inner leaflet of the plasma membrane, friend,’’ as his thesis advisor. ‘‘Bob was greatly increases the current from acti- very patient and willing to listen to all ‘‘My time as a postdoc vated touch channel proteins in frog of my unformed and misinformed ideas. oocytes (12, 15). MEC-2 is a PHB-domain He was also a clear and deep thinker. made me the scientist protein; other PHB-proteins also appear He was soft-spoken, but what he said to regulate membrane functions. was important and thoroughly consid- I am today.’’ Chalfie recalls that in 2004, he re- ered,’’ recalls Chalfie. ceived a call from Benzing, who was For his thesis, Chalfie used cell sus- studying a similar PHB-domain protein, pensions from rat pheochromocytomas stimulating. Everything was provided; so called Podocin, which is found in mam- (adrenal tumors) to look at the biosyn- much so that you had no excuse for not malian kidneys. Benzing suggested that thesis and release of catecholamines (3). being able to work except your own lim- they collaborate to study how these proteins regulate activity. Together, they Chalfie initially looked for postdoctoral itations.’’ After five years in England, positions in the same field for his gradu- found that MEC-2 and Podocin share Chalfie left the laboratory in 1982. He ate work but soon decided that he wanted three properties: Both proteins bind to joined the faculty of Columbia Univer- to do something different. A visit from target proteins in membranes, to them- sity in the department of biological sci- high school friend Bob Horvitz, who was selves, and to cholesterol. Chalfie ex- ences and continued to study C. elegans doing a postdoc with Sydney Brenner at plains that multimerization and the touch mutants. He found that some mu- the MRC Laboratory of Molecular Biol- binding to cholesterol were significant tants were insensitive to touch because ogy (Cambridge, U.K.), prompted Chalfie because these events could ‘‘change the to apply to Brenner’s laboratory. the cells were missing or incompletely lipid environment around target proteins.’’ In 1977, Chalfie traveled to England differentiated, a result that led to the The activity of the different channel to work with Brenner. Although intend- study of how cell type is determined (7– proteins that bind MEC-2 and Podocin ing to study neurotransmitters in Caeno- 9). Other touch-insensitive mutants have could thus be modified by the presence rhabditis elegans, Chalfie instead took up fully formed but nonfunctional cells. of these PHB-domain proteins (1). a project started by John Sulston, then a These mutants led to investigations into Chalfie calls his collaboration with staff scientist in the laboratory, on the the molecular basis of mechanosensory Benzing ‘‘one of the most enjoyable I genes involved in mechanosensation.

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