A doctor’s son in Haverhill
James Edward Rothman was born on November 3, 1950, in Haverhill, Massachusetts, the eldest of three sons of Martin Rothman, a small-town paediatrician, and Gloria Rothman, née Hartnick, who ran the home and the practice. Both parents were Jewish. His father had wanted to do medical research as a young man but graduated into the Great Depression and was then caught up in the Second World War. He brought Jim along on night-time house calls and hospital rounds, had him measure the intervals on patients’ electrocardiograms, and let him help with blood tests in the small laboratory behind his office.
Rothman grew up in the age of the polio vaccine, the transistor and the space race, and from his earliest memories he wanted to be a scientist, especially a physicist. As a boy he built electronics and launched model rockets, teaching himself trigonometry in seventh grade to calculate how high they flew and calculus two years later to understand the physics. At Pomfret School in Connecticut he raced so far ahead that he graduated after his junior year.
From physics to biology
Rothman entered Yale in 1967 committed to theoretical physics. In his junior year his father, worried about job prospects for physicists, urged him to try biology. Physicists of the time looked down on biologists, he recalled, but from the first lecture he was amazed that the frontier of molecular biology seemed instantly reachable. He crossed over through the physics of membranes, working with Harold Morowitz and Donald Engelman on how cholesterol affects the fluidity of the fatty layer that surrounds every cell. Yale’s Scholar of the House programme let him spend his final year on research alone; his thesis won the prize for the best of the year, and he graduated summa cum laude in physics in 1971.
The Scholar of the House thesis was judged by a committee drawn mostly from the humanities. Rothman was mortified when Morowitz showed him the evaluation he had written for it, composed entirely in limericks, and was sure he was doomed; the humanists, it turned out, loved it. He later wrote that it was during that last year at Yale that he became a scientist.
His father persuaded him to go to medical school to learn biology. At Harvard Medical School, as a first-year student in a histology class, he learned about the cell’s secretory pathway, recently described by George Palade, and was astonished. How could a cell make little membrane bubbles, called vesicles? How did each one know where to go? How did it fuse with its target? Nobody could even imagine the answer at the time. He left the MD programme after the basic sciences and earned a PhD in biological chemistry in 1976 with Eugene Kennedy.
Rebuilding the cell’s postal system in a test tube
After postdoctoral work at MIT, Rothman joined the biochemistry department at Stanford University in 1978, recruited by Arthur Kornberg, and set out to tackle the vesicle question. Kornberg had told him that he chose to study DNA synthesis because it was important, everyone assumed it could not be done, and he thought it could. Rothman took the same approach to vesicles. Rather than study whole cells, he tried to reproduce vesicle transport outside them, in a test tube, so that each ingredient could be identified.
It worked. In 1984 his laboratory published three papers in the journal Cell describing transport between the stacked compartments of the Golgi apparatus, the cell’s sorting and packaging centre, in a cell-free system. At first the results were hard to repeat, but following a motto he learned from the biochemist Ephraim Racker, troubles are good for you, the team kept going and found it had captured a kind of transport no one knew existed.
The zipper that delivers the cargo
With the cell-free system Rothman’s team could hunt for the proteins that make vesicles fuse. With the visiting German enzymologist Felix Wieland and others, they purified a protein called NSF, then partner proteins called SNAPs, and finally, in 1993, the receptors those proteins work on, which they named SNAREs. One SNARE sits on the vesicle and its partner sits on the target membrane. When they meet, they wind together like the two sides of a zipper, pulling the two membranes so close that they merge and the cargo passes through.
Because there are many SNAREs and each pairs only with particular partners, the zipper also works as an address label: a vesicle can fuse only where its SNARE finds the right match. Some of the genes Randy Schekman had found in yeast turned out to code for the same proteins Rothman found in mammals, showing that this transport system is ancient and shared by all complex life. Thomas Südhof then showed how calcium triggers the zipper to close at precisely the right moment in nerve cells. Rothman moved to Princeton in 1988, to Memorial Sloan-Kettering Cancer Center in 1991, to Columbia University in 2004, and in 2008 returned to Yale as chair of the Department of Cell Biology.
Along the way his laboratory also discovered coatomer, the protein coat that shapes one class of transport vesicles inside the Golgi, and described how vesicles bud off from one membrane before fusing with another. In 1991 he moved to New York to found the Department of Cellular Biochemistry and Biophysics at Memorial Sloan-Kettering Cancer Center, where he also served as vice-chairman of the Sloan-Kettering Institute; at Columbia he later directed the university’s genome centre. In 2010 he shared the Kavli Prize in Neuroscience with Richard Scheller and Thomas Südhof for discovering the molecular basis of neurotransmitter release.
Why it matters for health
Vesicle traffic is how cells export almost everything they make. Insulin leaves the cells of the pancreas in vesicles; nerve cells release their chemical messengers from vesicles; immune cells release signalling molecules and antibodies the same way. The Nobel committee noted that faulty vesicle transport contributes to neurological and immunological disorders and to diabetes. Understanding the SNARE machinery has helped researchers study how insulin release fails in type 2 diabetes and how nerve signalling breaks down in disease.
The SNARE proteins also explained the deadliest poisons known. Botulinum and tetanus toxins work by cutting specific SNARE proteins in nerve endings, so that vesicles can no longer release their messenger; the result is paralysis. That same knowledge underlies the medical use of tiny, controlled doses of botulinum toxin to treat muscle spasms, eye conditions, excessive sweating and chronic migraine. Rothman has also worked with industry, serving as chief science adviser to GE Healthcare, and at Yale he founded a Nanobiology Institute that applies the physics and engineering of membranes to biology.
A scientist’s style
Rothman credits his training in physics with his way of attacking biology. Physicists approach hard problems by imagining the form a solution must take; he asks how he would design a system for the job, which gives a model to test. He memorises key numbers, from Boltzmann’s constant to the size of a virus, so he can tell at once whether an idea is reasonable. To young scientists he passes on the advice of his teachers: do not be afraid to look stupid by asking questions, recognise that stopping a failing project takes more courage than starting one, and remember Eugene Kennedy’s maxim that smart is good, but lucky is better.
He also stresses friendship. Long collaborations with scientists such as Graham Warren and Felix Wieland, he has written, shaped many of his best ideas.
Jewish roots and family
Rothman was born to Jewish parents; according to the JINFO list of Jewish Nobel laureates, his father’s family came from Russian Jewish stock. His brothers followed their parents’ respect for learning: Richard became a physician-scientist and neuropharmacologist at the National Institutes of Health, and John a lawyer specialising in mediation. Rothman has written warmly of his parents, who made him feel he could do anything and gave him an education free of financial worry.
He is married to Joy Hirsch, a Yale professor of neuroscience and psychiatry known for her research on human cognition, whom he calls his scientific partner as well as his wife. He has two children, Matthew and Lisa, both Yale graduates, and grandchildren. He and Hirsch have served as resident fellows of Branford College, the Yale residential college where he lived as a student.
Honours and legacy
Rothman received the Lasker Basic Medical Research Award and the Louisa Gross Horwitz Prize in 2002, the Kavli Prize in Neuroscience in 2010, and, with Randy Schekman and Thomas Südhof, the 2013 Nobel Prize in Physiology or Medicine for discoveries of the machinery regulating vesicle traffic. He is the Fergus F. Wallace Professor of Biomedical Sciences at Yale. Among his earlier honours were the Gairdner Foundation International Award and the King Faisal International Prize in Science, both in 1996, and election to the US National Academy of Sciences in 1993.
The question that caught a first-year medical student’s imagination, how a cell’s tiny parcels find their way and open at the right door, now has an answer found in his laboratory. It is written into every textbook account of how hormones are secreted, how nerves talk and how some of nature’s deadliest toxins kill, and it guides research into diabetes, brain disorders and immune disease.
Sources & further reading
James E. Rothman, Biographical, NobelPrize.org · Press release: The Nobel Prize in Physiology or Medicine 2013, NobelPrize.org · Jewish Nobel Prize Winners in Medicine, JINFO · Association of Botulinum Neurotoxin Serotype A Light Chain with Plasma Membrane-bound SNAP-25, Journal of Biological Chemistry, 2011 · James Rothman, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
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