Profile

Tim Mitchison:dynamic productivityWilliam Wells

It’s never easy to make a move fromone side of the US to the other, butTim Mitchison did it recently with anew baby in one arm and a newlyjealous dog in the other. Mitchisonhas left the University of California,San Francisco (UCSF), where heworked for the past ten years on howmicrotubules behave, make spindles,and move chromosomes, to be theco-director of a new Instituteattached to Harvard Medical School,the Institute for Chemistry and CellBiology (ICCB).

Mitchison brings with him areputation for great science, raucousparties and fishnet stockings onHalloween. The move brings him intoan environment where he can fullyapply the power of chemical synthesisto the solution of cell biologicalproblems. If Bostonians are lucky, hewill also bring along the fishnets.

“I always knew I wanted to be ascientist, certainly by the age of sixor seven,” says Mitchison. “Sciencewas definitely a family business.”Mitchison’s father, Avrion, was anoted immunologist working ontransplantation immunity (which atthe time was “totally opaque . . .absolutely mystifying”), his UncleMurdoch was a yeast physiologistwho trained Paul Nurse and KimNasmyth, among others, and hisgreat-uncle was the evolutionarybiologist J.B.S. Haldane.

Mitchison started at Oxford andthen moved to UCSF in 1979, first asa technician and then for his PhD.He toyed with the idea of workingon tumor virology with MichaelBishop, but a series of lectures byMarc Kirschner on timing and spatialorganization in cells turned him on tomicrotubules. “The ideas werepretty mind-blowing,” says

Mitchison. “He was taking problemsthat epitomize biology, that makeliving systems alive, and saying thatnow the time was ripe to understandthese at a molecular level.”

The first step for Mitchison waspurification of centrosomes, thestructures that direct microtubulegrowth and form the poles of themitotic spindle in eukaryotic cells.While studying these isolatedcomplexes, he noticed that reducingthe concentration of tubulin (thesubunit of microtubules) did notresult in a uniform reduction in therate of microtubule growth. Somemicrotubules continued to growrapidly, while many more underwenta “catastrophic” conversion to arapid shortening phase. The netresult — the only parameter thatother workers had looked at — wasless polymerization.

Mitchison first suggested theterm ‘microtubule jerking’ todescribe the alternate stable states ofgrowing and shrinking, but gratefullyaccepted Kirschner’s suggestion of‘dynamic instability’. WhenMitchison first presented the idea ofdynamic instability at a meeting,“the microtubule mafia were totallysurprised and didn’t really believeit,” he says. But after initialscepticism, the model was embracedby cell biologists. “It allowed peopleto see how plastic the system was,and how the cell could controlmicrotubule arrays,” says ConlyRieder of the Wadsworth Center inAlbany, New York.

After brief interludes as a post-doc in the Kirschner lab and as aresearch fellow at the NationalInstitute for Medical Research inMill Hill, London, Mitchison startedas an assistant professor at UCSF inthe late 1980s. He remembers thelab as an exciting, lively place,“People were really sparring witheach other to do their best work.”

Mitchison had just shown thatmicrotubule attachment to thechromosome (at a site called thekinetochore) is dynamic, with tubulinsubunits constantly coming and going.

To further prove this point he made a‘caged’ version of the fluorescent dyefluorescein. When this newcompound was linked to tubulin andadded to cells, it was incorporated intomicrotubules but did not fluoresce. Abar of light on the spindle, however,knocked off a chemical group fromthe caged molecule and gave a stripeacross the microtubules thatMitchison could track as it movedsteadily away from the kinetochoreand towards the spindle pole.

Repeating this experiment withactin, a student then showed thatactin remains fixed relative to theunderlying substrate as cells move.Mitchison now uses the intracellularmotility of the pathogenicmicroorganism Listeria as a model forstudying eukaryotic cell motility, andhas recently isolated proteinsinvolved in this process.

Studies of chromosomemovement began when a student inthe lab isolated eukaryoticchromosomes, then showed that theycan move in opposite directionsalong microtubules, depending onthe amount of phosphorylation of thekinetochore. Others in the lab haveused frog extracts to isolate proteinsinvolved in spindle formation, otherproteins involved in the change inmicrotubule dynamics in mitosis, and

R666 Current Biology, Vol 7 No 11

Changing time. Tim Mitchison with his newdaughter Lorna Mei.

even in chromosome condensation.“Everything he touches he leaves abig impact on,” says Rieder.

Mitchison is conscious of his shiftfrom describing phenomena toidentifying specific proteins that dothe work. He is perhaps more keenon the ‘how’ than the ‘what’, but sayshe does “want to get to the level ofmolecular mechanism.”

This is part of the reason for hisshift to the ICCB. Once he has aprotein, he wants to define itsfunction by switching it on and off atwill. “This is the major stumblingblock in modern cell biology,” hesays. “The high road is biochemicalreconstitution [combining allnecessary components in a testtube]. For Listeria and actin I thinkwe can do that soon, but mitosis istoo complicated at the moment. Inthe next few years we will probablyhave to be satisfied withreconstitution of simple sub-processes in mitosis.” Genetics hasits limitations, and methods such asantisense are far from perfect; thesolution, says Mitchison, is specificchemical inhibitors.

The new ICCB will involveapproximately equal numbers ofchemists and biologists, includingStuart Schreiber, the otherco-director, and researchers affiliatedwith other Harvard and HarvardMedical School faculties. Harvardhas provided 10,000 square feet ofspace, start-up funds, and a newprofessorship for Mitchison. He willsearch large libraries of chemicals forinhibitors of both specific proteinsand specific cell biological processes.

There will be distractions at thestart: the unloading of packing cases,the changing of diapers, and perhapsthe reconstruction of the “loveshack” in the back garden, completewith makeshift hot tub (a bath with aColeman stove underneath). But,with chemistry at his disposal,Mitchison will be in a position to pullapart mitosis, movement and more.

William Wells is a freelance writer based inSan Francisco, USA.

Gazetteer

The University ofTexas SouthwesternMedical CenterWhat is it famous for? To put itbluntly, Brown and Goldstein.Michael Brown and JosephGoldstein shared the Nobel prize inphysiology or medicine in 1985 fortheir discovery of the basicmechanisms of cholesterolmetabolism. In fact, UTSouthwestern in Dallas has nowattracted a plethora of shining lightsin biomedicine, but Brown andGoldstein were among the earliestrecruits and the first to make it big.

When did they move there? Goldsteinwas a homegrown talent (hisdown-home accent is well known onthe lecture circuit) who returned tohis alma mater in 1972. Around thesame time, he persuaded Brownthat this obscure southern medicalschool was going places, and thetwo have been working there eversince. Last month, a special CellBiology and Genetic DiseasesSymposium to celebrate the pair’s25 years at UT Southwesternattracted a heavyweight line-up ofspeakers, including this year’sNobel Prize-winner StanleyPrusiner.

Is UT Southwestern in the majorleague? Although its Ivy Leaguebrethren may look down their nosesat UT Southwestern, a 1994 studymeasuring the research impact of USuniversities placed it among the topeight institutions in the country. Itboasts more Nobel laureates thanany other medical school in theworld, with Johann Deisenhofer(1988 chemistry prize, for X-raycrystallography) and Alfred Gilman(1994 prize for physiology ormedicine, for the discovery of Gproteins) making up the quartet.

The Center has 1000 facultymembers and trains 3100 students ayear.

How did it rise from obscurity? Mainlythrough the determination of DonaldSeldin, its gritty and inspirationalChair of Internal Medicine for 35years. When Seldin arrived therefrom Yale in 1951, he found acollection of dilapidated army shackson a street corner in downtownDallas. With a commitment to basicscience, Seldin set about attractingyoung talent, but he was hamperedin the early years by the lack of fundsand a lack of air conditioning.Undaunted, he decided the medicalschool could grow its own, andstarted a highly successful mentoringprogram that nurtured the best andthe brightest.

How is it funded? During theCenter’s first major wave ofexpansion in the 1970s, Seldin rodethe Texas boom, using generousState funding to attract big names tothe wide open spaces of UTSouthwestern. But when the oilprice dropped in the 1980s, so didthe funding base. The gap wasplugged with spectacular success bythe new UT President, KernWildenthal. He netted sizeable giftsfrom several private donors, mostfamous among them the former USpresidential candidate Ross Perot,who gave $20 million in 1988, andanother $23.3 million last year. Now,more than half the Center’soperating funds ($429.6 million in1995) come from non-governmentsources, giving the Center anenviable independence.

What’s it like to work there? Thequality of its buildings has grown indirect proportion to its finances. TheMedical Center is expanding into awhole new section of the campus,and planning is well under way for atleast six new research towers. But itmay still be hard work to persuadeEast- and West-Coast scientists thatDallas is the place to be.

Magazine R667