19.9 Biophys Late Corr For

news feature Bridging the culture gap

Molecular biologists are deluged with data, and physicists, used to reducing complex systems to basic principles, might help to make sense of it all. But bringing the two disciplines together isn’t easy, says Jonathan Knight.

n late July, several dozen physicists with an interest in biology gathered at the Col- Iorado mountain resort of Snowmass for a birthday celebration. Hans Frauenfelder, a physicist who began studying proteins decades ago, turned 80 this year. But unoffi- cially, the physicists were celebrating some- thing else — a growing feeling that their discipline’s mindset will be crucial to reap- ing the harvest of biology’s postgenomic era. Of course, physics and its techniques have played a significant role in biology for decades. X-ray crystallography and nuclear magnetic resonance are essential tools for structural biologists. Biophysicists study everything from the forces exerted by molecular motors to the energetics of enzyme catalysis. And electrophysiologists need a working knowledge of the Nernst equation, which describes the movement of ions across cell membranes. Many of the founders of molecular biology were also originally physicists. But Deeper understanding: José Onuchic believes that physics can offer biology fundamental explanations. in the 50 years since people such as Max Delbrück and Francis Crick created the field, lot of facts that need an explanation.” ‘Opportunities in Biology for Physicists’ — it has abandoned its roots. Physics is theory- Physicists believe that they can help, aimed primarily at biology-curious graduate driven; molecular biology has become an bringing a strong background in theory and students and postdocs. empirical and descriptive science. Physics the modelling of complexity to nudge the But there are pitfalls. Although some uses mathematics to represent the laws of study of molecules and cells in a fresh direc- molecular biologists are happy to welcome nature; molecular biology relies on words tion.“What has been all too rare in biology is physicists into their labs, others perceive and diagrams to describe the functions of the symbiosis between theory and experi- them as interlopers who don’t really under- living things. The essence of physics is to ment that is routine in physics,” says Laura stand what they are getting into. Meetings simplify, whereas molecular biology strives Garwin, director of research affairs at intended to bring the two disciplines to tease out the smallest details.To cynics,the Harvard University’s Bauer Center for together still sometimes end up with the two latter has become an exercise in molecular Genomics Research, who has made her own camps failing to communicate. And even stamp-collecting, slotting new components transition to biology — she was once physicists who have made the jump into and interactions into ever more complex Nature’s physical-sciences editor. molecular biology say that framing biologi- biochemical pathways. cally relevant questions poses a huge chal- The two cultures might have continued Opportunity knocks lenge for those coming from outside. to drift apart, were it not for the revolution Funding agencies agree that there are real Onuchic is in the vanguard of this new in genomics. But thanks to a proliferation opportunities for progress in the area. In late breed. Originally trained in theoretical of high-throughput techniques, molecular July, for instance, the US Department of physics in his native Brazil,the centre he now biologists now find themselves wading Energy awarded a $36.6-million, five-year co-directs was last month given $5.5 million through more DNA sequences and profiles grant to a cross-disciplinary team at the over five years by the US National Science of gene expression and protein production Lawrence Berkeley National Laboratory in Foundation to seed collaborations between than they know what to do with. It may be California. Headed by physical chemist biologists and physicists. Onuchic owes his time to take a step back from the details and Adam Arkin, the group plans to develop introduction to biology to physicist John try to see the big picture. computational models of bacterial responses Hopfield, under whom he studied for “Biology today is where physics was to stressful environments. New centres are his PhD at the California Institute of at the beginning of the twentieth century,” also being established at the interface of Technology in Pasadena in the late 1980s, observes José Onuchic, who is the co-direc- physics and biology, and job opportunities working on the theory of biological electron- tor of the new Center for Theoretical Biolog- abound. Acknowledging the trend, the transfer reactions. ical Physics (CTBP) at the University of American Physical Society will later this Onuchic’s mentor is an inspirational California, San Diego. “It is faced with a month hold a meeting in Boston — entitled figure for biological physicists in general.

in New York, Hopfield has proposed that discrete biological functions rarely lie with individual genes or proteins but instead with modules comprising many interacting mol- ecules2. Examples include the ribosome, which manufactures proteins, and the signalling network of proteins that controls cell division. The researchers have suggested a number of ways to explore this idea,includ- ing efforts to reconstitute or build functional modules in the test tube, the behaviour of which would shed light on how well the underlying principles are understood.

Cracking the mould Physicists are also helping to explain molecular influences on the behaviour of entire cells. Herbert Levine, a condensed-matter physicist at the University of California, San Diego, and co-director of the CTBP, is collaborating with biologists at Cornell University in Ithaca, New York, to model the way in which cells detect and migrate towards chemical signals. The team is focus- ing on the slime mould Dictyostelium dis-

A. PASIEKA/SPL John Hopfield’s work on neural networks (inset) coideum, which lives as individual soil-living showed physics can model biological processes. amoebae unless food becomes scarce, when the amoebae aggregate to form a multi- biology. One of the projects at Onuchic’s cellular organism. This produces resilient centre is investigating whether networks of spores that hatch into new amoebae when gene regulation have parallels in neural conditions improve. networks. Just as neurons activate and The amoebae aggregate by sending and repress other neurons, gene products can receiving biochemical signals such as cyclic activate and repress other genes, directly or adenosine monophosphate (cAMP). But indirectly. The parallels may even extend to because cAMP diffuses rapidly, it isn’t clear similarities between learning — which alters how individual cells know which direction the firing pattern of individual neurons and the signal came from. Levine has devised a hence the network’s overall behaviour — model that depends on the time delay from and the way in which evolutionary pressures the moment a new wave of cAMP reaches alter patterns of gene expression. one side of the cell until it completely sur-

Hopfield, meanwhile, is now champion- rounds it. The cell-surface receptors that M. J. GRIMSON/R. L. TECH UNIV. BLANTON/TEXAS ing the idea of ‘modular’ biology. Together bind to cAMP first send a repressive sig- Hopfield, who now works in the molecular- with cell biologist Andrew Murray, director nal to all other receptors in the cell that biology department at Princeton University of the Bauer centre, geneticist Leland prevents them from binding for about 30 in New Jersey, made his own transition to Hartwell of the Fred Hutchinson Cancer seconds,Levine’s model proposes3. biology in the early 1980s when he developed Research Center in Seattle, and physicist This basic idea did computer models of neural networks that Stanislas Leibler of Rockefeller University not require any displayed properties of animal nervous special insight,Levine systems. His networks consisted of virtual All for one: computer models are revealing how slime-mould admits. But his back- neurons, equivalent units that could activate amoebae join forces to form these multicellular spore-bearing ground in modelling their neighbours according to certain structures. enabled him to generate mathematical rules. Although others had been designing artificial neural networks since the 1950s, Hopfield’s were the first that could recognize familiar patterns, correct errors and remember a sequence of events1. Neural networks “were a demystifying concept”,says Charles Stevens,a neurobiolo- gist at the Salk Institute for Biological Studies in La Jolla, California. They showed, for example,that complex behaviour could arise from simple repeating units, and that this behaviour could be modulated by altering the strength of the connections between the simulated neurons. Today, physicists are exploring applica- tions for network theory in molecular

NATURE | VOL 419 | 19 SEPTEMBER 2002 | www.nature.com/nature © 2002 Nature Publishing Group 245 news feature a set of quantitative predictions that can now still lingering doubts about the relevance of be tested experimentally.“A biologist in prin- he word ‘function’ earlier forays by physicists into biology. ciple could do the same thing, but in practice Frauenfelder was feted at Snowmass for his physicists have been trained to model com- Tdoesn’t exist in work on the energetics of protein folding — plex systems,”says Levine. he developed the concept of the ‘energy land- Projects such as Levine’s are a promising physics, but physicists scape’, in which valleys represent the stable start. But the ultimate goal for the physicists forms of the protein and hills are barriers to now entering the world of molecular biology need to learn about it, changing shapes5. But many biophysicists is to derive fundamental principles that otherwise they will be question whether Frauenfelder’s work on help to explain the characteristics of many the oxygen-transport protein myoglobin biological systems. It is early days, but bio- playing in a sandbox by will lead to useful generalities about protein logical physicists point to Leibler’s ideas folding, as the principles are based on this about ‘robustness’. themselves. John Hopfield single example. And for all their power, it Traditionally, biologists have thought of remains unclear whether neural networks cellular processes as exquisitely sensitive and communication breakdown. This proved a are genuinely mimicking the nervous sys- well-balanced. But Leibler argues that cells problem in April at a workshop on DNA tem.“We still don’t know to what extent they can withstand a great deal of noise and per- held at the Wellcome Trust Genome Campus have anything to do with life,”says Stevens. turbation. For example, circadian clocks, in Hinxton, near Cambridge, UK. The Frauenfelder is unfazed by such con- which govern organisms’ daily cycles of meeting, co-organized by the Institute of cerns, as he is interested in myoglobin as activity, tick at the same speed regardless of Physics, Britain’s main professional body for a system in which to study the behaviour temperature or the supply of nutrients. Yet physicists, aimed to foster collaborations of complex matter. He likes to quote the rate constants of any chemical or enzy- across the disciplinary divide. But the two what Stanislaw Ulam, the mathematician matic process should vary with temperature, camps struggled to understand one another. who helped to develop the hydrogen bomb, and gene expression should decline under “The talks were too highly specialized,” once said to him: “Ask not what physics starvation conditions. These sources of says Chris Phillips, a solid-state physicist at can do for biology, ask what biology can do ‘noise’ in the system put strict theoretical London’s Imperial College who chaired a for physics.” limits on the type of oscillation mechanism discussion session at the meeting. “A lot of But Hopfield and others argue that it is that cells may use, Leibler argues. According physicists would have come away none the critical for the physicists now flirting with to his models,a system that relied on a simple wiser.We needed an overview.” molecular biology to sit down with their new negative feedback loop to cause the produc- colleagues and agree on what are the impor- tion of a biochemical signal to oscillate up Fresh perspectives tant questions.“The word ‘function’ doesn’t and down over time would not tick reliably More fundamentally, molecular biologists exist in physics, but physicists are going to against a noisy background, whereas one and physicists tend to ask different have to learn about it,”says Hopfield.“Other- based on a fluctuating balance of positive questions when presented with the same wise they will be off playing in a sandbox by and negative influences would be relatively biological system. For example, when themselves.” insensitive to this interference4. considering a network of interacting pro- Onuchic believes that immersing young Such theoretical work teins, a biologist may first ask about the physicists in the culture of biology is the key. should enable molecular chain of events that occurs after one protein At the CTBP, postdocs train in both disci- biologists to sharpen the binds to another, whereas a physicist might plines simultaneously, developing projects focus of their experi- want to know the rate constants of all the that involve two labs, one in biology and one ments. But in many reactions. In a discussion session at the in physics. They attend two sets of group cases, collaboration is Snowmass meeting, a similar gulf opened meetings, and so learn the language and being held back by a up over the phenomenon of protein phos- mentality of both disciplines at the same phorylation. Phosphate groups are often time.“They get inside the culture of the two Study guide: Hans added or removed from proteins to modu- fields,”Onuchic says.“They get comfortable Frauenfelder uses late their activity. The biologists in the with the vocabulary and the journals. Life in myoglobin in his work room were interested in which proteins both labs is more important than any classes on complex matter. were switched on or off in this way. But the you can take.” physicists pondered a deeper question: why Time will tell whether the new generation phosphate, as opposed to some other of biological physicists avoid becoming chemical group? the lonely children of biology. But for now,

By asking different questions, the prospects look bright. “We have always T. EVANS/SPL physicists may in some cases bring been the odd kids in the playground,” says fresh and useful insights. But one of Onuchic.“But we never gave up,and now we the greatest concerns for the Snowmass are becoming very popular.” ■ participants was the risk of wasting time Jonathan Knight is Nature’s contributing correspondent on issues that have no biological meaning. in San Francisco; additional reporting from Natasha As several attendees pointed out, not McDowell. every feature of a biological system has a 1. Hopfield, J. J. Proc. Natl Acad. Sci. USA 79, 2554–2558 (1982). functional importance, nor is every system 2. Hartwell, L. H., Hopfield, J. J., Leibler, S. & Murray, A.W. Nature 402, Suppl. C47–C52 (1999). likely to operate with optimal efficiency. 3. Rappel, W. J., Thomas, P. J., Levine, H. & Loomis, W. F. Evolution doesn’t chose the best option, Biophys J. 83, 1361–1367 (2002). just the best available option. Physicists 4. Barkai, N. & Leibler, S. Nature 403, 267–268 (2000). stumbling into this minefield risk wasting 5. Frauenfelder, H., Wolynes, P. G. & Austin, R. H. Rev. Mod. Phys. their time on apparently interesting but 71, S419–S430 (1999). ultimately trivial questions. Opportunities in Biology for Physicists It’s a serious concern, because there are ➧ www.aps.org/meet/biology-physics/index.html