Than a Crystallographer

CAREERS TURNING POINT Insight into decision-making NATUREJOBS BLOG The latest on science- NATUREJOBS For the latest career helps neuroscientist advise on policy p.713 careers news and tips go.nature.com/ielkkf listings and advice www.naturejobs.com Twenty years ago, many academic labs existed just for X-ray crystallography. Col- laborators would send in samples of their molecules of interest, and labs would crystal- lize them and solve their structures. Nowadays, labs are much more focused on specific scientific questions, and X-ray crystallography is just one of a suite of tools that they use. Tech- nology has improved so much that the proce- dure is usually no longer a full-time scientific pursuit. As ‘pure’ crystallography jobs dwindle, people who are trained in the technique must KENNETH EWARD/BIOGRAFX/SCIENCE PHOTO LIBRARY PHOTO EWARD/BIOGRAFX/SCIENCE KENNETH broaden their expertise to encompass skills such as protein expression and purification, biochemical assays and cell biology. In fact, many crystallographers now refer to themselves as structural biologists, reflecting the variety of techniques that they use to probe molecular structure. They may have PhDs in biophysics, biochemistry, bioinformatics or computational biology, and find work in aca- demia or industry. But they are united by a desire to ‘see’ the invisible molecules that make up cells. Those structures, often breathtaking in their beauty and intricacy, provide important clues about functions or sites that might serve as drug targets. CRYSTALLIZING THE HISTORY X-ray crystallography has been around for A digital model of a nucleosome, drawn with the use of X-ray crystallography data. about a century, since scientists realized that atoms in a crystal could diffract X-rays, pro- STRUCTURAL BIOLOGY ducing a pattern of spots on a detector. The angles and intensities of the diffracted beams reveal the structure of molecules. Until recent decades, only specialists with More than a years of training and expensive equipment could perform X-ray crystallography. But in the 1990s, the technique became much more accessible. As synchrotrons — large, ring- crystallographer shaped particle accelerators that produce powerful X-rays — spread across the globe, researchers could take or send their crystals Researchers trained in X-ray crystallography are still in to the synchrotron facilities, where resident demand, but must diversify their skill sets to be competitive. experts guided them in collecting data and interpreting results. The automation of crys- tallization, improvements in methods for solv- BY LAURA CASSIDAY crystal structure of a DNA–protein complex ing structures and a boost in computing power called the nucleosome (see K. Luger et al. Nature greatly sped up the process, giving researchers arolin Luger was bitten by the crystal- 389, 251–260; 1997). time for other scientific pursuits. lography bug during a biophysics lec- Now a Howard Hughes Medical Institute Increased competition for research grants ture in 1986. “One person gave a talk on investigator at Colorado State University in Fort also forced crystallography labs to become KX-ray crystallography,” she recalls. “The lecture Collins, Luger still uses X-ray crystallography was not that good, but the diffraction patterns to study chromatin, the DNA–protein complex CYSTALLOGAPHY AT 00 were so beautiful that I thought, ‘I really want to that packages genomes tightly inside cells. But A Nature special issue learn how to do this’.” She learned. As a postdoc, like most in her field in recent years, she has nature.com/crystallography she was first author of a paper that reported the expanded her toolkit to include other methods. 30 JANUARY 2014 | VOL 505 | NATURE | 711 © 2014 Macmillan Publishers Limited. All rights reserved CAREERS more well rounded. Instead of just solving Mol. Cell 51, 662–677; 2013). She says that one structure after another, researchers must anyone who is interested in structural biol- now link the structure of a molecule to its func- ogy should consider learning this technique, tion through biochemistry and cell-biology as well as nuclear magnetic resonance (NMR) experiments. “It’s no longer enough to conjec- spectroscopy. ture about the function of a particular protein. You have to test it,” says Wayne Hendrickson, FRESH APPROACHES who specializes in biochemistry and molecu- Now that synchrotrons are widespread, crys- lar biophysics at Columbia University in tallography labs no longer need their own New York. expensive X-ray facilities. Luger’s lab does The story of major crystallography projects retain an X-ray generator for quickly screen- such as the Protein Structure Initiative (PSI), ing crystals and training students; the device is supported by the US National Institute of Gen- powerful enough to collect publication-quality eral Medical Sciences (NIGMS), encapsulates data from well-ordered crystals that diffract the evolution of the field. The PSI has solved well, but non-ideal crystals or those that are more than 5,300 distinct protein structures quickly degraded by X-rays are sent to a syn- and spurred innovations in crystallographic chrotron, says D’Arcy. The team has access to methods. Last year, however, NIGMS director a beamline — a path of X-rays coming off the Jon Lorsch, acting on the counsel of an advi- accelerator — at the Advanced Light Source Karolin Luger, a researcher in X-ray crystallography. sory panel, decided that the project had run its synchrotron at Lawrence Berkeley National course, and it will terminate on 30 June 2015 Laboratory in Berkeley, California. says. “Sometimes we are less involved, and (see Nature 503, 173–174; 2013). The crystallography purist who prefers not sometimes we are more involved. But quite Critics argued that many of the structures to dabble in other techniques might consider a frequently a collaboration results.” that the PSI has solved have little relevance to career as a beamline scientist, loading crystals important biological and medical problems, for researchers and overseeing them as they NEXT GENERATION and that PSI scientists did not adequately collect data. As well as permanent positions, Structural biologists are developing methods to poll the biological community to select inter- many synchrotrons offer training programmes expand the capabilities of conventional X-ray esting targets. In addition, such ‘big science’ in crystallography. They also offer summer crystallography, with potential implications for programmes consume precious funds that, in programmes and internships for students, future practitioners. In November 2013, the US the minds of some, would be better spent on postdocs and other researchers who want to National Science Foundation (NSF) awarded a individual researcher grants. learn the technique but lack their own X-ray US$25-million Science and Technology Center UNIVERSITY STATE JOHN EISELE, COLORADO Despite the PSI’s closure, Hendrickson, facilities. Grant to the University at Buffalo in New York whose lab specializes in membrane proteins The European Synchrotron Radiation Facil- and seven partner institutions to fund the and was part of the initiative, says that it is too ity (ESRF) in Grenoble, France, offers a six-week BioXFEL research centre. The centre will fur- early to gauge the impact on crystallography Summer Bachelor Programme for undergrad- ther the use of recently developed tools called job prospects. “It will depend on whether PSI uates, which includes lectures, tutorials, lab X-ray free-electron lasers (XFELs) that produce centres like ours are able to gain alternative work and site visits. The Cheiron School at the much shorter and more intense pulses of X-rays means of support to keep things going,” he SPring-8 synchrotron than synchrotrons (see page 604). says. His centre, the New York Consortium in Harima, Japan, has According to Eaton Lattman, a struc- on Membrane Protein Structure, is applying ten-day training ses- tural biologist at Buffalo and director of the to other research organizations and founda- sions for graduate stu- BioXFEL, XFELs can analyse crystals that are tions for grants. dents, postdocs and 1,000 times smaller than those required for young scientists who conventional X-ray crystallography. “This TRIAL AND ERROR wish to pursue careers opens up a whole new universe of protein mol- Crystallography work increasingly requires a in fields that involve ecules for crystallography that we couldn’t do good scientific question rather than just solv- synchrotron radiation. before because we couldn’t grow big enough ing structures — something Sheena D’Arcy And the Advanced crystals,” he says. The intense X-ray pulses knows well. As a graduate student, she worked Photon Source in can also capture frozen images of molecular in a crystallography-only lab. “For my postdoc, Argonne, Illinois, pre- motion, opening the door for dynamic studies I wanted a lab that was a bit more driven by sents an annual two- and molecular movies. scientific questions,” she says. She is now work- “Taking the time week National School The BioXFEL centre will make use of an ing with Luger, using crystallography — and to sit down and on Neutron and X-ray existing facility at the SLAC National Accel- other methods — to study how DNA is pack- teach yourself Scattering, in which erator Laboratory in Menlo Park, California, aged into chromatin. the theory graduate students among other facilities. A smaller XFEL facility Early in her postdoc, D’Arcy recognized the and computer attend lectures and began operating in Harima, near the SPring-8 value of approaching a problem with multiple programs is tutorials and conduct synchrotron, in 2011. And a larger one is sched- techniques. She wanted to obtain a crystal going to pay in short experiments. uled to open in Hamburg, Germany, in 2015. structure of nucleosome assembly protein 1 the long run.” Alexei Bosak began Lattman anticipates that the NSF grant will (Nap1), which helps to package DNA in the Sheena D’Arcy working at the ESRF result in a “modest number” of new jobs at cell.

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