FROM the BLOGOSPHERE the Protein’S Structure, We Can See the a Recent Literature Search Had Identical

AUTHORS Vol 463 | Issue no. 7280 | 28 January 2010 Abstractions MAKING THE PAPER FIRST AUTHOR David Frank Warfarin has long been a household name thanks to its uses as a drug and Wealth of data cuts uncertainty in controlling rodent in climate-warming predictions. pests. Its protein target is less well known — the Human activities are largely to blame for the enzyme VKOR, which, rise in atomspheric carbon dioxide that has in mammals, catalyses the generation of seen global temperatures climb since the mid- vitamin K hydroquinone. This is an important twentieth century. But higher temperatures component in the vitamin K cycle and is also cause more CO2 to be released into the required to sustain blood coagulation. Until atmosphere through the natural processes of in individuals’ heights could skew the average now, no one had been able to determine the carbon cycle. This feedback loop may play one way or the other, preferentially using data exactly how mammalian VKOR worked an important part in amplifying anthropogenic sets that indicate a small temperature variation because nobody had succeeded in purifying sufficient quantities for structural studies. warming. However, determining the magnitude and a large change in CO2 would result in cal- Weikai Li at Harvard Medical School in of such an effect has been a challenge. culating a large feedback between the carbon Boston, Massachusetts, and his colleagues “We know that anthropogenic CO2 is having cycle and temperature. have now discovered a stable bacterial an effect on climate,” says David Frank, a clima- The solution that Frank and his colleagues version of VKOR that has allowed them to tologist at the Swiss Federal Research Institute came up with was to use every piece of data examine the enzyme’s crystal structure WSL in Birmensdorf. This is mainly because they could get their hands on. That meant (see page 507). Li tells Nature more. CO2 traps heat from the Sun’s rays, so the more combining data from nine large-scale tem- we release into the atmosphere, the more heat is perature reconstructions and CO2 records Why did you do this study? stored. But climate models have estimated that obtained from three Antarctic ice cores. After We wanted to understand how mammalian the feedback between the carbon cycle and cli- poring over “a heck of a lot of data”, they were VKOR works because its function has mate could contribute anywhere between 0.1 °C able to calculate more than 200,000 estimates important medical implications. Warfarin is and 1.5 °C per year on top of the rise in tempera- of how CO2 varied in response to temperature a commonly used anticoagulant drug that ture due to direct anthropogenic emissions. between 1050 and 1800. “These estimates take works by inhibiting VKOR, but it has a narrow It has been difficult to precisely quantify into account the uncertainties of reconstruc- therapeutic window. Too large a dose can the sensitivity of the carbon cycle to changes tions,” explains Frank. “If the data were perfect, cause lethal bleeding; too low and it isn’t in temperature, partly, Frank says, because we might not need so many estimates.” effective. Genetic variations exist in VKOR “during the past century the feedback rela- From these estimates, the researchers were among patients, which affect the enzyme’s tionship between temperature and CO has able to calculate probability distributions and sensitivity to warfarin, and that’s one of the 2 been obscured by the massive amounts of CO then determine a median value for the mag- reasons it is hard to get the dose right. 2 released by human activities. We therefore nitude of the carbon cycle’s sensitivity to tem- What challenges did you face? need to look at changes in temperature and perature. That value, 7.7 parts per million by First we had to screen a number of bacterial CO2 over a longer timescale, before the indus- volume of CO2 per 1 °C, gives some idea of VKOR variants to find one that would be trial revolution.” how much the ocean and terrestrial ecosys- appropriate for structural studies. Then we Other groups had already examined the tems will amplify anthropogenic actions by had to isolate the protein. For that, we had relationship between temperature and CO2 in the future (see page 527). “These values are to find the right detergent: one that could during pre-industrial times, explains Frank, similar to those obtained from climate models, dissolve the membrane surrounding the but they typically based their calculations on although models with lower feedback might protein without denaturing the protein. The a single reconstruction of temperature over be slightly more accurate,” says Frank. But he next step was obtaining pure and regularly time and a single CO2 record. “It is as though adds a caveat. “We don’t know whether addi- ordered crystals that would yield the best you want to determine the average height of a tional processes that have not been operating diffraction. That’s an essential and often rate- population by measuring the height of one or or significant in the past will have an important limiting step in structure determination. two individuals,” says Frank. Just as variations role in the future.” ■ Are your findings of value to human health? Some people have mutations in VKOR that make it resistant to warfarin. By viewing FROM THE BLOGOSPHERE the protein’s structure, we can see the A recent literature search had identical. One is published the second version without locations of mutated amino acids. A better Jennifer Rohn, a posdoc at in Cell, whereas the other the senior author’s knowledge. understanding of how these amino acids University College London, features as a chapter in a One commenter wonders interact with the drug may make it possible to seeing double. On her Nature meeting proceedings book. whether a duplicate set he devise a safer anticoagulant that’s easier to Network blog, Mind the Gap, “How common is this sort of found should be turned in dose than warfarin. Safe, appropriate dosage is crucial — a blood clot in the leg of someone she describes how she turned double publication? And how do as scientific misconduct. who’s received a subtherapeutic dose might up what seemed to be the people feel about it?” asks Rohn, Meanwhile, on a related note, travel to the lung and kill the person. exact same paper, with the opening up a lengthy discussion. another person observes that same author list, published in Those commenting speculate publishing papers in different Are there any other implications? two journals (go.nature.com/ that the book chapter was an languages reaches more A colleague of ours discovered that the SDZ8Ja). obligation filled with an easy, readers. Doubling up, it seems, bacterium that causes tuberculosis uses a On closer inspection, Rohn already-finished manuscript or is a grey area of scientific protein homologous to VKOR. It’s a separate finds that the two papers are that a junior author submitted publication. ■ study, but our work may help his group to Visit Nautilus for regular news relevant to Nature authors ➧ http://blogs.nature.com/nautilus and see design new antibiotics for tuberculosis. ■ Peer-to-Peer for news for peer reviewers and about peer review ➧ http://blogs.nature.com/peer-to-peer. 400 © 2010 Macmillan Publishers Limited. All rights reserved.

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