AUTHORS Vol 459 | Issue no. 7248 | 11 June 2009

approach for work- Abstractions MAKING THE PAPER ing out how to build LAST AUTHOR a molecule. The In 1999, researchers Phil Baran process normally reported that increasing starts with a single production of the Sir2 Natural clues offer fresh route target molecule and protein in the yeast to chemical synthesis. works backwards, Saccharomyces cerevisiae breaking apart stra- extends the organism’s Phil Baran still remembers the date that he ven- tegic bonds to make lifespan. This and other tured into new territory. On 12 January 2007, simpler and simpler findings spurred a flurry of activity and the an editor at Nature Chemical Biology contacted molecules, to help identification of similar longevity proteins, him to ask whether he might write a review outline possible syn- dubbed sirtuins, in other organisms. But how sirtuins promote long life remains article on terpenes — a large class of naturally thesis strategies. unclear. Shelley Berger of the Wistar Institute occurring molecules that have applications in But terpene synthesis is complicated by the in Philadelphia, Pennsylvania, and her everything from perfumes to pesticides. Until fact that highly oxygenated molecules have colleagues have now uncovered a clue (see then, Baran, an organic chemist at the Scripps functional groups that can easily react with one page 802). As yeast cells age, Sir2, an enzyme Research Institute in La Jolla, California, had another or prevent key reactions from proceed- known as a deacetylase, becomes less worked only on nitrogen-containing com- ing. So chemists often have to remove a recently abundant and so less effective at removing pounds called alkaloids. But he agreed to take added functional group before they can add a acetyl groups from histone H4 — one of the a look at terpene synthesis. Two-and-a-half different one, and restore it later — an approach proteins that package DNA into tight coils — years later, having learned to mimic a process that is obviously wasteful. causing the packaging to fall apart. Histone that nature has taken eons to perfect, he is set- As described on page 824, Baran and Chen H4 was known to be one substrate of Sir2, but ting precedents in the terpene field. set out to develop a more systematic process until now, not ageing-specific. Berger talks to Natural terpenes are built in a two-stage using the ‘eudesmane’ terpene class as a proof- Nature about her foray into ageing research. process: first, enzymes form the molecule’s of-principle. In the reverse direction, or plan- hydrocarbon backbone, which Baran likens to ning stage, each disconnection leads to a set of Why did you start this project? an undecorated Christmas tree; second, oxy- molecules called redox isomers (rather than just My research focuses on epigenetics, the study gen-containing groups are added to the back- one molecule, as in conventional retrosynthetic of modifications that occur in chromatin — bone, like ornaments to the tree’s branches, analysis). In each set, the molecules have the the combination of DNA, RNA and proteins to create a wide array of molecules. Although same number of ornaments, although in differ- making up chromosomes — and that are living organisms can churn out massive quan- ent locations, and all have one fewer ornament transmitted from one generation to the next, tities of these chemicals, chemists have been than in the previous set. This process continues affecting how genes function. I thought that yeast might be a good model system for frustrated in their efforts to synthesize them in until a set of bare carbon skeletons remain. addressing whether changes in chromatin are amounts sufficient for commercial use. During synthesis — the ‘forwards’ direc- involved in ageing. Yeast is currently the only Having pored over hundreds of manuscripts tion — the researchers started by making large organism in which we can easily manipulate spanning 50 years’ worth of terpene produc- quantities of a terpene with a single hydroxyl histones using genetic techniques. tion, Baran realized that most approaches group, which Baran likens to the angel at the involved a large number of steps and a complex top of the tree. They then added ornaments in a What did you find? building process. This, he thought, would make methodical and controlled way, without having We were surprised to find that Sir2 protein it difficult to make large quantities of any com- to remove one thing before putting another on. levels decrease as yeast cells age. Other pound. “At a molecular level we’re pretty good In this way, they synthesized five types of eudes- groups had looked at the levels of Sir2 RNA, at making Christmas trees, but not so good at mane in far fewer steps than had been done and those remain constant. As the protein’s putting the ornaments on,” he says. using conventional synthetic approaches. levels drop, there is a corresponding increase He reasoned that the key to success might be The molecules synthesized by Baran and in acetylation of the amino acid lysine at to find a way to simplify terpene synthesis by Chen are simpler than commercial terpenes position 16 of the histone H4 in the chromatin mimicking natural mechanisms. To do so, he such as the anticancer drug Taxol. But Baran located near the ends of yeast chromosomes. and research associate Ke Chen applied a twist says that their methodology lays the foundations to ‘retrosynthetic analysis’ — a commonly used for synthesis of more complex terpenes. ■ Does this have implications for higher organisms or therapeutics? It’s likey. Several sirtuins function as histone deacetylases in other organisms, including FROM THE BLOGOSPHERE mammals. And, in mammalian cells, the The blogosphere was a-twitter psychologist Richard Wiseman independent, Wiseman, at the ends of chromosomes, or ‘telomeres’, are last week with news of the will use Twitter to test ‘remote University of Hertfordshire, known to become unstable and shorten with age. In terms of therapeutics, we identified first scientific experiment viewing’ — the psychic ability UK, calculates that getting a an acetylase, Sas2, that has the opposite to be conducted on Twitter, to identify a distant locale majority of voters to ‘hit’ on his function to Sir2. The hunt has been on for the Internet-based instant- without being shown or told location by chance in at least 3 activators of sirtuins as longevity drugs. But messaging service (http:// what it is (http://tinyurl.com/ out of 4 trials would be 1 in 37. with Sas2, perhaps we can start thinking twitter.com). The experiment kpjf76). Wiseman will ‘tweet’ However, the nature of social about inhibitors. may lack rigour, but it does from an undisclosed location, networking means that voting encourage public participation and then allow those following will not be truly independent. Had you worked on ageing before? in the scientific process. him on Twitter to vote on five The results from four such trials No. Coincidentally, I was a postdoc in Leonard On The Great Beyond blog, possible locations posted as are expected to be published Guarente’s lab at the Massachusetts Institute assistant news editor Richard photos on a website. on Wiseman’s blog this week of Technology, where the Sir2 pathway was Van Noorden reports that If the voting were (http://tinyurl.com/kls85q). ■ first found to increase lifespan. But I left just Visit Nautilus for regular news relevant to Nature authors ➧ http://blogs.nature.com/nautilus and see as Lenny was starting studies on ageing. ■ Peer-to-Peer for news for peer reviewers and about peer review ➧ http://blogs.nature.com/peer-to-peer.

750 © 2009 Macmillan Publishers Limited. All rights reserved