Where did the magic go? (Asian Scientist, 23rd September 2013)

Every undergraduate dreams of winning the Nobel Prize. A PhD student, however, dreams of getting a clone or converging a simulation, or perhaps today, of scooping competitors. This difference in ambition is not merely a transition from the starry eyed to the practical, but a reflection of something deeper, a loss of a sense of magic. Students as diverse as Bertie Bott's every flavour beans are taken into PhD programmes. Mix well and condition for five years under an unrelenting competitive atmosphere, and they emerge as specialized agents, as wary of sharing new knowledge as a Gringotts goblin. What is responsible for this? In my view, competition and specialisation. Specialisation taken to an extreme has become an accepted way of doing science. The number of academic job positions are increasingly fewer than the number of PhDs being trained yearly, putting both students and post docs under pressure to generate more data. Laboratories work on a tiny detail of a problem, often communicating only with other labs also engaged in the same sub-field and, therefore, convey their findings to only a select and already primed audience. I did a cursory search on the Pubmed website to see how many paper titles I as a trained biologist could understand. The very first one stumped me- 'A Role of Kindlin-3 in Integrin αMβ2 Outside-In Signaling and the Syk-Vav1-Rac1/Cdc42Signaling Axis'. The emphasis on publishing as many papers as possible and the increasing demands on the amount of work in each paper means that professors hiring new post docs routinely ask for people with prior experience in the field: they do not want to waste time training ‘inexperienced’ scientists. The fallouts of this are many; increased stress, increased reports of data manipulation and a gradual stifling of the happiness and creative freedom that people who opt to do science hope for. This corporate outlook that has seeped into doing science (without corporate-style pay) means that every aspiring scientist is busy trying to do experiments before his competitors do them and then couching the results in a manner likely to please the reviewers of specific journals. There is little time or inclination left to think outside one’s own area of sub-specialisation, let alone time to indulge in hobbies, traditionally supposed to stimulate creativity. As an undergraduate I attended a series of science lectures at a summer camp, and was thrilled by a talk about how microbes sense their environment. I remember a colleague asking the speaker afterwards ‘If I join your lab, can I find out how they move?’ The answer was prompt 'Maybe. But you must work hard'. The answer struck me as chilling, in hindsight perhaps unfairly so coming from a speaker tired after a long talk. But it was an abrupt bump down to earth from the magic of the visuals in the talk to the apparently disciplinary and confined real world laboratory. Perhaps it is unrealistic to talk of a Leeuwenhoek (a janitor) or a Spallanzani (a priest who did experiments in his spare time) who did all their work in a world where science was not yet institutionalised. The survivors of our system certainly include a subset of people who manage to work creatively and enjoy the process, but what about those we have left behind? Have we forced other leisurely and creative Spallanzanis to fall behind simply because our current system of science does not cater to them? Can we estimate the loss incurred to creative science? Certainly, institutes would be hard put to departmentalise Louis Pasteur . Very likely he would be refused funding for jumping so skittishly from the stereochemistry of tartarates to disproving spontaneous generation, and from wine making to silkworms. Perhaps all we need is a change in the way we view science. The question remains, can we bring back the wonder?

A cryptic gene converts prey to predator (Deccan Herald, 17th September 2013)

'Cryptic genes' are genes that appear perfectly functional but are not expressed, that is, they do not seem to make any RNA or protein. They look just like regular genes and can only be told apart when one checks to see whether or not they are actively being used by the cell. Their presence in bacterial genomes which mutate rapidly has been particularly puzzling. This is because genes that are no longer functional are extra baggage for the cell to carry, and usually tend to accumulate mutations and get weeded out. Recent work has suggested that several such genes annotated as 'cryptic' may in fact be expressed readily under natural conditions; it is just that the laboratory conditions in which bacteria are studied are often unsuitable for them to be expressed. Robert Sonowal and co-workers from the Indian Institute of Science and National Centre for Biological Sciences, Bangalore, have carried out a study1 that provides a unique role for one such cryptic gene system using laboratory bacteria as well as bacteria isolated from the soil and belonging to Enterobacteriaceae (intestinal bacteria). Their model system of study was a gene system consisting of many genes in a stretch (operon) called the beta glucoside (bgl) operon. This operon encodes enzymes that act upon complex sugars released into the soil by plants. Plants release several compounds that are by products of their own metabolism into the soil, and many of these are used as food by other soil inhabitants, such as bacteria. They break down sugars called 'aromatic beta glucosides', such as for example the sugar salicin, and in doing so release glucose, which is a source of food and therefore energy for the bacteria. Standard laboratory bacteria, perhaps from lack of exposure to the substrate (which is present in soil but not in standard laboratory media where bacteria are cultured) are unable to break down salicin unless their operons are 'activated' by mutation. That is, their genetic material needs to be changed before they can utilise salicin as a food source. The authors found that in contrast to this, several soil bacteria possess functional bgl operons and use it not only to obtain energy but also in another survival strategy: to ward off predators. The study used simple experiments to uncover this novel phenomenon: bacteria that could break down salicin (Bgl+) and bacteria that were incapable of the break down (Bgl-) were grown separately with two predators, in each case in the presence and absence of the sugar. The predators used were a soil amoeba called D. discoideum and a nematode or round worm called C. elegans. Both are well studied laboratory organisms routinely used in biological studies, and are known to prey on bacteria as their food. It was found that only Bgl+ bacteria proved toxic to the predators in the presence of the substrate salicin. The Bgl- bacteria along with the sugar salicin had no impact on predator viability, and nor did the Bgl+ bacteria in the presence of a different sugar- for instance glucose. This indicated that the Bgl+ bacteria were making something using salicin, which was proving toxic to the predators. To identify what substance this might be, the authors used the medium in which the bacteria were grown and subjected it to analysis using chromatography and NMR (Nuclear Magnetic Resonance). By this they were able to identify the toxic breakdown product as the chemical saligenin (2- hydroxyl benzyl alcohol). The C. elegans worms used as predators were then subjected to what is called an 'occupancy assay' where they were placed at an equal distance from both kinds of bacteria, Bgl+ and Bgl- , on a petri dish. Salicin was supplied as the food source. The authors found that the worms actually moved towards the Bgl+ set. In other words, not only was saligenin toxic to the worms, but it actually lured them to their death. The authors also showed that bacteria in turn can use dead worms as the sole source of nutrition, closing the cycle of attract-kill-eat, and morphing from prey to predator. Bacteria take up chemicals using surface receptors on their cells. Many of these are now well characterized, and one can use mutant bacteria or mutant worms which are unable to take up one or the other chemical to understand more about how the signalling works. In order to investigate how saligenin is taken up by the worms, the authors tested mutant worms defective in various receptors, choosing them on the basis of previous studies2. Worms with a defective receptor for taking up the chemical dopamine (dop1) showed decreased migration towards Bgl+ bacteria, indicating that saligenin could act through this receptor. This was with laboratory worms. Examination of natural soil nematodes showed that some species of worms avoided saligenin rather than moving towards it, suggesting that they could have evolved to recognize the toxin in their environment. The authors argue that in addition to sugar breakdown, the ability to 'repel or lure predators and thereby gain a nutritional advantage' could be a major reason why the 'cryptic' bgl genes have been retained. They also suggest that aromatic sugars made and released by plants could be used in controlling crop pests such as parasitic worms and amoebae. Future research might further demystify the role of 'cryptic genes' and lead to greater surprises. References 1 Sonowal, R. et al. Hydrolysis of aromatic beta-glucosides by non-pathogenic bacteria confers a chemical weapon against predators. Proc Biol Sci 280, 20130721,(2013). 2 Collin, D. T. et al. Saligenin analogs of sympathomimetic catecholamines. J Med Chem 13, 674-680 (1970).