Take on a Big Problem? A ton of money or a tub of water?

Two Nobel laureates were interviewed recently on the BBC Radio 4 program, The Life Scientific, and they said some relevant and interesting things.  The program is new series, interviews with some of the most influential scientists alive.

Paul Nurse, who won his prize for work on the genetics of cell division, was interviewed in October.  His prize was earned essentially because cell division is in many ways a similar process in all forms of life.  In light of evolution this could be said not to be a surprise: the same process might be expected to involve the same mechanism.  On the other hand, there is a lot of parallel evolution and given the complexity of many controlling mechanisms, one gene might substitute for another for the process.  But, at least in terms of some of the controlling genes, evolution somehow maintained the same mechanism over more than a billion years.

The other scientist of particular interest, interviewed in November, was John Sulston.  He innovated methods for mapping (locating) the genes on the genomes (chromosomes) of an important experimental model, the tiny flatworm called C. elegans, and then led the race to sequence the entire human genome.  A main part of this work was done at the Sanger Centre, near Cambridge, England, where I was fortunate enough to spend a sabbatical in 2005.  In his modest self-description, Sulston said that his job was just to identify the entire genome, and let people more clever than he have that information to do the work to find out what different parts of the genome do.

C. elegans; Weiss and Buchanan, The Mermaid's Tale, 2009

This moved the field from 'genetics' that dealt with single genes and classical hypothesis-driven science (where you have a specific, restricted idea, and then design experiments to test it), to 'genomics' or what is called hypothesis-free science: sequence everything in every individual you study, and search for unsuspected pattern to emerge that can then be specifically tested.  The latter is more like Victorian plant and beetle specimen collection, that we so often love to criticize as useless, not even 'science', really.

There are two aspects of this that are relevant to the current drive to understand life, largely from the genome perspective. First, Nurse said one should start out a science career by picking a really Big Problem.  Even if you work on a narrow scale, do it to solve a major problem about life--he started out with yeast, before turning to human cells and generalizing how cell division work.

Sulston got a similar prize but by taking a diametrically opposite view: his job was to collect the beetles and let everyone have a crack at the data to see what they could find.  Genomics has been driven by the technology that makes it possible. But it is in some ways the opposite--or even the antithesis--of Nurse's idea.  It is doing a really big study on a really small problem.

GWAS (genome wide association studies) to understand, say, the genomic basis of diabetes may not seem like a small problem.  If the genomic approach works, and it leads to major reductions in diabetes morbidity or mortality, it would be a big success.  But the problem itself is very local and particular, and there is no intent that solving it would apply to a bigger problem.  One can criticize the blind following of this Big Science approach, and it richly deserves the criticism for the manifest, numerous reasons we often point out.

But is this also a big problem hiding under a big budget for a small question?  It is often argued so.  In defense of ever-larger studies of biobanks, GWAS, and the like (or, in regard to evolutionary genetics, of ever more whole genome sequencing from ever more species, applying ever more detailed and exotic statistical tests for evidence of natural selection), defenders often argue that yes, it's expensive, and yes it may be decades before it bears fruit, and yes, GWAS may not identify major causal genes, BUT these studies will reveal biological mechanisms or pathways that will have much broader applicability.

There is no answer to this.  We are clearly, however, training a generation of technocratic scientists who think big budget and big technology either first, or immediately after whatever question they are asking.  And the questions are nowadays mainly applied ones: what causes diabetes or stomach cancer, for example, or what cause skull shape variation.  However the studies are routinely justified for what they will reveal more generally.  We often, if not routinely, point to chance discoveries in the history of science, and say that's what we're aiming for.

Of course, the vast majority of science is routine, if not hum-drum and with little likelihood of any impact other than to feed the investigator and his or her lab group.  It is vainglory of a high magnitude to promise serendipitous Eureka! moments as justification for dipping so deeply into the public treasure for each of our studies.

On the other hand, it is certainly true that Eureka! discovery moments do arise.  So is this an acceptable justification for investment in, say, big-scale genomic approaches?  This is for you to decide.

But what we're doing clearly is proposing the kinds of studies to answer the kinds of questions that require big data and expensive, extensive, and often very complex instrumentation and statistical methods to address.  Inevitably and systematically, perhaps, some issues are being closed to us while others are being opened.   One can argue that the narrower your training or focus the less likely you'll have one of the major moments, but in any field in any era it has always been only the very rare, lucky person who has had one.  Also, without the investment, they certainly can't happen.

Or are these correct arguments in support of the way we do things today?  In the past, it was individuals slogging doggedly after a problem (Galileo, Newton, Darwin, Einstein, others) rather than big factory operations (which, to be fair, didn't really exist until fairly recently), that delivered Eureka! discoveries.  Will the lone, persistent, investigator have the next transformative insight?

Nurse had substantial though we think not enormous funding.  Sulston and the Human Genome project garnered enormous funding for their work.  Both got Nobel prizes for their work.  On the other hand, Darwin just worked in his backyard after a low-cost sailing trip round the world, Mendel in his modest garden out back of a monastery, Galileo with a cheap telescope and under house arrest.

And the real Eureka! moment?  That just required Archimedes to take a bath.