A Day in the Life: Bridging the Gaps to Personalised Medicine
Dr. Elhaik’s recent work includes the development of the GPS technology that identifies and dates the origin of genomes and promotes a new understanding of cot death and mental disorders. This is what a typical day looks like for him in his own words.
By now I have been working for the past 2-3 hours, which technically makes me a night person. Together with a US colleague, we develop infographics to represent the relationships between various cultures through time and space using ancient DNA. Anthropologists have already classified them as “hunter-gatherers” (HGs) or “farmers” and similar. Such names allow our minds to construct very clear images of bare-foot hippies dancing around trees in the nude and grabbing fruits from the low branches, or of people dressed for work in some primitive overalls and straw hats, their backs painfully arched as they clear the stones from their field and sweat is pouring from them. No doubt which of those are our ancestors – our mind tells us. It is the same mind that tells us that the well-dressed lady on the train works in a bank and the gentleman with paint-splattered trousers is a housepainter. It’s called typology, and it is one of the gravest dangers in science. Anthropologists cannot tell us how genetically related these HG and farmers are. After all, farmers were yesterday’s HGs and some HG’s would be tomorrow’s farmers. Are they really that different? At first scientists thought that they are, but now they are not so sure. I try to imagine the encounter between these people, since there is little doubt that the ripening fields attracted the HGs at some point. Did the farmers give the HGs some seeds (why would they? Why help the competition?)? Did they enslave them (maybe some, but what of the others?)? Paid them off (probably, but to what end?)? Paid them to ruin the competitor’s field (this would invite retaliation)? Most of these are not questions for geneticists, of course, but they are useful nonetheless to develop hypotheses.
I am taking on some light reading before getting really tired. Nowadays it is the history of the Near East and Mesopotamia with an emphasis on Jewish history. Here we have “The Great Sea” (David Abulafia), “Babylon” (Paul Kriwaxzek), “The Beginnings of Jewishness: Boundaries, Varieties, Uncertainties” (Shaye Cohen), “The Construct of Identity in Hellenistic Judaism: Essays on Early Jewish Literature and History” (Erich S. Gruen), “Identity of the Diaspora: Jews in Asia Minor in the Imperial Period” (Krystyna Stebnicka), and “Jewish Communities in Asia Minor” (Paul Trebilco). Most of these books strictly depend on typology, although as I explained above, they cannot say for sure. They assume, and are probably correct, that cultures far away from each other are genetically distinguishable, but what about crossroads like the Near East where people of different origins have been mixing for generations. Is there a point to distinguishing people as Jewish or Greek in a mixed society? What if they are of the same gene pool but with different names? Some of these books won’t be as long, that’s for sure.
I am flipping over the headlines to make sure the world is still in one piece and that we don’t need to run to the nearest bunker. If we do I’ll take my chances in the woods. UK bunkers got stuck in their WWII version. Fortunately, we have at least one more day here.
Overnight I got 30 emails from Google Alert and Google Scholar Alerts mentioning news and scholarly articles covering all my fields of interest from Sudden Infant Death Syndrome (SIDS) to Genetic Genealogy. This happens every day. Together with journal alerts and, of course, Twitter, each day starts with a hefty pile of papers to read. No point sighing, it won’t make it go away.
A 3rd year student walks in. He chose bipolar disorder as his topic for a 4000-word project and got excited after finding a marker that appeared in all 42 GWA studies he analysed. It is an intronic variant with odds ratio (OR) of about 1.5, at best. I explain the meaning of these terms and encourage him to search for markers with larger effect size. The next time he comes he is far less excited. Yes, there are variants with higher ORs, but they don’t replicate across studies, that is the literal definition of GWAS. I recall how one of my colleagues got manic with excitement when he found out that olfactory receptors came up high in our work on bipolar. It was followed by depression. Now, here comes the eternal question – “what should I do now?” I explain that everyone has their own “grandma recipe” for finding variants, so as long as he is consistent and making reasonable assumptions, it is OK. He is not happy about it, he would much rather “find something,” but science is not about being happy. It is pretty much about failing miserably and tweaking it to appear like a great achievement. Success is either accidental or the result of very hard work.
Lunch time. Lunch is probably the best time to exchange ideas and meet new colleagues, but we don’t have a luncheon room so I just eat at my desk. If it wasn’t for the university’s emails we would be practically cut out from the rest of the university. If only they would be as informative about newcomers as about those who passed away, there would be a point in regretting not having a luncheon room.
Ignorance of population genetics has dire consequences on epidemiological studies. Allele frequencies can vary tremendously even within the UK. To demonstrate that I analyse an enormous genomic database for which we were provided data on people’s place of birth. The GPS algorithm we published in 2014, predicts the place of birth from the genomic data with impressive accuracy. By large, northern and southern people emerged from different founding populations, most likely northern Europeans and Southern/Western Europeans, respectively. It is easy to use GPS Origins on English genomes to see where people migrated from. Had we knew that, we would be in a much better position to study their drug response, drug metabolism rate, and other pharmacokinetic traits necessary to develop personalised medicine. It would also allow us to perform epidemiological and clinical trials much more accurately without the risk of stratification bias (mismatched ancestries). Two emails come in from the GPS Origins customer support one after the other. The first congratulates GPS Origins for pinpointing their origins 50km away from their home. The second is much more furious – condemning GPS Origins for the very same reason. I can see now why people stay away from this field.
A conference call with a company involved in clinical trials. I explain that our newer GPS-based tools – allow optimize case/treatment control matches using both demographic and genetic criteria to minimize stratification bias. In this manner, trials can be more accurate and, hopefully, more likely to be show the real effect of the drug or treatment. The neat thing about the tool is that, even if the trial has failed, it allows you to genetically characterise the groups of responders to identify any personalised effects that the treatment may have. The company reps are impressed. A follow up call is scheduled.
Jetlag is hitting me now since I just returned from Australia. I was advised to give it a few days, but in a few days I’ll be in Finland and then Israel. How many jetlag’s can one person have? Do they cancel each other out? I am taking a quick walk in the freezing weather. If it worked for Elijah of Vilna, it should work for me too. Upon my return I review my postdoc’s work. I try to pinpoint the mistakes, but the more tired I am the more likely I am to just correct the mistakes myself. I am a bit surprised that no one at my lab picked up on this pattern. If they had, they would have gotten me a hammock by now. Their loss. This study deals with the environmental factors associated with autism. We are looking at some factors that have been largely ignored in the literature in an ecological link study. I wonder how many more such factors are there that our culture trained us to ignore. Mental disorders are considered “complex,” that is, the product of genetic and environmental factors. Applying one’s “grandma recipe” to search for pathogenic variants is rather simple. Accounting for the nongenetic components is a completely different story. That’s the “low hanging fruit” paradigm of genetic studies.
I head home with extreme care. The problem is not with the long walk or even the hill, but with the slippery road – pretty much like science.
Dr. Elhaik completed a ph.D in molecular evolution at the University of Houston, studying the evolution of mammalian genomes. He then completed two post-docs at Johns Hopkins working on population genetics and mental disorders. As a lecturer at the University of Sheffield he focuses on medical, evolutionary, and population genetics.