Churchill alumnus Professor Laurence Hurst has been awarded the Humboldt Prize, an award given to internationally renowned scientists and scholars in recognition of their lifetime’s research achievements. Presented by the Alexander von Humboldt Foundation of Germany, it recognises his world-leading research on evolutionary genetics.
Prof Hurst is one of the most highly cited evolutionary biologists in Europe and has authored more than 300 research papers. Now Professor of Evolutionary Genetics at the University of Bath, and founding Director of the Milner Centre for Evolution, he started out as an undergraduate at Churchill College. We caught up with him to find out more about his research and career.
How did you come to specialise in the area of evolution of genetic systems?
In retrospect I can see that what I do now had its roots in what I did as an undergraduate. I particularly enjoyed the way the evolution lecturers in Zoology focused on things that don’t obviously make evolutionary sense – for example, why do organisms act altruistically. There was a clarity of thought that I relished then that I relish still. I knew then that I really liked these why questions (more than the “what happens” and how things work questions that are the focus of most biology). In part this was the seduction of a few powerful ideas that could explain vastly more than by rights any ideas should be able to explain.
While those lectures were focused on animal behaviour, I recall too meeting in genetics lectures the fact that even in species with same sized sex cells the cytoplasmic DNA (in mitochondria and chloroplasts) was nonetheless inherited from only one of the two parents. I remember thinking at the time how peculiar that was from a why point of view (we were just told it as a fact to know and remember). What was odd was that there was no cross talk between the material on how genetics systems worked and the lectures on why things are as they are. To this day I find that odd. Genomes have behaviour and anatomy just as organisms do. I guess that was the kernel of my interests.
As it so happened, for my D.Phil I returned to (stumbled onto) that very issue. I showed that this inheritance from one parent was also closely related to an even more striking problem which is why so many species have two sex cell types even if these sex cells are the same size. There is no inevitability of just two types (mushrooms don’t have two types for example). This is such a delicious problem as having two types is not just a bad solution at first sight; in terms of finding a mate it is the worst solution.
This was the start of my career trying to understand why genetic systems are as they are and I developed from there in part following the data (gene sequences were becoming available). While I really enjoyed the cross fertilization of taking the why ideas and employing them to examine strange biology that is more usually considered from mechanistic angles, part of the reason I moved towards genetics and away from whole animal biology is, I think, because I can’t get my head around complex things and don’t enjoy studying them. I never enjoyed ecology for this reason – all just far too difficult and complex. With genes I have at least a hope – although it often seems forlorn – of understanding what might be happening and why.
I have been so lucky to be granted positions where I have been allowed to freely roam in a manner defined by intellectual curiosity, not because I can see an immediate translation of the result nor even because I know in advance that the answer would be intellectually important. All I could say is that we don’t know the answer so must be missing something. That something might be a big something or a minor detail. I have a horrible feeling that my generation may be the last to be permitted this luxury.
What makes this area of research interesting?
Seriously, don’t you think it fascinating that most human embryos die before a mother knows she is pregnant while in fish nearly all embryos are fine. Who wouldn’t want to know an answer to that question? Give me five minutes and I’d hope to convince anyone that the problems I have wrestled with are intriguing problems and hopefully they will, like me, want to know the answers. Isn’t that what makes humans different – we have big brains and enjoy engaging with good intellectual problems. I could go on: why do organisms produce enzymes to digest a particular chemical even when that chemical isn’t present, why is our X chromosome rich in tissue specific genes, why do we have some genes in two copies but use only one of them, why when we make sex cells and go from two copies of every chromosome to one copy do we first make 4 copies?
Other questions are not so much paradoxical as unexpected. I was told that the genetic code was a frozen accident but found strong evidence that it doesn’t look anything like an accident. Similarly, it was believed that there is no rhyme and reason as to why genes are where they are on chromosomes but we discovered that our house-keeping genes cluster together. My current work (meaning last 20 years) has focused on a class of mutations that not only did we assume to have no selective effects but we even allowed this assumption into our language – we used to call them “silent” mutations. We discovered that many are anything but silent. They even cause genetic diseases. We have been trying to understand why. Their pattern of evolution can be used as an excellent guide to this problem. To me genetics is one great big whodunnit written in a manner whereby anyone with intellectual curiosity would be intrigued.
As it so happens many of our results have pretty direct applications. We are currently working on improving methods to work out which “silent” mutations would cause a genetic disease, of obvious utility for diagnostics especially of rare diseases. And we have, using the same evolutionary insights, developed new – and better – ways of making artificial genes for gene therapy and the like. By utter accident we also found a way to extract naive human stems cells which we have patented. But am I motivated by these applications? Not really. I just want to understand why strange and unexpected things are as they are.
Your discovery of naïve-like stem-cells has been described as finding a “holy grail” – why was it so pivotal?
This was a funny story. For many years people had assumed that there was no rhyme and reason to where genes are on chromosomes but in the early 2000s we discovered hidden patterns – genes expressed at the same time tend to sit close together on chromosomes. One possible reason for this is that expression of one gene causes the expression of neighbours. I was wondering how to examine this and noticed something odd: several hundred copies of a fairly new (to our genome) endogenous retrovirus (ERV) were all active in early human embryos (these ERVs are a bit like HIV that also integrates into our DNA). This meant that nature had given a rather lovely natural experiment – the same gene inserted all around our DNA all active about the same time. So how is this happening and what effects do they have on the neighbour genes?
To get at the former question I tried to work out how they were controlled and managed to develop a method to predict which transcription factors were acting on these sequences. We predicted one odd one that hadn’t been much studied (called LBP9). To show that it really was working the experiment was pretty simple – work out the binding site for LBP9, add this sequence in front of a gene that glows green when expressed and show that it works with LBP9 present but not when it is absent. Much to our amazement when we did the experiment (I say we, I mean my colleagues in Berlin), a few cells glowed green that, when collected together proved to be the elusive naive stem cells. Such cells that have the potential to become almost any other cell. This is why some call them the holy grail of stem cells. They were known about in mice but hadn’t been found in humans. Indeed, the zeitgeist was that they didn’t exist. I still think it funny that it took an evolutionary biologist asking a curiosity driven question about how one gene affects the neighbour to find these.
What achievements are you most proud of in your career?
I guess you are inviting me to look back and reflect. If I do this, I am not so much proud as grateful. Largely I am grateful for all the opportunities to live a life devoted to intellectual curiosity. I still get a buzz from new results and my favourite days are those when I can just program to digest genomes to answer my questions. There is even a simple satisfaction in writing code that works.
But there are things I am also proud of: my students. I have had the enormous privilege of mentoring some of the finest brains I know. They far outstrip me in their capabilities and interacting with them – and seeing them grow – has been a joy.
What stage of your career do you look back on with most fondness?
Actually I don’t find this a hard question. I am nostalgic about my undergraduate days at Churchill. When I first came to Churchill from Cornwall, I assumed that I was a below average student. Everyone else seemed so confident and I was admitted from the pool having been rejected by another college. I just felt so lucky to be there and relished learning just about everything (physical chemistry was a notable exception). I discovered I had a brain and really enjoyed using it. I was flabbergasted and delighted to find out that I was top of my class. After these days even for someone outwardly as successful as me, academic life is one of persistent anxiety about career, job, insecurity etc.. As an undergraduate I was blissfully unaware of this.
What stage of your career was the most challenging and why?
For my career one cannot speak of challenges. I have been the luckiest person I know (I assume there to be a very benevolent fairy godmother looking after me). I squeezed into Cambridge, got a fellowship to Harvard, a DPhil at Oxford followed by two JRF offers then a 10 year Royal Society University research fellowship, three years into which I was appointed a personal chair here at Bath university, after that ERC grants, prizes and fellowships. I never was between jobs, never worked for anyone else (even during my D.Phil I was left to intellectually roam freely). Pitch it as Hollywood movie and they would consider it too fanciful. It would be obscene to talk of challenges when I see all the problems in academia now.
Who or what has had the most significant influence on you and your work?
The most significant influences I guess were the ones that came earliest as these had a more profound impact on direction. To this end I remember the caring guiding hand of Dr Janet Moore (one of my zoology tutors who was based in Girton). She helped me develop if only by treating my wilder thoughts with encouragement. Intellectually, my evolution lecturers – Tim Clutton Brock and Nick Davies – were endless sources of fascinating questions well posed. And then my DPhil supervisors Bill Hamilton and Alan Grafen. Bill was by far the most original thinker I have known while Alan is clarity of thought personified.
Do you have any advice for others starting out in their academic/scientific career?
Trust the data. By this I mean that every generation has its accepted truths many of which are built on surprisingly thin ground. If prior consensus or theory predicts one result and the data disagree, go with the data. Check it, double check it and make sure it seems robust, but in the end go with the data. You may well be on the edge of something exciting and, if not, you are at least being intellectually honest (the most important currency for any scientist or academic – or human).
My other advice I am going to steal from Paul Nurse, and that would be don’t work too hard. By which I mean sitting in the lab doing experiments all hours does not make for good science. Go for a walk, get a bigger perspective on what you are doing. Think about the data and what you are doing as much as collecting data.
What is a big question related to your area of work you would like to work on answering?
Unfortunately, this question exposes one of my weaknesses – I am not strategic like this. I work on problems because I find them intriguing (and think I might be able to answer them) not because I have some long term plan. This being said, I suspect that I might have solved the problem of why there is so much selection on “silent” mutations in mammals – I think it is all to do with having really bad gene processing that means we have a large problem with transcripts that we don’t want. We then have filters to weed these out. Our native genes then evolve to avoid these filters which commonly means selection on inappropriately named “silent” mutations to prevent creation of unwanted transcripts or to appear to these filters and traps to be native transcripts. The thing that makes me suspect I might be right is that all the filters operate in the directions we predicted. This means we can a priori predict which changes to a transcript will make it work better – rather useful when designing artificial genes for gene therapy. I expect to be testing this for a short while yet.
Image by Royal Society CC BY-SA 4.0
