 February 12th is the 200th anniversary of the birth of Charles Darwin, the British naturalist who invented the concepts that we now call evolution. We are here at a scientific workshop sponsored by the National Human Genome Research Institute where some of the world's leading geneticists are discussing the genetic factors that cause disease. Let's see if they think whether Charles Darwin's discoveries are still relevant to today's research. Yeah, absolutely. Very much so. Darwin was really a pioneer person in terms of telling us how we are all related and not just human beings across the planet, but how we are actually related to things that we didn't think we were related to. Practiced every day in clinical medicine. He provided the first, I should say, synthesizing view of modern biology, which in his words were survival of the fittest, but that wasn't the only one, but really in trying to say that structure begets function. And he gave us a reason as to how that function comes about over time. I think the coolest thing is that he tackled something that everyone assumed was true and everyone assumed that species were relatively fixed over time and had been so for many, many, many generations. What he showed is that there's a spectrum of difference among different species and that that spectrum changes over time. So things are constantly changing and shifting and the power of biology is based on those changes in DNA and genes which we see in different species and in health and disease every day. His discovery really set the stage for what we are currently doing in terms of understanding human relationship, human history, and in our relationship to lower organism around the world. His theory and thinking is very, very relevant not only to the study of biology and understanding biology, but also in understanding human disease. The first, which I don't think we think about, but we use his name all the time, which is Darwin's concept of natural selection and is often simplified into survival of the fittest. So what Darwin figured out is by looking at agricultural populations, he realized what breeders were doing, whether it was breeding chickens or cows or pigeons, that the same principles applied in nature as well. And in terms of the breeders in agriculture, they obviously had a particular characteristic they were interested in selecting and what nature does naturally is select for fitness, leaving more babies to the next generation. The second thing that he did was to posit a theory, the theory of natural selection, as a way of explaining what comes through evolution and that's where there has been a lot of both debate and controversy that is what is the evidence, what is the nature of the evidence, who is fit, who is unfit, and how do these mechanisms play out? And we now finally are getting to see the actual mechanism by which that information is encoded and passed on and really understanding the basis of heritability at a much finer level. He did not know about genes. He proposed a model that essentially predicted and is entirely consistent with the existence of genes, but he didn't know about that. And that's the beauty of it, because his observations of nature led him to predict a model that's perfectly consistent with genes, but he didn't have to know about it to predict it. And that's the strength of evolution, is that once you do know about genes, you put those two pieces together, they fit perfectly together, strongly reinforce each other, and the genes provide the biological mechanism for Darwin's ideas. So what the genome project did is it laid down black and white or actually on a browser screen, because that's how we actually use it today, in black and white the differences and the similarities across every species in every gene. And we can now just look at that in black and white and say, here it's the same, here it's different, and understand right on a screen what's the same and what's different, and how evolution is making some things change over time, and how evolution is making some things stay exactly the same. There have been regions of the genome identified, where you can just look at variation in the DNA sequence and find an imprint of selection in the past. This is particularly so for genes that are implicated, for example, with immune response and other traits. There's even imprints of what we think are selection that occurred relatively recent during the Middle Ages, for example, resistance against the plague, for example, in Europe. There's certainly the signatures of evidence that certain types of mutations have been advantageous, certain types of mutations have been deleterious, and there's also evidence in different places of balancing selection. If there is a particular DNA change that was advantageous, then it drags with it a lot of other DNA changes around it. So what we call a haplotype? So if you see in the region of the genome that there is one haplotype which is much longer, all hung together, much longer than you'd expect from looking elsewhere in the genome, that's evidence that has been selection around that lockers. And now I think the task is to try and take that evidence for change, to try and understand how that leads to the adaptive changes that we know have happened in human societies for long periods of time. And that's a large task, but that's the kind of biological challenges I think we relish. Darwin had very incomplete, in fact, very old-fashioned views of where variation arose from, how that variation was maintained, in fact, molecularly how it was maintained, or how it was maintained by organisms. Variation comes ultimately from mutations, and there's many different kinds of mutations as we've heard at this meeting. Single base changes which are just errors in a copying from when the gametes, sperm and exels are created. There's also more complicated mutations which are basically whole bits of chromosome that are not really replicated very well. So DNA changes at a relatively fixed rate every time it's transferred from parent to child. That's normal variation, normal mutation rate, and that mutation rate increases the diversity of all species, and in a few instances when it occurs, in a crucial part of the DNA, causes a disease. One area in which Darwin's influence was not felt, I would say for about a century, and it's only now many are talking about, is, for example, the use of the theory of evolution in the context of human illness, health and disease. So as a practicing clinical geneticist, one of the biggest challenges I face every day is figuring out how to interpret sequence variation in patients and understand if that sequence variation causes the disease in that patient. So what that means is when I see a DNA change, I need to know did that cause the problem in the patient, or is it just a coincidence? And every day when I analyze those variations, I use evolutionary principles to understand how that change may relate to disease, because what the theory of evolution teaches us is that if a particular piece of a gene is really, really important, then that sequence will be similar or the same in many different species. So I can look across species from all the sequence data in many different animals and derive from that an idea about whether that's an important DNA change, or whether it's unimportant and isn't related to what the disease is in my patient. I think the types of studies that we're doing now have only very recently become possible, and it's still very much in the early phases of the research. Because we know from studies, for example, of the resemblance between relatives, in particular from twin studies, that a lot of the variation in disease also has a genetic component to it. And in fact, for diseases like schizophrenia and bipolar disorder, which I work on, in fact, the majority of the variation in risk in the population is actually due to genetic factors. So by trying to get a handle on these genetic factors, we can understand the biology and ultimately that may lead to treatments, for example, new drugs. So it can give us hints about how to manage or treat that patient, as well as it can give us the ability to predict the occurrence of that disease in future generations. There's a lot of things, a lot of power that gives us and our patients to understand those changes and what they mean for disease and health. Oh, absolutely. Very slowly on a genetic level. But in some cases, you know, we see evolution and action not in, you know, sort of real-time changes to our genetic patterns. But we can also see things sometimes exposed by the radical changes in the environment that we have introduced to ourselves in the past century. For example, the much more hygienic environment in which we now live is thought to, you know, provide perhaps a basis by which autoimmune inflammatory diseases might, you know, represent inappropriate responses where once they were useful responses. Oh, we see tremendous evidence of evolution. We see tremendous evidence of selection. You know, again, our ability to adapt to different environments is really, again, critical. And for example, if you look at things like Lysa fever in West Africans, you do see, in East Africans, you do see evidence of natural selection there, where there's selection for specific genes or specific gene variants that help protect people against that devastating disease. Again, because that's the environment where it was found, you know, sequel cell is another one, you know, which have those evidence there in terms of protection against malaria. Yes. Every species is constantly evolving. And what the key is is not whether we are evolving. The question is the degree to which selection is acting. And that was one of Darwin's key insights. The selection is the key because DNA changes. And those changes only matter if it changes the effect that it has on your health and your survival. And so selection is the key. And when we see a person with a disease that has a genetic cause, that's selection operating today on that individual and us as a species. I think the aspect of Darwin that it's cool in the sense and what school depends clearly on one's age is the fact that he was ignored as long as he was ignored. And I think it's cool in the sense that we currently in today's world where we are all very impatient and scientists want a lot of immediate recognition for their work that we should be patient. Perhaps it takes a century to be understood.