Larry Thompson: 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.
Mark Daly: Absolutely.
Peter Visscher: Very much so.
Charles Rotimi: Darwin was really a pioneer person in terms of telling us
how we’re all related and not just human beings across the planet but
how we are truly related in those two things that we didn’t think we are related to.
Les Biesecker: Practiced every day in clinical medicine.
Aravinda Chakravarti: He provided the first 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.
Biesecker: 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.
And 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 that the power of biology is based on those changes
in DNA, in genes, which we see in different species, and in health and disease, every day.
Rotimi: His discovery really set the stage for what we currently are doing in terms of understanding
human relationships, human history and in our relationship to lower organisms around the world.
Chakravarti: His theory and thinking is very, very relevant not only to the study of biology
and understanding biology, but also in understanding human disease.
Chakravarti: 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.
Visscher: So what Darwin figured out is by looking at agricultural populations, he realized that 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 that
they were interested in selecting, and what nature does naturally, is select for fitness, leaving more babies to the next generation.
Chakravarti: The second thing that he did was to posit a theory, a theory of natural selection,
as a way of explaining what comes through evolution and that’s where there has been a lot of both the 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.
Daly: And now we are finally are getting to see the actual mechanism by which
that information is encoded and passed on and really understanding the basis of hereditability at a much finer level.
Biesecker: 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 is perfectly consistent with genes but he didn’t have to know about it to predict it.
And that is 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.
Biesecker: So what the genome project did is it laid down in black and white,
or actually on a browser screen because that is how we actually use it today, in black and white,
the differences and the similarities across every species in every gene.
We can now just look at that in black and white and say, here it’s the same and here it’s different
and understand, right on the 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.
Visscher: 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, of resistance against the plague for example in Europe.
Daly: There’s certainly the signatures of evidence that certain types of mutations have been advantageous,
certain types of mutations that have been deleterious, and there’s also evidence in different places of balancing selection.
Visscher: 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 the region of the genome that is one haplotype that is longer
or all hunk together much longer than you would expect from looking elsewhere in the genome,
that’s evidence that there’s been selection around that locus.
Chakravarti: And now I think the path 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 that I think we relish.
Chakravarti: Darwin had very incomplete and, 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.
Visscher: Variation comes ultimately from mutations.
And there’s many different kinds of mutations as we have heard at this meeting,
single base changes which are just errors in a copying when the gametes, the sperm and egg cells are created.
There’s also more complicated mutations which are basically whole bits of chromosomes that are not really replicated very well.
Biesecker: 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.
Chakravarti: One area in which Darwin’s influence was not felt, I would say
for about a century and it is only now that many are talking about it, is for example,
the use of the theory of evolution in the context of human illness, health and disease.
Biesecker: So, as a practicing clinical geneticist, one of the biggest challenges I face, everyday, 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.
Daly: I think the types of studies that we’re doing now have only very recently become possible and it’s, you know,
still very much in the early phases of the research.
Visscher: And because we know from studies, for example, of the resemblance between relatives,
and particular from twin studies, that a lot of 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 a 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.
Biesecker: It can give us hints about how to manage or treat that patient as well as
it could 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.
Daly: Absolutely, very slowly on a genetic level, but in some cases, you know,
we see evolution in action not in 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, a much more hygienic environment in which we now live is thought to provide perhaps
a basis by which autoimmune inflammatory diseases might represent inappropriate responses where once they were useful responses.
Rotimi: Oh we see tremendous evidence of evolution.
We see tremendous evidence of selection,
again our ability to adapt to different environments is really again critical.
And for example, if you look at things like Lassa fever, in West Africans and East Africans,
you do indeed 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.
And the sickle cell is another one and is that there is evidence there that gives protection against malaria.
Biesecker: Every species is constantly evolving.
And what the key 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.
So selection is the key and when we see a person with a disease, that has a genetic cause,
that selection operating today on that individual and us as a species.
Chakravarti: On the aspect of Darwin that it’s cool in the sense and what’s cool 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 very impatient
and science and scientists want a lot of immediate recognition for their work,
that we should be patient, for perhaps it takes a century to be understood.
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