Empowering psychiatric disease research through genetics, with Mark Daly

TRANSCRIPT

NARRATOR
Hi. I’m Lisa Girard, director of scientific communications for the Broad Institute, and you’re listening to BioLogic, the logic behind the science: conversations with Broad researchers exploring what they do and why they do it.

For this episode, I sat down with Mark Daly to talk about how modern tools for analyzing the genome are empowering the study of psychiatric disorders.

Mark Daly

Mark is an institute member, co-director of the Program in Medical and Population Genetics, and investigator with the Stanley Center for Psychiatric Research at the Broad Institute. He is also chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital. He and his lab are interested in analyzing the genome for insights into complex diseases such as Crohn’s disease, ulcerative colitis, and schizophrenia. 

Mark has been involved with this field for the last three decades. Over that time, the tools for mapping and analyzing the human genome — as well as our ability to draw connections between our genetics and our health — have gone through some major changes. Here’s a little of his perspective, from the frontlines of research.

DALY
We recognized at an early time, as a field, that there was potential value in discovering the genetic underpinnings of disease, because that was really setting you on a path to understanding what really causes disease and learning how to, perhaps, ultimately intervene to fix it. But we learned at the time, when we were building maps in the ’80s and ’90s, that we didn’t really have the toolkit to do this at the time. I mean, at that time, we didn’t even have the sequence of the genome, or knowledge of what all the genes were or how many genes there were. So obviously we’ve come a long way.

So it’s an exciting time in human genetics because we have just a remarkable access to tools. Not only sequencing tools for studying our patients, but also references — that when we discover something in our patients, or we take a group of patients and aim to discover what’s unique about them, we have all of the available data that we need to make that comparison and to discover in our patient what’s been seen before and whatever may be the handful of really unique variants or mutations that that individual has.

So it’s a great time to be now, finally, after well more than 20 years for some of us, to actually see that we now have tools and technologies to tackle the discovery of genes for truly complex diseases. And so now it’s up to us, as we finish that job, to actually figure out what all those discoveries teach us about the biology of disease and what we can do about it.

NARRATOR
Mark turned his attention to psychiatric disease more recently and discovered that there are some unique challenges to finding the genetic mutations that may underlie disorders in the brain.

DALY
There was a long period of time in which there was a general recognition of the heritability of psychiatric disease, but ambivalence about the model under which that takes place. But I think, some time ago, some insightful researchers recognized that what was very likely the case was that there were many, many different genetic contributors. Because what we have in psychiatric disease is actually surprisingly very similar to what we have in phenotypes like adult stature — which is there’s an incredible heritability.

And I think what surprises people sometimes is to learn that autism and schizophrenia have actually higher heritability than things like type 1 or type 2 diabetes, or Crohn’s disease, or asthma, or any of these types of things. So that’s telling us that, fundamentally, the clues to disease largely reside in the genome that you’re born with.

However, the catch is that there’s also a great — and, you know, much moreso than in most other common diseases — a great force of natural selection acting against those psychiatric diseases, in that individuals with those diagnoses have far fewer children, historically, than individuals who don’t have those diagnoses. And so that really constrains the size and frequency of genetic variants that cause disease. So if natural selection is working that hard against the disease, a genetic mutation that confers strong risk to the disease will not be allowed to reach a high frequency — or even a modest or intermediate frequency — in the population. Natural selection simply wouldn’t permit it.

And as a result, the task of finding genes in those diseases proves to be much, much harder than it is in many other diseases.

NARRATOR
But genetics is still one of the most promising options for researchers who want to study the biology of these disorders. Modern analytical tools for probing the genome have helped make it easier.

DALY
Genetics really opens up these diseases, really, in a way that there’s almost no other alternative to, because there’s not any direct route into the biology of disease as there is in maybe immune diseases and cancers and so forth. Because obviously you can’t just take a blood draw and learn something from it as you can with many other medical areas. And for many brain diseases there’s not even any utility to imaging. You can’t look at a brain in a scanner and say it has schizophrenia.

And so, really with the technology allowing us to get to a scale in which we can study the genomes of larger and larger numbers of patients, over the last four or five years, we’ve actually been able to make tremendous progress in understanding the common variant patterns that lead to schizophrenia, specific genes in which rare mutations cause autism and intellectual disability and epilepsies and so forth — the brain diseases as a whole, which have been really the most challenging to study.

I think the impact of these methods and the technologies and so forth has been really quite profound and you know, I think there’s really a great energy in the research communities working on psychiatric diseases, and brain diseases in general, because they are finally able to have reliable pointers into the biology, the causal biology of disease, that they have never had before.

NARRATOR
Mark, like many in the field, hopes that genetic studies will offer some insight into the biological roots of these disorders. When I asked how he would define success in this area, he zeroed in on new diagnostics and therapeutics.

DALY
It’s the overarching goal and I think for complex diseases, very common diseases, we’re more focused on the therapeutic side of that. Because genetic, you know, the genetic architecture of a disease that has contributions from hundreds, or maybe even thousands of different genes or corners of the genome, is not something that is going to lend itself very easily to prediction. You’re not going to be able predict who’s going to end up with a certain psychiatric disease particularly accurately from just your genome. 

But what we’ve lacked for decades are really fundamentally new and effective approaches to therapies. And this is the primary hope, that unlocking the biology is the first step towards, ultimately, a much more rational set of therapeutics that are available for brain and psychiatric diseases.

NARRATOR
And even in the short term, Mark pointed out that genomic studies are changing how these disorders are seen by the public. Genetics, and biology more generally, is working to mitigate the devastating social stigma of psychiatric disease.

DALY
You know, the very substantial progress in unlocking the genetics of autism and intellectual disability has had some, hopefully positive, impact on moving the needle of societal understanding — that these disorders are not caused by bad parenting, or vaccines, or what-have-you. And that’s just, in the context of a lot of solid epidemiology that tells the same story, this is, I think, something that’s important. 

I think with respect to schizophrenia and bipolar disorder and other adult mental illnesses, simply having our society really understand and believe that these are medical conditions and not failures of character is something that I think progress in the genetic studies helps the discourse towards. Because concretely finding genes, and articulating biological processes and pathways and things that you can actually measure that correspond to disease, moves us ahead in that dialogue, in a way that simply describing things as “heritable” or “familial” doesn’t go quite as far.

And then, we’ve had some quite interesting findings with respect to the heterogeneity of autism. Not in terms of different mutations, having a deterministic outcome for a different flavor of autism, but really understanding that there are relationships between the genetics of autism and the genetics of IQ and educational attainment — but in a positive direction.

And that, starting to understand that genetics isn’t always telling us about what’s broken. It can help us understand what things are sometimes working too well. And, you know, we don’t need to think about fixing them, but think about “How do we adjust to that?”

NARRATOR
Advancing our understanding of disease through genetics can lead to these and other important outcomes along the way toward a long-term therapeutic goal. You can read about Mark’s research and learn about the computational tools his team is developing at broadinstitute.org. 

The BioLogic podcast is available at broadinstitute.org, as well as through SoundCloud, iTunes, Pocket Casts, and other podcast distributors.

For the Broad, I'm Lisa Girard. This will be the final podcast I host as director of scientific communications at Broad, but the series will continue with a new host — so keep looking for more great conversations with Broad researchers on BioLogic, and thanks for listening.