Welcome to the Oxford University Psychology Podcast series. My name is Daniel Morgan and I've got Professor Paul Harrison with me today.
Good morning, Paul. Thank you very much for joining me. You have a very interesting research field into translational neuroscience where
you have quite a broad range of research areas where you way from the lab work or
work through to potential clinical applications and will perhaps would be interesting
to begin by you just giving a broad overview of your of your research area.
Well. So my research area originally was was, in fact, neuropathology.
So having done my research degree and outside in the early part of Alzheimer's disease,
I then wanted to apply the same kind of neuropathological techniques to schizophrenia, which is a notoriously difficult area.
And we did a number of studies over 10 or 15 year period, which I think told us some things,
but increasingly became apparent to me that the answer to really unravelling the pathophysiology of disease or schizophrenia didn't lie entirely,
and perhaps even largely in studying the brains of people who'd had the illness.
And so as a result of that, over the past 10 years or so, the research has broadened to include, as you suggested,
a range of other approaches and techniques which inevitably taken away from questions about the biological correlates of our psychiatric syndromes,
will get us more into understanding that that that treatments and their clinical implications.
So that's really where the translation side is. And so, in a sense, when we see a clinical picture,
we know that there's a whole of several layers of sort of understanding that feeds into that behaviour from neurotransmitters to psychological
frameworks to understand some behaviours that have been specifically looking at and some of the genetic components of of that behaviour.
So could you tell us a bit about that? Yes, that's right. So perhaps that's been the main shift in focus.
And so because originally we did in sense case control studies where you take a series
of brains from patients who are analysis necessarily the brains of people without.
And you're looking for things that the occurrence of the diagnostic differences by the problems of those kind of studies, really,
whether you do them in post-mortem brains or you do them in established living patients with analysis,
it's very difficult to separate causes from consequences of illness.
And the same in many ways applies to environmental studies of the risk factors for psychiatric illness.
One of attractions in the genetics is not only that we know the major psychiatric
standards have a substantial and often underestimated genetic component,
but if we find genetic discoveries, essentially they can't be confounded by anything.
You may still be very puzzled as to what they mean. But at least if you find a robust genetic association with a botanical syndrome,
you can stop for matters into peckerwoods, which you can hang on to our studies.
So that's really why we moved to understand the genetic basis of mechanisms like schizophrenia and bipolar disorder.
OK, thank you. So what do we know about these sort of very broad, perhaps umbrella diagnoses of bipolar and schizophrenia?
What do we know about the genetic contributions of that? And just broadly speaking?
Well, the glass around half full and half empty. The simple answer is we still don't understand it at all.
On the other hand, it is clear the research the last 10 years is Regenesis particularly to produce,
firstly, that there is a substantial genetic component to,
depending how you measure it, between about two thirds and three quarters of whatever is causing these illnesses is in our genes.
We also know that about two thirds of the genes that contribute to schizophrenia also contribute to bipolar disorder and vice versa.
And there's also an overlap genetically with autism, with learning disability and with major depression.
So certainly a clinical sense of these drugs that really caused nature to join this.
Many cases that are a mixture of two things is only one pure case of any diagnosis.
That's certainly what the genetics is looking like in terms of what is the nature of the genetic basis of these various syndromes.
Again, it's not one gene. There probably isn't even 100 genes.
There are probably hundreds, if not thousands of genes contributing individuals small amounts to the genetic risk of these disorders.
There might be a few rare genes, which then, if they happen to be present, are rare genetic abnormalities, which,
if they happen to be presented to a patient, may make that person's illness slightly more attributable to a small number of penetration.
So there's many genes that have perhaps a small impact on on on the risk of developing these these conditions.
So, I mean, that makes your job very complex, doesn't it, because you're looking at so many different genes and all of if you look at any particular
one gene that it might lead to somebody having a condition or not having condition.
Are you looking at how they say. They say with one another or you're looking at them individually.
So you're right, you've you've you've touched upon what is really on the key issues in matter
of just how do you prioritise the many genetic discoveries and implications,
because it's now quite quick to discover or to survey the genome with the Human Genome Project, the techniques that go with that.
So it's very easy to identify hundreds or thousands of genes which are individually, statistically doing something.
But then following those up and understanding the biological implications is very difficult and does need a lot of prioritisation.
And the questions of what kind of grounds do you prioritise and what kind of models do you have to have for school,
the genetic architecture of these conditions to help you make rational decisions about what to study.
Now, some researchers are going for these rare, very rare, but if present,
very penetrant genetic factors on the grounds that that gives you attraction to biology.
Other people say from an epidemiological perspective that they're not important enough overall to invest it.
We need to go for these common genes. And even that effects are very small.
That's ultimately where the real breakthroughs need to be made. You can then say,
do I take an individual gene or do I hypothesise that these genes interact with each other and you go for some kind of higher level or sometimes
good points of convergence of genes and you go for what you think of the biochemical pathways that be downstream of a lot of these genes.
The metaphor that sometimes uses you know,
you try and go after every trick or treat when you go for the big river or all the tributaries have joined up to have a bigger effect.
And again, at the moment, I think there's different people applying different strategies.
And it remains to be seen which if mean, is the more fruitful and comes to fruition.
So a lot of exploration needs to be done about these many different genes and
their contribute contribution towards what we recognise as psychiatric diagnoses.
But I guess the question comes as to the nature nurture question,
and are you doing any any sort of investigations on on how particular house Constellation's
or groups of genes might interact with with adverse circumstances in people's lives?
For sure. As you said, it's another level of complexity because the evidence is that many of these
genes are probably not having a direct and immediate effect on disease risk.
They may well be affecting individuals.
Responses to environmental events and environmental events could be anything from our infection to smoking cannabis to having a head injury.
And, of course, experimentally gets even more difficult when you try and combine genetic factors with environmental factors, as you can imagine,
because of things with combinations of things rapidly multiply beyond any meaningful control,
we as a generally have stayed away from the environmental side of things just to try and retain a degree of focus.
But with these temperatures are all CitiPower here we have an interesting interaction
and one of the particular genes with with tetrahydrocannabinol the active ingredient of
cannabis and exploring some of the mechanisms that may underlie the apparent association
between your genetic makeup and the effect of smoking cannabis earlier in your life,
has your risk of developing schizophrenia later. So that's an example.
Some of got a gene environment interaction. So the nature nurture question remains sort of a lofty, lofty ideal and research at the moment.
It certainly does.
The problem, as I say, is that it's now possible to measure the genome very quickly in very large numbers of people to measure the environment,
the people's environment, to the necessary level of detail.
And longitudinally, not just cross-section, of course, is a far more expensive and long term and frankly, unfeasible operation.
So I think the genes, the environment, bit of risk for psychiatric illnesses will go on,
be more mysterious in some ways than the genetics will be just for that practical reason.
So moving on to thinking about practical implications of your your research on genetics and how that might apply to the clinical room,
you've written a bit about how what you've understood about the genetic contributions to mental illness might impact on on Ansonia medications.
Could you tell us a bit about that? Yes.
So I think potentially genetics can help treatment, but not necessarily exclusively drug treatments in several ways.
One is it may turn out there are genetic predictors of response to the drugs we have available at the moment.
Let's call pharmaco genomics. And again, there are some data, but nothing which at the moment means that, as you know,
in clinical practise, we routinely would measure something genetic to help us decide which drug to use.
But that's more interesting. You had given that we know current drugs have many, many limitations, is whether the disease could help us identify new.
Or new drug targets, and I think, again,
it's too early to say if you look at a few of the many genes that we have to think schizophrenia as an example,
although there are many genes, they're not independent of each other in terms of what we think those genes are doing.
So it was a clear convergence of many of the genes on certain core pathways,
some of which were already potential drug targets for other reasons and others which are novel.
So, for example, treatment and energy receptor signalling and synaptic plasticity seem to be common effects of a number of the risk genes
and strategies to try and normalise or improve glutamate transmission had already been under development in the field.
So one would imagine, I would hope that the genetic discoveries may both increase the focus on that and
sharpen the focus to decide exactly where within what is an exciting pathway.
The drugs of the next generation can more usefully targeted civilians and have a
focus on some of the genes across schizophrenia and bipolar disorder and calcium.
Certainly so calcium channel antagonists, for example, which we already have in medicine,
cardiology, for example, if they have any as yet untapped potential, is novel drug treatments.
But whether, you know, whether that's going to prove to be the case,
whether those drugs will turn out to be effective and safe and meet all the usual problems of developing new psychiatric drugs remains to be seen.
And I think the genetics, at the very least, is giving the field of psychiatric drug discovery a well needed boost.
And it's helping, I think, reverse the previous decline of interest by the pharmaceutical industry in our field.
We work in psychiatry using a descriptive diagnostic classification system where we have these well, perhaps some some might argue,
quite old fashioned diagnoses of schizophrenia and bipolar and perhaps depression and anxiety in your in your work of understanding
genetics and how this sort of quite a common thread of genetic contributions and sort of mental disorder across the spectrum.
Have you had any thoughts about how or any thoughts about our current diagnostic system?
Do you think it needs to be shaped in light of your understanding of genetics?
Well, I think most people I'm quite sure our current system is wrong, but I'm not quite sure what I would do to make it any better.
We can make it different from what any better because the genetics is not deterministic.
It's not like a single gene disorder where you can start to redefine the syndrome by the genetic mutation, for example.
It's naive to think we're ever, ever going to get to that sort of level of redescribed or syndromes on some biological basis.
However, I think we can wield a lot better than the current time descriptive form of classification.
So, for example, if we I mean, let's say we compare psychosis as a broad category with the book category,
we still use the term dementia as a descriptive syndrome to describe see the constellation of symptoms.
But we have individual dementias, the group defining the 4G and increased according to their genetic origins.
Now, I would imagine what will happen to psychosis is it would begin to be picked apart in that kind of way.
The majority of cases will continue to be idiopathic in a causal sense for a while, and they will need to continue to be described as such.
But there will be, I suspect, individual rare causes of psychosis which become defined by their aetiology.
Let's take another very topical and controversial at the moment,
the possibility of some cases of psychosis due to anti autoantibodies and essentially autoimmune disorder presenting as schizophrenia.
Now, that raises fascinating scientific and most logical questions.
But that's, I think, an example where it may be that a small portion of cases become viewed differently and,
of course, treated differently if the science or the evidence that holds up is fascinating.
Hearing you talk about potential futures of of understanding in psychiatric presentations,
in clinical practise and how your work is informed that I am speaking to you,
it is is clear to me that your your your research is is very informs your practise, even though it's very scientifically based.
It's very almost a pure science. It still has an ability to sort of make you think in a fresh way about about what when you see patients.
And it would be just really interesting to hear how how you feel about being an academic psychiatrist.
What do you think it brings brings to your professional life?
And what would you say to actually aspiring academic psychiatrists?
Well, I love the combination, I think it's a real privilege to both be a doctor, a clinician and sort of have all the, I guess,
the trappings that go with that whilst also having the academic freedom to pursue or to me are interesting and challenging intellectual problems.
And of course, the problem is that in the end, something might make a difference to somebody if in the long term future.
My my contribution has been minor. I think at least 50 battles have picked up in the morning and feel motivated to to go on working both tonight.
So I would encourage anybody who's interested either in psychiatry or in my case, in the neuroscience.
The combination really is very rewarding. And there are still, despite the difficulties in funding, both on the clinical and the research,
there are still real opportunities for a few bright and often hard working enough.
You know, I would I would certainly be dogged in your pursuit of that in terms of career advice.
Again, I would encourage young people to to read around, to look around,
to ask around, to meet people in my personal experiences that certainly work for me,
finding a person or feel that inspires a particular thing,
a person who really can get you to the right starting point for your career and then goes on inspiring you.
I've had the privilege to work with a number of really inspiring people throughout my career, and I think that's my biggest advice being inspired.
Professor Paul Arrison has been great speech here this morning. Thank you very much for your time.
Pleasure. Thank you. And thank you for tuning in to the Oxford University Psychiatry podcast series.
We hope you listen to some more. Thank you. Goodbye.