What is the Genetic Overlap Between Autism and Schizophrenia? with Peter Penzes, PhD

Erin Spain, MS: Over the past decade, our understanding of the brain has begun to shift in new and important ways, especially when it comes to complex conditions like autism and schizophrenia. These are disorders that affect millions of people worldwide, and for years, one of the biggest challenges has been understanding what's happening at a biological level with these conditions, and how to translate that into better treatments. Today we're talking about new research that could help move that effort forward. A Northwestern Medicine study published in the journal Neuron has identified a novel biomarker for schizophrenia, offering new insight into how brain circuits function and potentially opening the door to new ways to treat the cognitive symptoms of the disease. This work is part of a broader effort at Northwestern Medicine to understand the biological basis of neurodevelopmental disorders, and why conditions like autism and schizophrenia may be more connected than we once thought. Joining us today is Dr. Peter Penzes, director of the Center for Autism and Neurodevelopment at Northwestern University Feinberg School of Medicine, and corresponding author of this study that was published in Neuron. Peter is also the Ruth and Evelyn Dunbar Professor of Psychiatry and Behavioral Sciences at Feinberg. Welcome to the show. 

Peter Penzes, PhD: Thanks for having me. 

Erin Spain, MS: It's wonderful to have you here. You first joined this podcast as a guest back in 2018 when your center first opened. Now, eight years later, what are some of the biggest changes you've seen in the field of neurodevelopmental research? 

Peter Penzes, PhD: Several things have advanced significantly. On the genetic side, much larger genomic studies involving hundreds or even thousands of subjects have yielded many more risk genes for schizophrenia, autism, and related conditions. One important conclusion from these human studies is that schizophrenia and other psychiatric conditions are really a collection of disorders with common features, but very broad genetic causes. That can include rare and orphan disorders caused by specific gene mutations, which are individually very rare, but have a very large effect size. On the biology side, we have developed better tools to study the brain and circuits in animal models, but also organoid models — miniature human brain structures grown from stem cells which are generated from the blood of patients. And these mini brains grown in a dish could give us a much closer insight into human biology. And finally, brain imaging studies at all levels, microscopic, nanoscopic, but also at the whole brain level have provided better windows into the function of brain circuits in live human subjects. 

Erin Spain, MS: So many big changes, but I will say autism has been getting a lot of attention, especially right now, and the diagnosis rate does continue to rise. From your perspective, what are the most important research questions that we should be focusing on at this moment when it comes to autism and other neurodevelopmental conditions? 

Peter Penzes, PhD: I would say that we made a lot of progress over the past maybe 10, 15 years in understanding the genetic causes of all these. So that area already generated a lot of material for us to work on. The next step would be to try to understand what those risk genes do, and how they affect brain development. And how their incorrect function derails this normal development of the brain. That can be done in mouse studies even uh, people use other animal models, or in these brain organoid models that I've mentioned. And then finally, the next step would be to really use this knowledge to develop new treatments because as we know, there are currently no treatments for the core features of autism. That is actually the biggest need right now for families and for patients who are on the severe side of the autism spectrum. 

Erin Spain, MS: So getting to those treatments includes the studying of the biology behind conditions, autism, schizophrenia. This is central to your work. And I do wanna talk about one thing, autism and schizophrenia. They're different. They're different disorders, but you have said there's a lot of genetic overlap. Can you tell me about this? 

Peter Penzes, PhD: Yeah. So this distinction actually has been going back and forth over the past century or so. So initially when the first cases of autism were reported, people conceptualized it as a form of childhood schizophrenia. And then as more and more patients were included it sort of became a disease on its own, but still a very heterogeneous disease. That's why it was called the autism spectrum disorder. And, over the past 15 years with these large genomic studies where people found that actually a lot of the genes that increase risk for autism also increased risk for schizophrenia and also bipolar disease and intellectual disability made people rethink this idea that actually there's a huge genetic overlap between autism, schizophrenia, bipolar disease, suggesting that there's some sort of basic form of altered brain development that could later diverge and become more similar to what we know today as autism, or more similar to what we know today as schizophrenia and so on. 

Erin Spain, MS: Very interesting. That brings us to your study, the new study published in Neuron. One of the key findings is this new biomarker for schizophrenia. This is something that you and your team have been searching for. Tell me about this discovery and what was that moment like when you realized this could be something significant? 

Peter Penzes, PhD: This is a great challenge because treatment and research in many other diseases like diabetes or heart disease has been really advanced thanks to biomarkers. So we all know about the blood sugar measurements, blood pressure and cholesterol, and these are basically biomarkers. They are correlates of what really is going on in our body. And unfortunately there is no such thing for psychiatry. So a lot of the diagnosis in psychiatry is, I would say, fairly subjective. Is based on a questionnaire. It's really not measuring accurately some biological function. And in this case a biomarker which would measure accurately some biological change in an objective way without subjective contribution, would be extremely useful for clinical trials, for finding the right treatment for the right patients, for following the treatment course and even for early diagnosis. And we think that this cerebrospinal fluid and potentially blood biomarker could be one of those. 

Erin Spain, MS: Why has it been so difficult to identify biomarkers for these type of psychiatric disorders? 

Peter Penzes, PhD: Most of what happens in psychiatry happens inside the brain, and the brain is very difficult to access in live people. Blood communicates with the heart and the organ. So if you probe the blood with an injection, you can get a chemical readout of what's happening. But we had to be a little bit tricky because in, similar way the cerebrospinal fluid, which is a fluid that surrounds the brain and then drains everything that the brain produces, can actually be probed in live humans. It's unpleasant, a spinal tap, but actually it can be done and it's done often and it can yield readout into the brain. So that's exactly what we found. We found some molecules breaking off the synapses, which are the connections between the brain cells. These small molecules break off and end up in the cerebrospinal fluid. And we can read them a few hours later. What we found is that when we compare the proteome or the collection of all these secreted proteins in the cerebrospinal fluid of normal control patients without a disease, and patients with schizophrenia, we find a few of these ectodomains or proteins that are cleaved and shed away from the brain in the cerebrospinal fluid, to be reduced in schizophrenia. And one of the proteins we followed up on, called Alpha2Delta-1, is one of those. 

Erin Spain, MS: So this protein, like you said, seems to play a role in how the brain circuits function, the signal is reduced. How does this play into the idea that it could possibly connect to cognitive symptoms that you see in subjects who have schizophrenia? 

Peter Penzes, PhD: We measure this molecule in the cerebrospinal fluid. But that is basically just the way the body gets rid of it. Its primary function is that each brain cell, when it's highly stimulated, when it's very active, sheds this molecule and this molecule diffuses to other brain cells. And it signals to other brain cells to quiet down. So this is sort of a switch. It's called a feedback switch in a neuronal circuit in the brain. So this is part of a normal mechanism of the brain to control its normal operating level. On the other hand in schizophrenia, some types of brain cells are overly active, but other brain cells are inactive, or not active enough. And that we think is caused by the reduced level of this switch molecule. 

Erin Spain, MS: This is important because there are treatments right now for some of the symptoms of schizophrenia, like hallucinations, but when it comes to some of these cognitive issues, there isn't a treatment right now. Why is that a problem? How does that affect these folks who have schizophrenia? 

Peter Penzes, PhD: Schizophrenia in general is characterized by three types of symptoms. The positive symptoms which include hallucinations, delusions, bizarre thoughts, can be controlled by medication today because these are caused by dysfunction of the dopaminergic system, which is one of the neurotransmitters in the brain. The current antipsychotic medications reduce the activity of these dopamine receptors. On the other hand, there are two other types of symptoms called cognitive symptoms , which involve problems thinking correctly, problems with memory recall, sociability, and social cognition. Or, negative symptoms, like, avoidance of everyday life, difficulties organizing thoughts, difficulties with executive function. These are not treated by any of the drugs on the market. But it turns out that while the antipsychotic work well, and they give the patients some comfort from their hallucinations and delusions, patients can still be very unfunctional in the society and not hold a job, not be able to run an organized structured life, because they still have their cognitive and negative symptoms. Our biomarker and the biological mechanism related to it, we think is closely related to these cognitive and negative symptoms. And the switch side, other side of the biomarker is that we think that by replacing this molecule into patients who have reduced levels of this biomarker, actually, it can act as a therapeutic and target specifically the circuits that underlie cognitive and negative symptoms in patients. 

Erin Spain, MS: Your team has actually developed a synthetic peptide version of this that you've even called something like an ozempic shot for schizophrenia. Is that right? 

Peter Penzes, PhD: That's right. The actual name we gave it was SEAD1. And the goal, coming hopefully sooner than later, is to develop an ozempic for schizophrenia. SEAD1 is a peptide, and we want to improve it. We want to make a smaller, longer lasting, more stable form of it. And we injected SEAD1 into a genetic mouse model of schizophrenia and it rescued exactly the cognitive and social deficits in these mice, which correspond to the cognitive and the negative symptoms in patients. We hope that we're gonna improve this molecule and make it stable and injectable just like ozempic. So we called it, ozempic for schizophrenia. 

Erin Spain, MS: What could something like this mean for people with schizophrenia? In theory, how could it change their lives? 

Peter Penzes, PhD: So it would be immensely useful because just in our society many of the people who are homeless have mental disorders, including schizophrenia. And, some of those problems actually stem directly from their inability to organize a regular life. Hold jobs, hold bank accounts. So we would see immediately an improvement in the lives of many people. And I would say that current medication has a lot of side effects, has to be taken regularly, several times a day. So that causes problems with a lot of patients who don't have an organized daily schedule. But let's say a once a week injection. You give it to yourself and you forget it for a week. So it could change the dynamics very much. You know, many patients with schizophrenia are underemployed and also depressed. Some commit suicide. So, this would be really a quality of life changing development for all of those. 

Erin Spain, MS: We often think of schizophrenia as something that happens in teenage years or young adults when it's diagnosed. Could there be a situation or example where if this mutation is found, this protein is found in a child that this peptide could be given in advance of there ever being a sign of schizophrenia occurring? 

Peter Penzes, PhD: Exactly, that would be the best because in these neurodevelopmental, even other chronic disorders, the earlier you intervene with a treatment the better the outcome is. If somebody has this genetic mutation, one could follow them clinically and that one of the earlier signs they could potentially start on this treatment and not ever develop schizophrenia. You're very right about that. 

Erin Spain, MS: It would probably bring a lot of hope to some families. I would think. 

Peter Penzes, PhD: Yes. And the other thing I wanted to point out about our biomarker is that we replicated this finding on several patient cohorts and we found the most robust difference, the strongest difference between controls and patients in a younger group of patients. So these are patients within five years from their first psychosis. So it shows that it's an even better biomarker for early stage schizophrenia. And I would like to point out that out of people who have one psychotic episode, only a fraction, go on to develop full-blown schizophrenia and others don't. So we would need to separate these two groups, those who are at real danger of developing schizophrenia and those who are likely to have a more positive outcome. So this biomarker may actually help us with that because it might identify exactly that group that is likely to move to schizophrenia within a few years, but also the subgroup that could actually benefit from this peptide treatment. 

Erin Spain, MS: To develop a research project like this and get it to the point where it is now, this is something that's often thought of as high risk, but high reward research. Tell me about how this was funded and how you were able to develop this project. 

Peter Penzes, PhD: So I have some endowment money, which is coming from one of these endowments that a private donor donated to the university. And I get a certain amount of that money each year for my lab. And it's exactly for these type of riskier projects. Then when we had some preliminary data, we applied to the Brain and Behavior Research Foundation, which is a fairly large private foundation that supports research related to brain disorders and in general to brain function. And now we published the paper and we hope to use now the paper and the preliminary data we generated to apply for a larger NIH grant. 

Erin Spain, MS: You have received some major NIH grants in the past, just a few years ago, a $17 million grant to work on this type of research in the autism space. Can you tell me about some of that other work that you're doing with the funding you received from the NIH? 

Peter Penzes, PhD: Yeah, so that is a large Sylvia County Center. It was established by a US Senator Sylvia County and each year two centers are funded throughout the country. And last year we were one of them. And this funding brings together several laboratories. So in this case, seven laboratories that cooperate in an extremely, complex and multilevel research. So we are studying several genes that are very important for the biology of both autism and schizophrenia. So again, we're focusing on this biological and genetic overlap between autism, schizophrenia, and in the proposal we want to understand how these genes work at multiple organizational levels. So at the level of the single molecule, like how is that molecular machine working? How is it turning, how is it doing its job? And then within brain cells and then within brain circuits. How does it help brain cells connect and communicate with each other? Brains develop. And then at the level of behavior, how does this gene affect normal behavior and also how disease associated mutations in these genes cause disease, clinical features. And the second part of this is to model mutations in this gene using these mini brains or brain organoids that are generated from patients' blood cells and then developed into tiny little microscopic brains in a dish that can replicate some of the biology of the patient. So you can do experiments on them outside of the body of the patient. And yet the third angle of this is to develop small molecule pharmacological compounds drug-like molecules, drug candidates that could correct the function of these molecules in patients. So those could be developed in new drugs for schizophrenia and Autism. 

Erin Spain, MS: With all of this work that you're doing, and especially with this recent discovery, what gives you hope for the future for these families and patients who have loved ones with schizophrenia, autism, and other types of disorders and diseases? 

Peter Penzes, PhD: So my hope is that, built on the research and the big scientific developments in our fields and outside, over the past 10, 15 years, we are really at a position when I see some of the newest breakthroughs being really within reach. So I understand that the timescale of patients and families is a lot shorter than the timescale and perception of time of scientists. Scientists understand that these experiments take a long time. They work sometimes and they don't work many times. It's a long and sometimes challenging road.  I totally understand that the patients are looking for treatments as soon as possible, and we are actually trying very hard to deliver them as soon as possible. But I would like to be cautious in saying that, development of a new drug, especially a drug that can be used in clinic takes sometimes longer than we hope, just because it's a very challenging process and it has a lot of unexpected twists. 

Erin Spain, MS: I wanna go back to that moment where you're like, whoa, we found something here. You're like, Eureka. Can you just take me back to that moment though? What's that like for you and your team when you're able to say, wow, we have something here that hasn't been discovered before? 

Peter Penzes, PhD: It's exciting. That's our drug basically. I could say that making a discovery gives you the same dopamine kick in your brain as any other as playing in a casino or doing bungee jumping or any of these high dopamine activities. Because it's really something that you work on for very long, and it's frustrating because sometimes it doesn't work out as you expect. And when it finally works and all stars or planets line up and it just glows, it just shines. And then you can see immediately it's an immediate reward, but you also realize the implications. So if this was true, then you know, we could do this, we could do that, we could do that. So it's almost like it's an end, but it's also an even bigger beginning of a new step, a new range of projects that you can pursue after you make a discovery.  The research that led to the discovery of this biomarker and potential therapeutic has also uncovered several dozen other similar molecules that are present in the cerebral spinal fluid, come from the brain, are changed in patients and potentially have a biological function. So we started studying some of them and our idea, our goal is, to use this template of biomarker and associated therapeutic strategy for as many of those as possible. And it might be that they may be useful for different subtypes of schizophrenia, different subtypes of autism, or maybe bipolar disease or other conditions. So this is really our grand plan. 

Erin Spain, MS: Just the beginning in a lot of ways. 

Peter Penzes, PhD: Exactly. 

Erin Spain, MS: Well, thank you so much, Dr. Peter Penzes, for coming back to the podcast sharing this incredible new research and an update on the field itself. We really appreciate your time. 

Peter Penzes, PhD: It was my pleasure. Thank you. 

Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media @NUFeinbergMed to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

Accreditation Statement

The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Credit Designation Statement

The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

Successful completion of this CME activity enables the learner to earn credit toward the CME requirement(s) of the American Board of Surgery’s Continuous Certification program. It is the CME activity provider's responsibility to submit learner completion information to ACCME for the purpose of granting ABS credit.

Disclosure Statement

Peter Penzes, PhD, has nothing to disclose. Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.