Understanding the Biology of Autism

Erin Spain: This is Breakthroughs podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, editor of the Breakthroughs newsletter. Today we're talking about the topic of autism spectrum disorder. One in 68 children has some form of autism spectrum disorder. The number of cases has spiked in recent years. The new Center for Autism and Neurodevelopment at Feinberg is focused on understanding the biological basis of autism, unrelated neurodevelopment disorders, and using this knowledge to develop treatments.

Peter Penzes: My name is Peter Penzes, says I'm a professor at Northwestern University and I'm the director of the Northwestern Center for Autism and Neurodevelopment.

Erin Spain: Thank you so much for joining me. So if you could give me a little background about yourself. Where did you study and how did you find your way to Northwestern?

Peter Penzes: Yeah, so I grew up in Romania, in Transylvania, and I studied biochemistry there and then I came to the U.S. to do my PhD also in biochemistry. Then I continued to study neuroscience because it was a very fascinating field to me and within neuroscience I studied synopsis, which are the connections between brain cells. Fifteen years ago I got an offer at Northwestern and I joined the faculty here and I became an assistant professor and I've been here at Northwestern since 2003.

Erin Spain: Can you talk a little bit about some of the struggles that people face who are diagnosed with autism?

Peter Penzes: Yes. So, autism as a condition comes very often associated with other problems such as seizures, epilepsy, intellectual disability, which is present in about 50 percent or 70 percent of children with autism, gastrointestinal symptoms, aggression, difficulty to eat, difficulty to sleep, many other problems that are behavioral but not only behavioral that make the care for these children very, very difficult.

Erin Spain: So, this brand-new Center for Autism and Neurodevelopment here at Feinberg is focused on, like you said, understanding the biological basis of autism and other neurodevelopment disorders and then developing new treatments. So how has basic science crucial to understanding and treating autism?

Peter Penzes: One of the main goals of the center is to understand what the normal functions of these genes that have been implicated in autism are in the brain and what mutations in these genes do the brain circuits during development. And what we learned is that not all this genetic risk is inherited, many are the called de novo mutations which occur in the parent and are transmitted to the child. We also learned that probably hundreds or maybe even thousands of genes contribute to autism, but they contribute in a very complicated way. Some of these genes, when the have some severe mutations, they cause autism in those specific patients. But these are rare mutations and they might cause they might cause autism in a handful of patients. On the other hand of the genetic spectrum are so called common variants which have a very small affect size. So they only increased risk of autism by 20 percent. But when many of these line up that may lead to autism and in the middle of other types of variations called  number variations in which several genes are deleted or duplicated. And those types of mutation increased risk of autism by 10 or 20 fold.

Erin Spain: So, this is something that people who are diagnosed with autism or parents of children who were diagnosed maybe interested in knowing more. Do you talk to parents? Sometimes they want to know more about sort of that basic science, the genetic information about what has caused autism and me or my child?

Peter Penzes: We actually want this to be one of the main goals of the Autism Center at Northwestern. We want to educate the public about what the different genetic mutations mean what they, how they can be used to inform treatments and also we use. We would like to use this information to develop better treatments that are more suited to individual patient.

Erin Spain: So, the personalized medicine approach is something that is a dream for you when it comes to treating autism someday.

Peter Penzes: Yes, exactly. Because autism is a spectrum disorder, which actually means that no two children with autism are alike, so their genetic mutations that are environmental contribution are all different. So clinical trials and development of new drugs for autism have been really made difficult because of this heterogeneity. So one approach that has been used in some other diseases in the past is to group patients these done mutations as opposed to symptoms, and when you group them based on mutations you can develop or repurpose known drugs that treat that specific gene or mutation, not the symptoms. So, this is what we, one of the goals of the center is still identify patients that have mutations in a specific genetic pathway, group them into a study, a so-called basket trial, and the try to repurpose drugs from other diseases or to develop new drugs for these subgroups of patients.

Erin Spain: Right now, when someone is diagnosed with autism, are they given a genetic test? Do they know which mutations they have of certain genes?

Peter Penzes: There is not sequencing, (of) the DNA of each patient, it is not part of the current standard of care in autism, but it is, for example, for pediatric epilepsies. So, one of the goals of the center is to expand this and include all autistic children that are seen at Northwestern in the sequencing program and that will help us first group patients based on these genetic sub groups, and will help us guide individualized treatments for these children.

Erin Spain: So, you said one of the major goals of the center is to help develop treatments using existing drugs to treat autism. How far away are we from clinical trials for treatments for autism and related diseases?

Peter Penzes: In fact, there are several hundred clinical trials going on right now. Mostly from academic centers. Most of those trials are based on a repurposing existing drugs. But there are many difficulties with these type of trials. And often they fail because of the genetic heterogeneity of autism. Some patients could respond very well to a drug, but other patients don't because they have a different genetic makeup. So when you mix them all together, it looks like the drug is not working. So what we would like to do is start from the genetics, it's called genetics first approach, not from the symptoms. And based on that group patients based on their genetic mutations and knowing, understanding better these functional pathways that are affected in the patients, we could use existing drugs that target that specific pathway.

Erin Spain: Right now, what, what are parents to do our caretakers to do for someone diagnosed with autism? What sort of the treatment? Right now,

Peter Penzes: The current treatment on one hand addresses some of these comorbidities. For example, epilepsy or aggression or depression, anxiety sometimes with medication. On the other hand, there are psychosocial interventions which seemed fairly effective, but there are extremely work intensive and may require full time specialists to work one-on-one with a child.

Erin Spain: You mentioned that there's genetic mutations and genes that contribute to autism and there's also some environmental factors. Can you talk a little bit about that? There's a lot out there in the media and social media about autism and environment. What do we know?

Peter Penzes: Certainly, environmental conditions are thought to contribute to autism, for example, a maternal infection during pregnancy or a specific medications taken by the mother during pregnancy or drugs or chemical exposures, increase risk for autism. There has been a lot of hype and scare about vaccines causing autism. But, I would like to emphasize that has been shown repeatedly not to be the case. So, it is now very clear that vaccines do not cause autism.

Erin Spain: When you talk about that autism is genetic or highly genetic, what'd you say? Seventy to 90 percent. But a lot of this is the de novo a first, the first time, they didn't inherit it from their parents, is that correct?

Peter Penzes: Yes. In many cases the mutations occur in the germ line cells of the parents in particular in fathers. Uh, so, uh, it has been shown that all their fathers have a higher risk of having such mutations. So, autism has actually been associated with an older age of the father, not the mother. So that means that mutations can occur in the sperm and be transmitted the children. So it's a genetic mutation, but it's not inherited through manage generations.

Erin Spain: Very interesting. And boys are oftentimes diagnosed with autism disorder more often than girls. Why is that?

Peter Penzes: Yes. It's not very clear why, but the ratio seems to be four to one boys to girls. I'm the reasons might be complicated. There have been suggested that girls are maybe under-diagnosed. So I'm maybe more girls who have autism than that are currently diagnosed. Also, when you include other factors in the diagnosis such as intellectual disability, the ratio could change to two to one.

Erin Spain: So, the center is brand new. You have about 25 members so far. What are some of the different projects that are taking place at the center right now?

Peter Penzes: There are several interesting lines of research, several labs are studying so-called mouse models of autism. So, in mice we can study brain circuits because we can do experiments on them. So, we make these mutated genetic mutations in mice which replicates the mutations that happen in patients, in human patients with autism. And then we can study these mice and what we learned from the mice, we extrapolate to patients so we better understand what's going on in their brains. So, several labs in the center are involved in studying these so called autism mouse models. Other laboratories are studying human brain cells that are grown in a dish. This is a new technology that is very revolutionary and it allows scientists to study brain cells from the actual patient. And the way this is done is  from a blood sample, blood cells, can be made into brain cells in special conditions in a dish, and then we can study these cells, that model that replicates the brain cells of the patient. So these cells have a specific mutation that the patient carries and these cells can be used to understand specifically the disease of that patient or that patient group and could also be used to develop drugs specifically tailored for that patient group.

Erin Spain: There's also this overlap between autism and epilepsy that you mentioned before. You have people in the center who are really looking closely at this. Tell me about that.

Peter Penzes: Yes, that is a major focus of the center because about 30 to 50 percent of children with autism also have seizures or epilepsy. And at Northwestern there is a very strong group of epilepsy scientists and clinicians and many of the patients they see for epilepsy actually turn out to also have autism. Many genes that cause epilepsy also cause autism and vice versa. So, we think that by understanding the genetic and neuro biological causes of this childhood epilepsy, we can also understand the biology of autism and by potentially repurposing drugs that treat ion channel dysfunction or seizures, we could potentially address the behavioral symptoms of children with autism.

Erin Spain: While the goal of the center is really basic science and how you can use basic science to understand autism and hopefully one day create treatments. You're also teaming up with organizations such as Autism Speaks for seminar series. Tell me a little bit about the relationship between the center and an outreach group like Autism Speaks. Why is it important to have these relationships with outside groups and what are some of the activities do you have planned?

Peter Penzes: Yeah, so we are running a seminar series about once a month to which we invited world renowned scientists in the field of autism and we will make these seminars public so the public is invited to attend and the goal is really to keep everybody up to date with the newest developments in autism and we have these seminars will be followed by receptions, where interested families could meet, in person, the members of the autism center and also the speakers. We also teamed up with autism speaks and we'll have an Autism Speaks town hall meeting at Northwestern and those town hall meetings organized several times a year and the offer the opportunity again, the families of patients with autism to learn about new standards of care and be in touch with the community of parents and the whole country. We will have the director of Autism Speaks as one of the guests in our center and he will give a public talk sometime in April.

Erin Spain: You can learn more about Dr. Penzes research and read the full article online at Feinberg.northwestern.edu/breakthroughs. I'm Erin Spain, editor of the Breakthroughs newsletter. Thanks for listening.

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 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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. Feinberg School of Medicine's CME Leadership and Staff have nothing to disclose: Clara J. Schroedl, MD, Medical Director of CME, Sheryl Corey, Manager of CME, Jennifer Banys, Senior Program Administrator, Allison McCollum, Senior Program Coordinator, and Rhea Alexis Banks, Administrative Assistant 2.

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