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Today on The Fundamentals is Dr. Maria Castro, the R.C. Schneider collegiate professor of neurosurgery, and a professor of cell and developmental biology at the University of Michigan Medical School. Her research program aims to develop immunotherapies for primary and metastatic brain cancer, studying basic immune biology mechanisms leading to clinical implementation. She has been inducted into the American Association for the Advancement of Sciences, the Latin American Academy of Sciences, and the American Institute for Medical and Biological Engineering College of Fellows. She has won numerous awards for her contributions to basic science and cancer research and is a diversity ambassador for the Cancer Biology Graduate Training Program.

Learn more about Dr. Castro, and you can follow her @castro2355_mg, the Rogel Cancer Center @UMRogelCancer, and the department of neurosurgery @umichneuro, Michigan Neuroscience Institute and @UM_MNI 

Resources

• Find out more about the research stories mentioned at the top of the show at the links below:
  • Gene therapy for brain tumor shows promising early results in humans
    The first human trial combining drug therapy and immunotherapy showed improved survival for glioma patients
  • Two genes linked to autism implicated in brain cell connectivity
    Discovery potentially reveals mechanism behind brain changes in people with autism
• You can learn more about The Fundamentals on our website.
• Learn more about other exciting research happening at the University of Michigan, by checking out Health Lab, Michigan Medicine's daily online publication featuring news and stories about the future of healthcare.

Transcript

Kelly Malcom:

Welcome to The Fundamentals, a podcast focused on the incredible research and researchers at Michigan Medicine. I'm your host, Kelly Malcolm.

Jordan Goebig:

And I'm Jordan Goebig. And today we'll be diving into cancer research. This is the first time we'll be covering this topic on the podcast, and we're fortunate to have a prolific scientist joining us to talk both fundamentals and big picture about their research, the field, and clinical translation.

Before we get started, I wanted to tease a recent study that our guest led that has gained international attention. The University of Michigan Rogel Cancer Center researchers led the first human trial combining drug therapy and immunotherapy that showed improved survival for glioma patients.

Kelly Malcom:

And in other brain-related news. A recent U of M study links two autism-associated genes together for the very first time, potentially revealing a mechanism behind brain changes seen in people with autism.

Jordan Goebig:

We'll provide links to the full articles and info about our featured guest in the show notes. Now let's meet our guest.

Kelly Malcom:

Today's guest is Dr. Maria Castro. Dr. Castro is the R.C. Schneider collegiate professor of neurosurgery, and a professor of cell and developmental biology at the University of Michigan Medical School. Her research program aims to develop immunotherapies for primary and metastatic brain cancer, studying basic immune biology mechanisms leading to clinical implementation. She has been inducted into the American Association for the Advancement of Sciences, the Latin American Academy of Sciences, and the American Institute for Medical and Biological Engineering College of Fellows. She has won numerous awards for her contributions to basic science and cancer research and is a diversity ambassador for the Cancer Biology Graduate Training Program.

Dr. Castro, we are delighted to have you with us today.

Dr. Maria Castro:

Thank you so much.

Jordan Goebig:

Yeah, welcome to the podcast. Thank you so much for spending your day with us. So we're going to dive right in and hopefully start with a little bit of a question to get to know you. I'd love to hear more about your journey, how you came to Michigan and what led to your interest in brain cancer research. You're the first cancer scientist we have today, so I'm looking forward to this.

Dr. Maria Castro:

Delighted to be here. Thank you so much. So I grew up in Argentina and I trained there. So I went to college and I did my graduate work there. At the end of my graduate work, I knew that I wanted to expand my horizons and train abroad. So my supervisor mentioned and suggested that I come to the National Institutes of Health in Bethesda, Maryland. And that's how my scientific journey outside of Argentina started.

The reason why my work now relates to brain cancer, that's not how it started. It started more in relation as to how the endocrine system works and how hormones modulate the functions of the body. And slowly, slowly, I became interested in neuroscience when I was at the National Institutes of Health, at NIH. And then when I started my own lab, there was a goal for a grant support.

And of course I started my own lab in England and you end up with an empty room and nothing in it. So I had to get some money to start working, and hire people, and fill the lab with reagents, and chemicals, and plastic work to the research. And this goal seemed appealing to me because it bridged my knowledge in neuroscience and biochemistry. And it happened to be that they wanted to increase the number of people working on brain cancer. At that time, the field was very sparse and there were not a lot of people working in it. Because it's not a huge cancer in terms of the numbers of patients it affects every year as opposed to breast and prostate where you have thousands of people that die every year of a prostate, breast, or lung cancer.

Brain cancer effects in the United States, 25,000 people. So it's a smaller target population, but they did want to increase the number of people doing research because it's a deadly disease. Everybody dies from the highly aggressive cancers. So they were promoting younger investigators and I applied for my first grant and I got it. And the rest is history because I became really interested in how brain cancers grow and how do they evade the immune system. And because they grow in the brain, I had a lot of training and experience in neuroscience. That's how I got started and I never looked back.

Kelly Malcom:

Wow, that's pretty amazing. We didn't have a question about this, but just from reading a bit about you and your history. And reading some of the stories written about you in the Health Lab blog, I know that you have a close relationship with your lab partner right now. And I'd love to hear about how that came to be, how you met and how that relationship started and now you're working together.

Dr. Maria Castro:

So that was another interesting story. So I came to the NIH. When you emigrate, you're kind of lonely and I was single. So my roommate, her name is Stella, was also a neuroscientist. And she said, "You should call him. There's no point in being lonely." So I hesitated and for a month I think I was, "Oh, should I call him?" One day I said, "That's it. I can't keep being lonely here." So I called him and he happened to answer the phone and we talked for an hour. I said, "Oh my gosh, there's a lot to talk about with this person."

And then he said, "In two weeks, I have a birthday party of a friend at NIH. So if you want, I can come and pick you up from your lab, and I can ask him if you can come." And they said yes. And yeah, we hit it off very quickly. I think it's interesting because sometimes the more you look, the less you find. And serendipity just brought us together.

Kelly Malcom:

Right.

Jordan Goebig:

Yes.

Kelly Malcom:

We stayed together ever since. So first we became good friends, but then we had a lot in common. He's also a neuroscientist, but he was working at Johns Hopkins, and it's very close so we could meet over the weekends. Our relationship developed over time. So we've been together 30 years.

Yeah, that's amazing. I love that story so much. And my husband and I had the same commute. He was at Johns Hopkins and I was working in D.C., so that's so funny. So I know you study brain cancer. Brain cancer, like you said, is not one of the most common cancers, but it definitely is one that scares people. I mean, it's deadly. And can you explain for folks, what is really happening at the fundamental level when brain cancer develops?

Dr. Maria Castro:

Sure.

Kelly Malcom:

Where does it come from?

Dr. Maria Castro:

So the origins are not well known and a lot of people are doing research on it. Essentially what happens is that some cells in the brain become cancerous and they start dividing without any breaks in their speed and they create a mass. That is what really impacts the physiology of the brain. What happens is that usually the patients develop neurological symptoms like they can't button their shirt, or they become wobbly in their movements, or you're eating soup and suddenly you can't bring the spoon to your mouth. So essentially they're neurological symptoms and the patients come to consult their doctors. Usually they either go to the primary care physician because they're not feeling well. Also, they may have psychological symptoms, they change their mood. And then they get referred to a neurologist that may do an MRI, or a scan, and that's where the tumor mass is discovered.

Then they undergo surgery, chemotherapy, and radiation therapy. It's all very quickly because you have to act fast, but for these tumors, there is no cure. So essentially you prolong their survival, but you can't cure these cancers. Unlike other cancers where if you catch them quickly, they're curable. Like breast cancer, or colon cancer, or melanoma for which there are very accurate early diagnostic systems. For example, in colon cancer, a colonoscopy can detect a polyp. That polyp can be very easily removed and the patient is cured, will never develop a colon cancer. The same with breast. A nodule is detected a via the mammogram. That nodule can be removed or treated. And again, the patient has a very, very good prognosis.

And the same for melanoma because they're skin diseases, skin cancers, and they can be easily seen. So if you go to the doctor and removes the melanoma on time early on before it becomes infiltrative, then again patient has very good prognosis.

For brain cancer because there are no early diagnostic systems available, when the patient comes to the doctor, the cancer is already very advanced. So these tumors are not curable essentially. They're very deadly. And for a high-grade glioma in an adult patient, the median survival now is between 18 to 24 months. So it's really a huge need to develop new treatments.

Jordan Goebig:

Could you talk a bit about how your lab specifically is using the human body to develop cancer therapeutics?

Dr. Maria Castro:

Sure. So our lab, we believe that the immune system is going to be a great ally in our fight to get better treatments for this cancers. And the reason for that is because the brain cancer grows in the brain, and the brain has a bony surrounding, so it can't stretch. Unlike in other places of the body where there's room for a little expansion. So in the brain, that's why they're so deadly and that's why they kill the patient so quickly because you have a mass effect. The neurosurgeons can remove the tumors very efficiently, not always. Because it depends on which area of the brain these tumors grow. So sometimes they can't remove it all.

And also now it's believed that the brain cancers are systemic brain diseases because there are cells that have escaped the main tumor mass and they have invaded the rest of the brain. The surgeon can't see them because they may be single cells or small groups of cells. So the only cells that have the capacity of seeing and killing those lonely cells that have escaped the main tumor mass are the cells of the immune system. So we believe that we have to train the immune system to be able to act like the sentinels of the body, find the tumor cells and kill them. And we believe that training the immune system to do that is what's going to give us the breakthrough in these cancers and allow us to develop better treatments and longer survivals.

Kelly Malcom:

That's amazing. Because I was going to ask you, how do you even begin to start to know how to address this type of tumor? Because it's in your head.

Dr. Maria Castro:

Sure.

Kelly Malcom:

You can't see it. So yeah, I never really thought about the connection to the immune system. But my question is about how do you stay motivated when it takes such a long time to bring something from looking at cells at the cellular level and then taking it to a therapy?

Dr. Maria Castro:

That's an interesting question because science has a lot of, in a way, you fail a lot, has a lot of failure and also has a lot of uncertainties. So you have to be very resilient and really have a big belief in what you're doing and in yourself to keep going. Without that, there's no one and there's nothing that can do it for you. It has to be inside you.

In my case, because I see the big picture and I see the need, so these patients are really very inspiring to me because those are the people that will not give up. So I think if they don't give up, how can I give up?

And also I get inspired by the students because the students are the future, our future, and I see them. That's why I love to teach and I love to engage with younger people because they're in awe of everything. Their enthusiasm is contagious, and I think they benefit from my knowledge, and I benefit from their energy, and their passion, and their hope. So those two things, the patients and the students, the postdocs that people that work with me, and also I love the process of discovering new things.

Kelly Malcom:

So your career has spanned decades at this point, and you are a living legend in this field. What are some of the fundamental changes that you've seen as maybe a woman in science. And over the years, what has changed about the process of discovery or doing science, especially as a woman?

Dr. Maria Castro:

So I think in terms of the process of science itself, it's remained pretty. You can go back to Darwin, to Galileo. It's the ore of discovery, the scientific method. So that has remained the same process. The same, you need to be imaginative, you need to be creative. You need to believe in what you're doing. You need to be passionate about what you do because it's like the arts, writing, it's a very special type of job because it's a creative job. So you can't be in the supermarket. Yeah, I go to the supermarket and I buy my things, but I'm always thinking about, it always comes back. So that's why I find it very interesting, I find a lot of analogy with people that write, or people that do arts, sculptures, painters, dancers, movie makers. You carry it with you. It is very difficult to not do that. That's why you have to love it. And there's many ways of doing science.

So I create and I develop projects. There's people that may decide that they don't want that. They just want to work at the bench, and that's fantastic, and they want to have their nine-to-five job, and that's a fantastic area. I think the key is to figure out, you have to be in tune with what you do. I couldn't work as a bank teller, but bank tellers are critical for life. And that's what I tell the people that come to work with me. You need to find out what moves you and what's your life philosophy. And then you have to find a job that is in tune with that because otherwise you're not going to find happiness either in your life or in your job. So that's the way I approach science, and that's the way I've always approached it.

It's very interesting the role of women in science. When I started, I started with a woman that was my boss as a postdoc at NIH. And the last day I remember she told me, I don't know how I might have been looking at her. She said, "Maria, I know you might be asking yourself why I am the way I am." And I said, "Yes, since you said it." And she said, "Because I'm petite, I'm Chinese, I'm a foreigner and I'm a woman, and I have to survive in science." And she was really nice, a very nice person, but she was stern and a little bit removed, and dressed in a very nonfeminine way. I said to myself, "I don't want to be like that because that's not who I am." So that's really, as a woman, you need to find your role models who made it that you aspire to be like. I couldn't find anyone really. Very, very hard.

I have an anecdote here. In one of the corridors of the medical school, I was walking around and back from a lecture. And this girl runs to me and approaches me and she says, "I would like to ask you to be my mentor." I said, "Oh, well." In the corridor out of the blue, I didn't know the person. And I said, "Why? Why me?" And she said, "Well, because you're a mother and you have a kid. And you're successful in science, and you dress like a woman. I would like to have you as my role model." I said, "Oh, that's a huge compliment." I said, "Yes." And the good side of that story is that that girl came from the farms in the North. She had no one to talk to and she flourished. She got a 4.0 GPA from here, then went to do her PhD, Harvard Medical School. She's now a postdoc at Berkeley, and now she's applying for assistant professorships here. And she keeps in touch with me. Every time she comes to Michigan, she comes to visit. So I think we walked a long road.

But lately what has really changed the playing field is social media. And why has it changed the playing field? Because I feel social media is an equalizer. You don't need any big person to allow you to post anything on social media. So if you are intelligent and if you do good work, you put it out there and the world can decide how good you are. I think that's phenomenal. That gives a lot of power back to the individual, and I really, really like it.

Kelly Malcom:

Yeah, we've had some other guests in here who have really leaned into that power of social media, and it's been really neat to hear about their experiences, and going through the pandemic and still being able to connect with other scientists on social platforms. And find community, and jobs, and papers that they never would've found if they didn't get on social media. So it's really neat to hear that and to hear the importance of just scientists shouldn't just fit into a box. Right?

Dr. Maria Castro:

Exactly.

Kelly Malcom:

You're all humans too.

Dr. Maria Castro:

Sure.

Jordan Goebig:

I have a young daughter and actually interacted with a professional in another setting, and they were dressed pretty cool, I thought. But they apologized for their attire. They're like, "Sorry, I don't normally look like this. It's just fashion Fridays at work." Which I go, "No, don't apologize. I want my kid to walk out in the world and see all people who look like all types of people succeeding in all types of ways."

Dr. Maria Castro:

Sure.

Kelly Malcom:

Because why not? They should. You should feel like you can be [inaudible 00:19:06].

Dr. Maria Castro:

I think you have to be yourself. And being a mother in science and in academia, I also found it very hard because you have to look the part. I said, "I've always been a rebel." I have. When I see something that doesn't fit with what I think works for me, then I do something else. The fact that, oh no, you can't speak about your kid at work, you can't bring, I always brought my kid at work. I mean, he was out of school, he would do his homework in my office. He's part of it. I think it was great fun to tell him what I worked on, and he was a big part of my journey as a scientist. So I'm very grateful to him as well.

Jordan Goebig:

Yeah, that's beautiful.

Kelly Malcom:

Yeah, it's amazing because Jordan and I both have little kids. I mean, representation is just important across the board as a woman, as a mother, as an immigrant. I mean, it's just important to be able to see yourself in the role that you want. I think you probably played that role for a lot of people.

So I know when we talked to you earlier, you noted that you were involved in DEI work before it was called that.

Dr. Maria Castro:

Sure.

Kelly Malcom:

We talked a little bit about what it's like to be a woman. But what are some of the challenges that you face personally or been a witness to when it comes to diversifying the research workforce?

Dr. Maria Castro:

Sure. Yeah, I think that's a very important question because it's a huge need. I think you know DEI work is very important work. But what I think it's missing, and I've been doing DEI work since I arrived in the U.S., first with Amnesty International. When I joined the University of Michigan there is this organization called Women of Color in the Academy Project, WOCAP. And the role of WOCAP is to increase representation, increase promotion, retention of women of color in the academy.

And what we've noticed is that there are no bridges. So there are different islands of people working on different areas of diversity, equity, and inclusion, but we don't get to know each other. At one point we had that exercise that we had to do, which is okay. Invite a friend of a different ethnic denomination for a movie, coffee, a colleague, go for lunch. And it was so hard. I mean, the exercise was so hard.

So we're always talking and preaching to the converted. People that go to DEI activities are people that are already enrolled, they're already very aware of what's going on. And we don't talk to the people that don't think like that. We should create more spaces where there are more conversations so that things are more... Because it's a matter of getting to know the other person. So the main challenges that I faced in academia is I feel that people are always looking with a magnifying glass at what I do. Am I doing it right or am I doing it wrong? It feels tiring after a while to have to show that you're good at what you do, whatever that is, mentoring, science, lecturing. It's tiring. I think it's because of this what's called unconscious bias that we all have.

I don't know if you heard about this MD from New York that resigned to her job and became a writer and an advocacy for Black African American medical doctors. And she wrote a book that appeared this week, I think the name of the book is Legacy. And she tells the story of patients walking into the ER room and not wanting her to treat them, wanting the white doctor to. So it's not that the patient is mean, it's just that they don't know that an African American doctor can be equally good or better than a Caucasian doctor. And the same for Latin American.

It's a huge amount of work that we need to do and we need to do it together. So we still have a long way to go. I think we've improved in many areas, but in many other areas we haven't. My take on that is because we don't sit at the table and talk. And when I've had encounters with people that we didn't see eye to eye, and we sat at the table and talked, we even became friends. So it means that within a conversation, magic can happen, but we need those conversations. We need many more of those conversations.

Kelly Malcom:

Absolutely. Yeah. It all comes down to communication and just connecting on a human level.

Dr. Maria Castro:

Sure.

Kelly Malcom:

We are really not that different from each other.

Dr. Maria Castro:

Yeah, exactly.

Jordan Goebig:

Yeah, and you're totally right. I'm working on a social media campaign and I'm meeting so many people that I would not have without it. A lot of PhD. I'm working with PhD and MD students, and it definitely is making me realize that no matter how big I think I'm making my world, it's still really small and I still have a lot of people to meet and things to learn. So thank you for saying that.

Before we let you go, I do want to get back to what you're working on though.

Dr. Maria Castro:

Sure.

Jordan Goebig:

I know just via social media, a recent study that you and your lab partner worked on together with human clinical trials has gained quite wide recognition. Like I said, it came to me first via social media, even though it was published at Michigan. So I'd love to hear about that and what projects you're working on, and what collaborators you work with.

Dr. Maria Castro:

Sure. So that is a very long term project. It was between me and my husband, Pedro Lowenstein. We also co-lead the lab. So he has his group of people. I have my group, but we work together very seamlessly and very collaboratively. So that started when we were in England. So our main scientific career started in the U.S. Then we went to England. We were in England for 10 years. Then we came back to the U.S. We were recruited by UCLA. And at the time we were at UCLA, we were there 10 years, and Cedars-Sinai Medical Center. The clinical trial was about to be started, and Michigan became interested in it. So we got recruited to the University of Michigan to start that clinical trial here. It was really a phenomenal undertaking. There were many departments that collaborated, so I'll explain what the therapy is all about.

So we developed a gene therapy strategy that trains the immune system to recognize the cancer cells and attack the cancer, and eliminate it. So that was the theory. We call it gene therapy. It's because we use two genes, which is genetic material that is used as therapeutics, and the carriers or the delivery vehicles for these therapies are viruses. Our viruses are now en vogue and everybody talks about COVID. So virus is something that we all have at the back of our mind. So what we do is we take all the genes from the virus that can cause disease, and we replace them by these therapeutic genes. So the viruses are super safe. And not only safe, they will also elicit a therapy that will eradicate the brain cancer. So of course, that takes many years to develop.

We did all the basic science, all the science that tells you that yes, the therapy can train the T cells. The T cells are the killer cells, the immune cells that kill and attack foreign invaders in the body. So in this case it will be the cancer.

And then the FDA gave us the approval to start clinical trials. So the clinical trials started here and we treated 18 patients, and it was published late last year. So now that's going to be the spring. Very good results. So we saw the T cells going into the brain, into the tumor cavity, some patients lived over three years, another patient lived over five years. The results are really encouraging. So that's now going to be the springboard to do other trials. Now we are planning one with Harvard, and with UCLA, and with UC Irvine, and us to increase the number of patients. And then we're planning several. We're planning another trial to treat kids. Kids can also have these high grade deadly gliomas, and that's going to be done here at the University of Michigan.

So that trial is going to be the springboard to do many more trials, more advanced trials, combination trials, and we're very excited about it.

Jordan Goebig:

Yeah, that's amazing. That's really exciting. I also would love... You said you've been to a couple of different universities throughout your career and institutions. Could you talk a little bit about how the University of Michigan has really supported your research in this progress?

Dr. Maria Castro:

Sure. That's why we came here because we feel the University of Michigan is a highly collaborative place. And to do this trial, we had 31 authors, people from neurology, it's the neuro-oncologists, then radiation oncology, radiation, neurosurgery, neuropathology, statistics. So you need a lot of departments and a lot of people that can work seamlessly together, not only on the trial, but on the care of the patients. So you have the nurses, and all the physician assistants. It's a huge undertaking. I think Michigan is the best place where we could have aspired to do it because of the collaborative nature of the people that are parts of the different teams.

The trial was funded by a foundation in California called the PHASE ONE Foundation that specifically funds phase I clinical trials in cancer. But then we needed a little more money to complete some of the studies. And the Rogel Cancer Center contributed financially as well, and our department as well. All the neurosurgeons and other physicians donated their time to do it. So it was an incredible undertaken and we couldn't have done it if we would not have been at the University of Michigan. It was really a phenomenal environment to do this phase I trial. So we're very proud of.

Kelly Malcom:

Yeah, that's wonderful. And that's something we hear all the time is how collaborative U of M is. And we're just really blessed to be in an environment like this with amazing scientists like yourself who are willing to work together to tackle these really hard problems. And so I'm excited to see what comes of all this work.

Dr. Maria Castro:

Sure.

Kelly Malcom:

And we just want to thank you for taking the time to tell us your story and to talk to us. And this has been really, really intriguing and wonderful to have you on the show.

Dr. Maria Castro:

Thank you so much. It was great fun. Thank you.

Jordan Goebig:

Yes, thank you. We appreciate your time. This was super interesting. I am really looking forward to diving into these topics more.

Dr. Maria Castro:

Sure.

Kelly Malcom:

The Fundamentals is produced by the Michigan Medicine Department of Communication in partnership with the University of Michigan Medical School. Find us and subscribe, wherever you listen to podcasts.