Neurological research extending the frontiers of scientific knowledge

Neurological diseases are disorders that affect the brain and the nervous system, and include Parkinson’s disease, dementia, and Alzheimer's disease. As researchers work diligently, the goal of better understanding these diseases and appropriate treatment becomes paramount. Trained physician and scientist Dr. Lalitha Madhavan is an Associate Professor of Neurology, and also a member of the Evelyn F Mcknight Brain Institute and BIO5 Institute at the University of Arizona.  Her research merges the fields of Neuroscience and Stem Cell Biology to understand how the brain works and contribute towards the development of treatments for disorders such as Parkinson’s disease.

I would love to hear more about your background and how you became a physician researcher, which is incredibly noble and difficult, and there's not a lot of people that manage to do one or the other, much less both, and merge them into a successful career. Could you talk a little bit about going to medical school and being raised in India?

I was raised in India, and I did go to medical school there, so I became interested in the health sciences very early. As a child, I always wanted to do something related to the health sciences, but my first love and my first stop was really medicine. I was lucky enough to get into Medical School, and then I was just going along trying to build my career as a physician. As things happen in life, very often, things took a little turn, and I ultimately landed up in research, so prominently now I am engaged in research. 

The backstory of all of this is I was in the clinical arena for those few years, and a few things became clear to me, especially in terms of neurological disorders.  We didn't understand these disorders very well at all, and that was a big part of the problem in terms of developing treatments for these disorders. There aren't really treatments that can address these disorders meaningfully, that can stop the progression of these disorders, and there are very few options for physicians in the clinic to provide to patients that can really help them. These sorts of realizations were coming up on me in my clinical years.

I had moved abroad, and I got a chance to research, something that I hadn't had the chance to engage in during my medical school years, and then everything started to click. It started to seem to me that, in order to make advances in brain disorders, advances in basic research were important. Then things took a turn, and I started to delve into research and went on the long road of the PhD and the postdoc and all of that. That's how it all started. 

Could you talk a little bit about your work today? How did you find research that fit what you wanted to pursue as well as start out on the path of neurological disease?  You have a primary focus on Parkinson’s disease. Was there a personal interest in this work or did your focus eventually evolve? 

During my PhD I was lucky, because just around the time that I joined the program, there were two researchers who joined as faculty in my department who were pioneers in the area of stem cell biology and cell transplantation. They came to the department, and I was lucky enough to be able to impress them and join their lab as a student. 

When I started to get exposed to this field of stem cells, it really became obvious to me; this sophisticated and cutting edge idea that this research was at the frontiers of science. There was just so much potential and so many avenues through which there could be solutions for some of those problems and some of those issues that I had been thinking about, especially during my clinical years. Then moving into that whole period of trying to swerve into the research side of things, and that's where my journey with stem cells started, and then when I went on to do my postdoc, I joined the lab that had expertise in Parkinson's disease. My mentor was one of the very well known scientists in the Parkinson's disease area, and so there came the interest. My job there really was to kind of apply and bring my stem cell expertise to bear upon those issues relating to Parkinson's disease in that lab, and I've just followed the path since.

Brain diseases have become so prevalent and damaging to virtually every family at some point. How is it possible with all of our technology and emerging science, that we are still far behind in understanding the brain? I'd love for you to talk about the benefits of work in stem cell biotechnology and the potential to develop biomarkers for earlier diagnosis, or perhaps novel treatments and therapies.  

Let me take a step back and just kind of talk about what stem cells are, what these things do, just to give a perspective. The brain is one of the most highly evolved and complex organs that really makes us who we are and defines what we do in many ways.

It's also a very remarkable organ in the sense that it is learning, it is changing, and it is adapting throughout our lifespans. The scientific term for that kind of adaptation is plasticity, and I think that this terminology probably has been thrown around a lot, but plasticity means that stem cells are really at the core of this adaptive process. They have the ability to divide and generate new cells and replenish tissues in a way that other cells cannot. These cells really remain as sort of reservoirs of plasticity in our brains throughout life. Reservoirs that can be used to support brain health and maintain brain resiliency in a way, but also we now know that we can grow these stem cells in the laboratory. We can study them and use them to test drugs and develop treatments for disorders where certain cells have died. 

Stem cells can become other different types of mature cells, and we've developed these techniques where we can drive the stem cells in the laboratory to become these cells that are dying off in brains in particular disorders. 

You know, there's this idea of trying to replace cells right back into the brain. There are patients who have lost some of these cell types, so those sorts of possibilities are there with stem cells. That's been really exciting, and this is not possible to do with other cell types in the body or other types of technologies.

The University of Arizona is a very unique space where we have a lot of recognized scientists and researchers working in the field of normal aging. What is aging? What is normal aging versus diseased aging? 

I actually work very closely with the aging biologists here at the UofA. I'm part of the McKnight Brain Institute run by Dr. Carol Barnes. It's just been fantastic being part of that environment too, because when I initially came here I wasn't into the aging field as much. 

Aging is just so intrinsic to chronic neurological diseases like Parkinson's because we know that Parkinson's has a higher chance of occurrence in people as they age. Not all people who age are going to get Parkinson's but generally, Parkinson's occurs in people who are older. 

That connection between aging is very interesting, and to understand what is normal aging and then what differentiates normal aging from pathological aging, or disease, is really important to understand. 

Stem cells are very useful in studying those kinds of issues too, because although they are a fountain of youth, they are also affected by aging, to some extent, and so they can be recorders and tell us a lot about aging, actually. We have used them as a tool to study aging from that point of view.

When we're talking about stem cells and looking at them again in regards to aging versus disease and how they can re-energize, how they die. Can you look at individuals and their specific set of stem cells and study the causes of a particular disease or just look at it and say, ‘This is a normal aging process’? 

That's really a complex issue and difficult to study, but we are able to study diseases from a very individualistic point of view using stem cells. It goes back to this technology called induced pluripotent stem cell technology. It is something that I've established in my own laboratory since joining the University of Arizona. 

The scientists who developed this technology were given the Nobel Prize Award in 2012, and this technology really is about isolating adult cells, like a skin cell or a blood cell from an individual, either diseased or normal. Then you could, through a series of research manipulations, drive the cells to become embryonic-like cells. 

Embryonic stem cells are the ones that give rise to all other cells in the body. From an adult cell, you’ve given rise to this embryonic-like stem cell, without delving into embryos. There are a lot of ethical issues associated with that, and feelings and emotions run high in that area. 

Here, there’s a different way to generate embryonic cells, and then once you have embryonic cells, they can be grown technically forever. They can be backed in laboratories. Then you can dry these embryonic cells from there into other cells, like certain types of neurons, for example.  Neural cells that one would like to study that are of importance in Parkinson's disease, which is what we do. 

Now we are able to access brain tissues from living individuals in a way that we haven't been able to access before. It's really not possible to study brain tissues from living individuals; you can't take a brain biopsy from somebody like you could take a little skin biopsy, if there was a tumor or something and look at what cells are doing. This really gives us this indirect way of generating brain tissues from different individuals, and the unique and really exciting thing about this whole technology is what we're finding: that these cells can actually be reporters of what's happening from individual to individual. 

For example, cells from somebody who had Parkinson's behave differently in culture compared to somebody’s who doesn't have Parkinson's disease. Even between individuals who have Parkinson's disease, each of them has a difference. Their cells behave differently, even within the group, so we all know that everybody's disease is not the same. Everybody expresses the disease differently, and that's important because the same medications that we think may work for everybody may work well for some and then not so well for others. This studying the disease individual by individual really has the advantages that you can be very precise in what you learn about individual variation. You can also understand the disease better; first of all, what the variations are, and then you can test drugs on some of these cells. Maybe the drugs work on cells from individual A and individual B, but then the drug doesn't work on cells from individual C.

This way you can really be a little bit more focused and strategic in terms of how therapeutics are developed. I think the broad terminology for this these days is precision medicine, and so this technology really allows for precision medicine to be applied in a way that, again, we haven't been able to do in the past.

I know another passion of yours is mentorship and making sure that you are passing on this experience to others. These students are lucky to be in your classroom, when you are teaching in your lab, working side by side. Talk to me a little bit about how you involve the students and how this has evolved. 

I am passionate about working with a diverse slate of students because I really think that diverse opinions matter for anything. It propels creativity, and it also tremendously helps students in gaining confidence and a worldview.

I enjoy interacting with students at different levels from all kinds of backgrounds. My basic philosophy is that it's not really important where the students are academically or what they learned in the past. It's more about what they want to do, and the motivation and the interest and the drive that they show to want to get somewhere or want to learn. In the lab or in the class, wherever that might be, it's just been fabulous interacting with such bright and engaging individuals. 

I love interacting with undergraduates because I feel that it's a very important time period and the trajectory when students are trying to make decisions on where they really want to go. I feel like I can make a meaningful impact at that time. They are very fresh, and they're not afraid to ask questions. They bring a lot of new ideas onto the table. 

You know as we get older, we develop a few more inhibitions, and we are worried about what other people might think of us. I find undergraduates are a lot more free in how they go about things, and sometimes they ask those those so called ‘dumb questions’ that are really very important. It's been fun interacting with them, and I usually tend to give them independent mini projects as they learn and do things so they can really try to understand the ropes of research and understand from the beginning to end what the research process means, and also what it means to clinical medicine. 

Taking care of the patient, I truly feel, involves both arms: the basic side as well as the clinical side. They need to go hand in hand, and they need to talk to each other. I can convey that to the student or people that I mentor, at least I try to convey that. I think that's a very important message that I can give to them.

You mentioned this concept of diverse thinking and backgrounds, that is such a huge part of what makes BIO5 a special place. The University of Arizona, I think, really does a good job of actually walking the walk of that and not just saying that that's what we do. It takes special people like you that are willing to put that time in and see the benefit, both from their perspective but also from your own, and that's really admirable. I love that.

Yeah well that's nice of you to say, Lisa. You know it's really a two way process. The students teach me so much. I am better because of the students. 

That's the best kind of relationship, a two-way benefit, for sure. I know you're a busy person, but what do you do with any free time that you might have? Do you have any hobbies, or what is your favorite thing to do if you're not in your lab or not teaching?

I don't get enough time to do it, I wish I had more time, but I love the outdoors and Tucson is beautiful. That is something that attracted me to Tucson. In 10 minutes, you can be out in the wilderness walking on some beautiful trail. I love hiking, so I try to get out there and do that as often as I can. My husband is an avid hiker too, so we both like doing that together. I like listening to music and reading, all kinds of varieties of things. Those are a few of my interests that I try to do in my free time.

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