Q&A with Robert Vassar, PhD, Director of the Mesulam Center

What have you learned from Marsel Mesulam, the previous director of the center? What do you intend to carry forward with you as you assume this new role?

It's a great honor for me to be now assuming directorship from Dr. Mesulam, who started the Mesulam Center almost 30 years ago. He built it from the bottom up. He was the first person to identify the dementia called Primary Progressive Aphasia (PPA) and he's been studying it ever since. He is a giant of our field.

Dr. Mesulam has been a great mentor to me. I come from a more molecular and genetic background whereas Marsel is a superlative clinician, cognitive neurologist, neuroanatomist, and neuropathologist. We’re approaching dementia from opposite poles of the spectrum and meeting in the middle.

I have learned much about the clinical phenotypes of these devastating dementias and how they manifest pathologically. The theme that has emerged from the studies of Dr. Mesulam is that there is deep heterogeneity in aging and dementia. Different types of pathology can lead to the same type of dementia. For example, you can have PPA because of different problems at the molecular level, but they all are within the language center, hence the problem with speech. On the other hand, you can have the same pathology creating different types of clinical output. For example, the pathology that we know causes the memory problems in Alzheimer's patients can also cause degeneration in the language centers to produce the clinical symptoms of PPA. The theme of heterogeneity that runs through our work is what made the Mesulam Center famous, and I fully intend on keeping that theme.

I view my role as supporting the really wonderful research that's going on in the center and nurturing it to grow and flourish. We have a project here that is led by Dr. Emily Rogalski about people known as “SuperAgers” who are individuals above the age of 80 who have cognitive abilities that are equal to much younger individuals. These SuperAgers often lead a full life without having any dementia at all. Dr. Rogalski was recently awarded a very large NIH grant to study the SuperAgers further, and she’s going to be connecting the phenotype of these individuals with their brain anatomy and their genetics. Most of them donate their brains to research after they pass away, which allows us to look at their histopathology. We’re hoping to understand what makes their brain so resilient or resistant to the age-related pathologies that we see in individuals that have Alzheimer's disease.

Can you explain a discovery that you’ve made - one that you feel is a highlight of your dedication?

I designed what's called an expression cloning strategy, which I used as a way to identify the enzymes that make amyloid plaques, one of the hallmark pathologies in the Alzheimer’s brain. Using that strategy, in 1999 we discovered an enzyme that's called BACE, which is essential for the generation of the problematic amyloid plaques. Back then, there was enormous excitement, because that discovery meant that we could design drugs to inhibit BACE and reduce the accumulation of amyloid plaques.

Tell us a little bit about your journey to this position.

I had graduated from the University of Chicago in biological sciences and I didn't really know what I wanted to do for a career. But I knew I loved research, so I became a technician. That was fine for a few years, then my mother was diagnosed with Alzheimer's disease, and watching her go downhill slowly to the point that she was bedridden and comatose really devastated me. It was terribly heart wrenching for me and changed my perspective. At that point, I made the decision that I wanted to devote the rest of my career to understanding Alzheimer’s, because back then, in 1983, there was very little known about the disease. Not even the first Alzheimer’s genes had been discovered yet.

That spurred me to go on to graduate school at the University of Chicago. I got my PhD in molecular genetics and cell biology in 1992. My first step was to gain technical skills. Making transgenic mice was a hot new technology back then, but no one was doing it at the University of Chicago. So, my advisor, Dr. Elaine Fuchs, sent me to a lab that made transgenic mice so I could learn it and bring it back. Then, Elaine recommended that I go to Dr. Richard Axel’s Lab at Columbia University for my postdoc where they studied the molecular biology of olfaction, or smell. With that step, I could start making my move back into neuroscience.

Just before my postdoc, Dr. Axel discovered genes that encode odorant receptors that are required for how we sense and recognize odors. My postdoc was to study the expression of odorant receptors in the nose and how the receptors are connected to the brain to understand how olfactory information gets deciphered. I completed my postdoc in 1996 and then in 2004 Dr. Axel won the Nobel Prize for discoveries that were partially based on my work. It was a very exciting development for me to see that my work contributed to that discovery.

But then, at the end of my postdoc, I really wanted to do something for Alzheimer's patients. I didn't want to do another postdoc, so I chose to work at a biotech company called Amgen. They were just starting an Alzheimer program at that time, and in 1996, we still didn't know much about Alzheimer's disease. Mutations in a few genes had been discovered that cause Alzheimer's disease by increasing amyloid in the brain of patients. So, the increase of amyloid was a trigger for Alzheimer's disease, but we didn't know what made the amyloid. That’s when I made the discovery of BACE.

In 2001, I decided to go back to academia at Northwestern to have the freedom to pursue my own research ideas rather than the company’s. In the years that have passed, there have been drugs designed to inhibit BACE that lower the amount of amyloid in the brain. Unfortunately, clinical trials of these drugs showed side effects at high doses. I am now working to convince companies to conduct clinical trials using lower doses of BACE inhibitors to see if we can avoid side effects yet lower amyloid enough to be beneficial.

It is very satisfying for me and fulfilling to know that my work on the discovery of the BACE enzyme has had an impact on therapeutic development for Alzheimer's. Future exploration of lower doses of BACE inhibitors may hold promise for Alzheimer’s disease.

You've been a part of research in this space for over 20 years. Given what you've seen in the last 20 years, what do you think is possible 20 years from now?

I've seen the field come a very long way from the initial discovery of genes that cause Alzheimer's disease to a biological understanding of the pathogenesis of the disorder.

I think what we'll find is that Alzheimer's disease does not have a single cause but a spectrum of causes with multiple genetic and environmental factors. We're working on other potential therapeutic approaches in the lab based on this premise. Individuals with Alzheimer's may have different pathways that lead to disease, which means that we need to understand all these pathways and develop drugs against each of them. That way, in the future we can do individualized precision medicine for people that come into the clinic. No single “silver bullet” is going to cure all of Alzheimer's disease. We need a whole tool kit of different drugs that attack the Alzheimer's disease process at different points. That kind of approach has worked well for disorders like AIDS and heart disease.

Ultimately, that's what I want my research to do: to identify new targets in Alzheimer's disease that we can design drugs against. That's where I see the future of Alzheimer's research going, and I'm just happy to contribute to that, even in just a small way.

I think the future is very bright. My experience has proven to me that with persistence, you will make progress. That's a message to all the young scientists out there and for everyone really, including patients and their families. We eventually get to answers. It may take a long time, and we may take some detours from time to time, but that's just the nature of science. And it's a very exciting journey.

What advice would you have for younger scientists looking to follow in your footsteps?

The most important thing I can tell a young investigator would be to follow your passion. Life is short, and you don't want to waste your time in a career that you're not passionate about. I would say that to everyone, not just if you're a scientist.

If you find enjoyment out of what you're doing in your career, that’s one of the greatest blessings anyone could have. It's particularly true for a career in science because science is grueling. You spend long hours in the lab, and oftentimes, experiments don't work. Sometimes your hypothesis is wrong, but if you can prove that your hypothesis is wrong with a good experiment, then that’s progress. Sometimes experiments just don't work, because, who knows, maybe the test tube reaction just didn't go off right on that day and you have to start over again. You must be persistent, and I think that having passion helps you get through those times when it's just a slog. If you don't give up, you'll eventually be successful, and passion helps you do that.

Do you have any wisdom to share with physicians that care for patients with Alzheimer's or other dementias?

I think our physicians are absolutely wonderful. They do such a great job, and they work very hard. I’d reassure our great clinicians that just the act of listening and being empathetic is huge for your patients, their families, and their caregivers. Our clinicians here at the Mesulam Center do an outstanding job of that. It's unfortunate that in neurology, especially cognitive neurology, that effective therapies are generally lacking. We're just beginning to get the first disease-modifying therapies for Alzheimer's disease. There are many other neurodegenerative diseases where we do not have any therapies. But our clinicians can help by listening and being empathetic to our patients and their families.

Also, information is power. So, a clinician can empower patients and their families to prepare for the future by imparting whatever information is available to them as early as possible. For example, clinical trials are moving toward prevention studies in which enrollment early in the disease process is key.

You have an intimate relationship with Alzheimer’s disease, seeing your mother go through it and then having spent so many years studying it. What words of advice or solace would you have for patients and families that are currently facing Alzheimer’s disease?

I'd like to tell them that I really empathize with them because I've seen my mother suffer greatly with Alzheimer’s. It's a horrible disease and I want it eradicated from the face of the of the earth.

My other solace would be to say, “don't give up.” Keep active socially and intellectually as much as you can with your family and your friends. Maintain a positive attitude. Be involved in your community as much as you're able to. Go visit your grandkids as much as you can and enjoy life. Know that we, the researchers in the field, are working hard day and night all over the world to try to find treatments for this devastating disease.

We're making progress, though I wish it was faster. When we discovered BACE back in 1999, we were excited thinking there would be a drug on the market in five years. And, boy, were we wrong! But that's just a nature of science and research. Things take time, but with persistence and positive thinking progress is made. So, there is hope down the road.

I would also encourage individuals with Alzheimer's disease and their families to get involved in clinical trials or other research studies. Interested patients and families can contact us here at the Mesulam Center or look on our website to find out more about trials that are ongoing. Even people without Alzheimer’s disease can get involved, because there are trials going on now about prevention. We have ways of determining whether brains are developing the amyloid and the Tau pathologies. So, even if you don’t have symptoms, you could be eligible for one of those prevention trials.

Our research participants in our studies at the Mesulam Center are the real heroes of the story. They are the ones that are altruistically giving of themselves. I can't say enough about our study participants. Without them there would be no progress in research in not only the dementia field, but everywhere in medicine. They are the real heroes.