Dr. Jeffrey Conn

Having previously served as Head of the Department of Neuroscience at Merck & Co.,

Inc., Vanderbilt's Dr. Jeffrey Conn, the Lee E. Limbird Professor of Pharmacology and co-director of the Vanderbilt Center for Neuroscience Drug Discovery, has partnered with Dr. Craig Lindsley to introduce a new drug development platform model for academia -"derisking" drug discovery by blending academic basic research with state-of-the-art industry resources. By piecing together a detailed understanding of the mechanisms underlying chemical and electrical signal regulation in the central nervous system, Dr. Conn's group is working toward the development of novel treatments for schizophrenia, Parkinson's disease, and other CNS disorders.

Here, he discusses some of his most recent concerts, advice for incoming graduate

students, and the "What if?" question pertaining to the path he might've chosen if not for neuroscience.

The following interview took place on January 14 and February 2, 2018.

 

INTERVIEWER

Where did you grow up? 

 

CONN

Cleveland, TN - between Chattanooga and Knoxville.

 

INTERVIEWER

What did you want to be when you were growing up? Who or what were your inspirations?

CONN

I developed a strong interest in brain disorders when I was young. I saw friends and family members suffer from mental illness and wanted to provide help for those suffering from these disorders. Initially, I wanted to be a clinical psychologist, but developed a strong interest in neuroscience and research in college.

 

INTERVIEWER

What are your favorite books? Favorite books on science? They certainly don’t have to be mutually exclusive, but I guess I’m trying to tease out fiction versus books on science, which are generally more historical non-fiction.  

 

CONN

I have many favorite books, but especially love novels that are also educational. Pillars of the Earth by Ken Follett stands out. Also, The Poisonwood Bible by Barbara Kingsolver; The Kite Runner by Kahled Hosseini. I recently read All the Light We Cannot See by Anthony Doerr, and really enjoyed it. Currently, I am reading The Underground Railroad by Colson Whitehead, and it is terrific. I also enjoyed the Harry Potter series. I was a few years late in reading them, but after they became such a cultural phenomenon, I started the first and was compelled to read them all.

As for science books, I tend to enjoy personal accounts that touch on science or

brain disorders. I really enjoyed The Man who Mistook his Wife for a Hat by Oliver Sacks. I also enjoyed Tweak, a memoir by Nic Sheff, a young man who struggled with a serious addictive disorder. A book by his father, David Sheff, called Beautiful Boy was also a great book, and the combination was very enlightening. Also, I recently read a book called Mind Estranged by Bethany Yeiser, a very articulate young woman who struggles with schizophrenia. It is a gripping account and made me aware of aspects of the illness that I did not understand. 

INTERVIEWER

What is an aspect of your graduate school experience that current graduate students should be jealous of? Alternatively, what do you envy of current students’ experience?

 

CONN

My graduate experience was very comprehensive. I had wonderful mentors who took a major interest in helping me and other students develop as scientists. My primary mentor, Elaine Sanders-Bush, was an exemplary role model and taught me so much. There was less bureaucracy in science then, which made it easier to move quickly to address new ideas or questions. It also helped create an environment where faculty had more time for casual interactions and discussions about the big questions in science.

As for students today, they have such a tremendous tool set at their disposal. They

can do things and answer questions that we could not have imagined when I was in graduate school. Also, as science becomes increasingly multidisciplinary, today’s students often have more opportunities for exciting collaborations and to work across disciplines.

INTERVIEWER

In some respects, and this claim could be made for a number of current scientific endeavors, neuroscience represents this generation’s race to space. However, the battle for spaceflight supremacy against the Soviet Union culminated in a very specific achievement – traveling 240,000 miles and executing a lunar landing. What will be neurosciences’ moon landing?  

 

CONN

I do not see a single “moon landing” on the horizon for neuroscience. There are simply too many important questions and goals to be achieved. At a practical level, one of the most critical is discovery of “cures” for the most devastating brain disorders. With our aging population, Alzheimer’s disease alone threatens to be absolutely crippling to society at multiple levels. Also, we simply must develop a more sophisticated understanding of other major brain disorders, such as schizophrenia, bipolar disease, autistic spectrum disorders, other neurodegenerative disorders, etc. Each of these diagnostic categories likely represents multiple different disease states, each of which has effects on specific brain circuits that lead to common symptoms. Developing an understanding of the brain circuits that are critical in normal brain function and how they are impacted in CNS disorders is critical, and we are just at the beginning of having the tools to begin to develop this understanding.

Another major area that will be critical over the coming decades is building our

understanding of genetic and epigenetic influences on brain function and pathology. Again, we are just at the beginning of being able to perform studies that will be needed to develop an integrated understanding of complex genetic influences on brain function. The advances that are now in the early stages have the potential to fundamentally impact our understanding of the brain.

INTERVIEWER

Your colleague, Dr. Craig Lindsley, is a KISS fanatic. Does Jeff Conn have a fandom he’s apart of? 

 

CONN

I love virtually all music and am a big fan of everything from rock to bluegrass. I listen to a lot of indie rock and folk music and take full advantage of the music scene in Nashville. Some recent concerts that I have really enjoyed include Shakey Graves, Florence and the Machine, Evanescence (Amy Lee), Ricky Skaggs, Santana, Mumford and Sons, and the list could go on and on. We are very lucky in Nashville to have so much great music and to be able to see great bands in small venues. I could never narrow my interests to one group.

INTERVIEWER

Do you play any instruments yourself?

 

CONN

Not anymore. When I was young, I could play piano reasonably well by ear, and guitar, too. But you let 30 or 40 years pass and sit down to play the piano or try to play the guitar again and it's completely gone. So no, unfortunately, I don't.

INTERVIEWER

You mentioned earlier that you'd considered clinical psychology as a profession before transitioning to neuropharmacology. Both are mental health professions, but obviously different when it comes to the type of work. Do you maintain a strong interest in other fields of study involving the brain i.e. philosophy, metaphysics, consciousness, etc.? 

 

CONN

I am very interested in psychiatry, specific areas of psychology, and neurology. I am fascinated by the brain at all levels. I am also very interested in anthropology, history, and sociology. I am fascinated by the ways that culture can shape our perception of the world and the interface between neuroscience and cultural or environmental influences. To be honest, metaphysics, philosophy, and endeavors to fully understand consciousness are not of as much interest to me. I tend to be very pragmatic and goal-oriented, and while important, these areas are a bit too abstract for me.

INTERVIEWER

As you’ve also mentioned in previous interviews, being a neuroscientist in academia allows you to follow the data wherever it leads, providing, from a basic science perspective, an advantage over most industry positions. However, Nature and Science have published multiple articles on the lack of opportunities in academia for new PhDs. What advice do you offer students graduating from your lab?

CONN

The main advice I always give is to follow your passion and your strengths. At this stage, do not try to predict the future and do not become overly obsessed about contingency plans in the event that your first goals are not realized. Throw yourself fully into your work and be the very best that you can be. I have seen many students so focused on worries about future funding and alternate careers, that they become distracted from their main goals and passion. This often becomes a self-fulfilling prophecy in which we can all become less productive and limit our opportunities. Regardless of your future path, you need a highly productive period of graduate study. Every possible job you may consider in the future will look at that. They will want to see that you are highly productive, passionate, and driven. In graduate school, the main product of this that they will see are high quality publications, etc.  

I also almost always advise students to do a postdoc in the best academic lab

possible. Even for individuals who take another path after their postdoc, this allows building your CV and expertise. Many students make the mistake of going straight to industry for postdocs or entry-level permanent positions in industry from grad school. Even if you ultimately want an industry career, wait until after your postdoc. This allows you to build your credentials and will increase your options for the rest of your career. Even for students I have trained who go into completely alternative careers, such as law, public policy, journalism, etc., a strong postdoc with high profile publications invariably opens better opportunities than those that become available for those who bypass the postdoc.

INTERVIEWER

About 1 in 6 Americans take an anti-depressant – a dramatic increase compared to 20 years ago, which fits within the overall increase of patients prescribed psychoactive drugs. What’s the primary cause? Higher rates of depression? Improved diagnoses? Anti-depressants prescribed for off-target conditions like OCD?

CONN

This is complex, and I won’t pretend that I can give a single answer, but I think that everything you mentioned is part of this. The stresses that people experience today clearly lead to higher rates of depression. As drugs have been improved and awareness has increased, more people are seeking help than was the case 20 years ago. Also, there are many uses for these medicines outside of major depression that are now appreciated. Everything you mentioned contributes to the increase in prescriptions.

INTERVIEWER

As our understanding of the human brain improves, are we learning that there are more shared characteristics, systematic or mechanistic, of neurodegenerative disorders than originally thought? 

CONN

Yes, there are many symptom domains that cross multiple disorders and likely involve pathological changes in overlapping brain networks. The primary causes may be different, but the circuit changes and major symptom domains have commonalities. As we discover new risk genes for different brain disorders, we are finding that mutations in some susceptibility genes may be associated with a range of disorders. For instance, associations for a single gene may be identified for childhood developmental disorders, schizophrenia, major depression, and bipolar.  

INTERVIEWER

Regarding the pathogenesis of Alzheimer's, originally, it was thought that diminished cholinergic signaling initiated progression of the disease. Now, the two competing theories are that tau protein deposits and/or beta-amyloid plaque buildup are the main drivers. What's your stance here?

CONN

I honestly believe we still have a lot to learn. We still don't know what the primary pathophysiology or pathology underlying Alzheimer's is. I think all of those events are a part of it. I think the cholinergic degeneration occurs early and is part of the early cognitive decline that continues to worsen and go well beyond cholinergic dysfunction. But what is responsible for causing the early cholinergic cell death ultimately leading to tauopathy and plaque formation? Whatever those events are, they're happening long before any kind of Alzheimer's diagnosis.

I wouldn't want to go on record as having said anything favoring one hypothesis

over the other because at this point it's just musing, but it's conceivable that cholinergic neurons and cholinergic function plays a role in maintaining normal function, and when it's lost, that's when you start to develop the tau and beta-amyloid pathologies. We know that in certain animal studies, muscarinic agonists can reduce amyloid deposition and processing. I guess I'm just pointing to the amount that we don't know about the earliest stages of Alzheimer's pathology. 

INTERVIEWER

This is an interesting topic to read up on in the context of science reporting. Egos could be to blame, but in the case of Alzheimers, there's the tau deposits group versus the beta-amyloid plaque formation group, and depending on the source, you'd be forgiven for thinking that the two camps are competing factions, and that one side is in complete disbelief of the other.

CONN

Right. So those two factions do emerge, but the vast majority of scientists in the areas realize that it's not completely one or completely the other. That's what we should be able to do as scientists - acknowledge the things we don't know. Obviously scientists are human just like everyone else, and there are those who develop very dogmatic stances, and I always wonder how much of that is related to the human need for protecting your turf or securing funding.

I will say that 15 years ago I was in meetings where they'd pull together a group of

experts to talk about approaches for treatment of Alzheimer's, and the naivety in the room was staggering. Some experts were saying we'd have a cure in 10 years. There was so much confidence in the amyloid hypothesis, that secretase inhibitors and other approaches to reduce amyloid burden would lead to a cure. Sitting in a room of prominent, accomplished scientists and hearing that was completely staggering. I think people are coming around to realize that was wishful thinking and that we've got a long way to go.

INTERVIEWER

In that same vein, personalized medicine has quickly come to fruition, especially in the field of cancer therapy development. How much are biomarkers guiding schizophrenia and other brain disorder therapy developments?

CONN

It's a huge topic. It's something that's being talked about a lot and being invested in heavily. I think for all brain disorders, there's a recognition that we need better biomarkers, but we're so far from that in some areas. An area where I see major concerted effort across multiple groups is Parkinson's disease, there's been a huge investment in biomarker discovery. The same goes for Alzheimer's. For Parkinson's, even though there may be a hundred different paths to loss of dopamine neurons, there's a final common pathological state true to all Parkinson's patients, and that's loss of the neuron. So that gives you a place to focus in terms of thinking of biomarkers to give insights to how that progresses.

It's a more difficult for something like schizophrenia or depression, where the

focus of the field is still on symptomatic readouts. There could be disruption in multiple circuits, overlapping circuits because ultimately, when you have a given patient phenotype, there are brain circuit disruptions that are common, but the exact nature of that disruption and how it leads to the symptoms that manifest is really variable.

INTERVIEWER

It was announced last month that Pfizer is pulling funding from their neuroscience discovery program. Having an industry background, what's your reaction to an announcement like that? I imagine it differs from the public who may view the move as another callous display from big pharma caring only about their bottom line. 

CONN

First of all, I do think it's devastating for those of us who are interested in treatments for major brain disorders. And it's not just Pfizer, it's been happening throughout the pharmaceutical industry. When you look at the major players in neuroscience drug discovery and development, many have pulled out or dramatically reduced or narrowed their efforts. That's devastating, because we'll never develop new treatments without that industry investment.

From the company's side, I can understand it. They do have to look at their bottom

line, the risk involved, and what the likelihood is that they'll deliver that drug to the market. The challenges with neuroscience are tremendous - these are chronic disorders where the patient will have to be on the medicine for life, so the safety requirements are much higher than many other indications. These are often times patients who are functioning at some level, and so you don't want to do anything that has the potential of worsening or hastening their decline, which increases regulatory scrutiny. 

Also, there's a lack of predictive animal models. We don't have animal models for

schizophrenia or depression, or at least true disease models. In reality, I do think there's a misperception of what role animal models should play in the neuroscience process. Compare that with oncology, where although still not terribly predictive, those animal models are a little more closely aligned to the human state.

All of this together has led to a lot of high profile and high cost failures. What's

unfortunate is that we've come to a point where I think we're light years ahead of where we were 10 years ago in neuroscience. We know a lot about how to assess target engagement in the brain, how to assess animal models and brain circuitry, and how that might relate to the human disease. It's a time when industry investment would yield much greater dividends. 

INTERVIEWER

Do you pay any attention to developments in artificial intelligence and their application to neuroscience?

CONN

No. It is a fascinating area, but not one that I stay up with.

INTERVIEWER

If you weren’t a neuroscientist, what would you be?

 

CONN

I would work in some profession where I felt like I could have a positive impact on people’s lives, probably at an individual or community level. I could see myself working in a non-profit foundation setting focused on areas related to poverty, hunger, addiction, mental health, or education and economic development. If I were to pursue a different academic profession, it would probably be anthropology. I love interacting with people who come from different perspectives and cultural backgrounds and learning about their perspectives on life and the world.

INTERVIEWER

You’re stranded on an island with a record player and a Blu-ray-player-equipped TV. Let’s also assume it comes equipped with the food, shelter, and clothing, so you don’t have to worry about the "necessities." You can bring five things. What are they?  

CONN

I would not opt for an album. Anything I chose would get old too quickly. The same is true for most modern books. If a satellite phone to communicate with the rest of the world is an option, that would be at the top of my list. I would probably want a CD full of pictures, recordings, and short video clips of my wife and children. After that, I would want a bible. It is so rich with history, culture, and wisdom, that can never be exhausted. From there, it would be more mundane, but would include binoculars, an exhaustive guidebook of animals, birds, flora, of the region (if one exists). Finally, a good wagon to allow me to carry materials that would help with building or other projects that would keep me occupied.  

INTERVIEWER

After the 2016 election, there was talk in the media suggesting scientists should be coming forward to run for public office. If you had to nominate one scientist to run for President, who would it be and why? 

CONN

I am drawing a blank on this one. Most scientists would need to start with other offices to gain the experience needed. We learned in the 2016 election that experience is not a requisite for being elected. However, we really need to move back to electing strong individuals who have the broad experience and expertise needed for that office. 

 

INTERVIEWER

Last, but not least: Beatles, Rolling Stones, Zeppelin, or Pink Floyd?

 

CONN

They are all absolutely terrific! I listen to all of these bands often, and could add dozens more to the list. Unfortunately, the only one of the bands you mentioned that I have seen live is Pink Floyd, so they get my vote. It was a terrific concert.

Visit Dr. Conn's lab website to learn more about his most recent publications and the latest news from the VCNDD.

Feel free to leave your thoughts on the interview in the comments section.

©2019 by EG Lund.