Pruning Landscapes—An Interview with Jeff Lichtman

An example of a “brainbow” with distinct neurons given distinct colors. Photo credit: Jean Livet, the Cell Image Library

Pruning is something that Jeff Lichtman understands. A professor of Molecular and Cellular Biology at Harvard Medical School, Lichtman investigates connectomics, the structure of neural circuits, which he will readily tell you is all about pruning. During brain development, connections change as axons cut off unproductive branches while building a subset of connections that grows stronger. Lichtman wants to know how memories are stored in this tangle of branches.

At home in Cambridge, MA, Lichtman and his wife are also avid gardeners. The Lichtman backyard drew hundreds of visitors during a recent “Secret Gardens of Cambridge” tour. The Lichtmans are even prouder of their two daughters, one of whom is Flora Lichtman, science journalist and former Science Friday editor and producer.

ASCB science writer Christina Szalinski recently spoke to Lichtman about his upcoming talk at the 2014 ASCB/IFCB meeting. He will present his work on connectomics at the “Cell Structure Across Scales” symposium on Monday, December 8, at the meeting.

What is connectomics?

It is a nascent field of neuroscience to generate a neural circuit diagram at the resolution of single synapses.

What will connectomics tell us?

We’ve never had those [diagrams] before. For all nervous systems, save the C. elegans, where the neural circuit like this was developed in the 1970s. It took 10 years to do the 300 nerve cell connectome of that animal. Except for that example and most notably in mammalian brains, there’s been very little information about exactly what the quantitative details of neural circuits are. So people have known for many years that particular cell types are interconnected. But how many connections between nerve cells, how many target cells does a nerve cell talk to, how many different nerve cells talk to a single nerve cell conversion, how do the loops of circuits formulate the information transferred through them? These are completely off limits as questions because there have been no tools to see the wiring diagram at the necessary resolution.

The hope is that a certain amount of description at this deep level will provide insights into the way the nervous system does many of its mysterious functions. I can give you a few examples. The nervous system of mammals, [the] human is a good example, stores a lot of information about the world in the form of memories. These memories are stably maintained, that is, you don’t have to keep reminding yourself. The memory sits there, and many of the memories you have never come back into consciousness, but they are still there just in case you need them at some later point in your life. In what form does that memory sit there? What does it look like? I think many people suspect it’s somehow built into the wiring diagram that has been fashioned in some way based on experience, but there’s not much idea about the way those memories look. There are just no tools that have been able to do this until recently.

Another area where this would be very useful potentially is that there are a number of diseases of the nervous system that are probably diseases of the wires. Things I would call connectopathies, which is also a made-up word like connectome. But these connectopathies may be very common illnesses, maybe schizophrenia, maybe autism spectrum disorders, maybe obsessive-compulsive neuroses. Those brains are different from the brains of people who don’t have those disorders, but in what way? If you don’t know in what way, or if you don’t know what’s wrong, it’s hard to be very rational about curing diseases like that. In fact, most of our treatments for psychiatric diseases are kind of accidental. People discover not by rational thought, but by accident, that this or that drug had some effect. The subsequent drugs mimic the potency of the original sometimes without our knowing why that works. Lithium is a good example. There’s still debate about exactly why lithium affects people with bipolar disorder. But there’s not a better drug out there. It was not a rational thought that made lithium effective for bipolar.

What are you working on now?

My interest is very much related to this fundamental question of how information is acquired and stably stored in the brains of mammals, especially humans. Most of my work is on animals that are lower down the evolutionary tree, like mice. What I’m looking at is how brain circuits develop, how they change as they go from being naive to being knowledgeable about the world, about what kinds of rules establish the final wiring diagram. It’s not that every human’s wiring diagram would be identical. In fact, in mice we already know, in one area where we’ve looked in detail, that each one is different. But at some slightly higher level, they all follow the same rules. It’s sort of coming up with the rules that underlie neural structure that we’re looking for. We use electron microscopy as one way of doing this. We also use a technique we developed to label different nerve cells different colors, which we call a brainbow. It allows us to have many different nerve cells in the same field of view all colored differently so we can look at their wires and distinguish one from the other.

How did you become interested in studying the brain?

When I was in college I had no neurobiology training whatsoever and then I went to a medical program [at the University of Washington in St. Louis] that also allowed me to get a PhD. I was looking around for a lab to do my thesis in and I just loved the lectures I heard about the brain in the introductory year of medical school. I joined the lab of Dale Purvis, who was a neuroscientist. And I’m still in love.

Do you consider yourself a cell biologist?

Definitely. Though I actually consider myself a “cellular psychologist.” I’m interested in the behavior of cells. That’s really what I consider myself. Neurons are just a peculiar individual type of cell. They need more therapy than most types of cells because their behaviors are so weird compared to most cells. Neurons are definitely a special case of cells.

Given your interest in neural development, raising children must have been especially interesting for you. Do you think you parented from a different perspective?

I think a little bit. I’m much more aware than most parents of how plastic and impressionable young brains are. And especially much of what of my own work is related to is the fact that the adult wiring diagram is a small subset of the wiring that is present when animals, including babies, are young. A lot of what learning is, is the pruning away of all but a small subset of what you could have been. That’s a kind of indelible one-directional change. You choose a path and it’s hard to jump off and choose another path. Adults realize this. They get more set in their ways. When you talk to your parents or your grandparents, you may get the sense that they are narrow-minded; it’s wisdom in the sense that the narrowness is progressively deciding what the world is all about, and that everything else is no longer interesting. It’s probably for good reason that you pruned away these things. I’ve been a little cautious of being too overbearing with my children, perhaps to their detriment.

I’ve read that you’re an avid gardener. Do you consider that a break from science or science on a larger scale?

Well, we do a lot of pruning. I see this all as one big thing. My wife and I are very serious gardeners. Don’t confuse that with being very expert gardeners. We have a uniquely challenging gardening problem that has required us to learn how to deal with something that most people don’t have to deal with, which is a combination of two really difficult things for plants. It’s very shady and it’s very dry. Dry shade is the hardest kind of gardening. We’ve focused on how to deal with that.

You teach a course on science communications. How did you become interested in this?

Well, this was a product of going to medical school and going to class five days a week with often seven lectures a day, of which virtually none were intelligible. Most of my colleagues, the other students, just stopped going to class and would just wait for the transcript and study from that or from books. I don’t know why but I was a glutton for punishment, and I would sit there and after a while I began thinking: “Why is it that I cannot understand what they’re saying even though I understand the words, and I understand the sentences? But for some reason I can make no sense out of this talk.”

I bet this has happened to you, that you’ve gone to a talk with all the intention in the world of paying attention, and at some point in the talk you realize you don’t know what they’re talking about even though they’re still speaking English. Everyone around you is taking notes, but you seem to be in a fog yourself. What you don’t realize is that everyone is in the same boat, but they’re just acting.

I made a sort of study of why someone loses track of a talk. Then I realized that these things are related to cognitive dissonance. It’s often that the speaker is distracting you by saying one thing and showing you words on the screen that are different. So you have to choose, you’re either going to read the words and ignore what they’re saying, or you’re going to listen and stare blankly at the screen because there’s not enough synchronization between those two forms of communication. I just made a list of these and I began telling people about it, so people said I should tell the students about this.

There’s nothing magical about people who speak clearly, it’s just that they understand, often innately, how easy it is to have someone lose their way. I teach this with Mike Greenberg, who’s the Chair of the Neurobiology Department in the medical school, and after we give them some introductory lectures, the students each pick Nobel Prize winning work and then talk about that [research]. We do that largely so that we don’t have to get into an argument over whether the presentation was bad or the science was bad. We get to hear these wonderful stories of these great discoveries.