Pleasure or pain? He maps the neural circuits that decide
The work of the neuroscientist Ishmail Abdus-Saboor has opened up a world of insights into precisely how much pleasure and pain animals experience during different forms of touch.
“The molecular study of touch is still in its relative infancy,” said Ishmail Abdus-Saboor, a Columbia University neuroscientist. Yet he is changing that with the research into the perception of pleasurable and painful touches that he is leading at the Zuckerman Mind Brain Behavior Institute.
Sasha Maslov for Quanta Magazine
Introduction
Ishmail Abdus-Saboor has been fascinated by the variety of the natural world since he was a boy growing up in Philadelphia. The nature walks he took under the tutelage of his third grade teacher, Mr. Moore, entranced him. “We got to interact and engage with wildlife and see animals in their native environment,” he recalled. Abdus-Saboor also brought a menagerie of creatures — cats, dogs, lizards, snakes and turtles — into his three-story home, and saved up his allowance to buy a magazine that taught him about turtles. When adults asked him what he wanted to be when he grew up, “I said I wanted to become a scientist,” he said. “I always raised eyebrows.”
Abdus-Saboor did not stray from that goal. Today, he is an associate professor of biological sciences at the Mortimer B. Zuckerman Mind Brain Behavior Institute at Columbia University, where he studies how the brain determines whether a touch to the skin is painful or pleasurable. “Although this question is fundamental to the human experience, it remains puzzling to explain with satisfying molecular detail,” he said. Because the skin is our largest sensory organ and a major conduit to our environment, it may hold clues for treating conditions from chronic pain to depression.
To find those clues, Abdus-Saboor probes the nervous system at every juncture along the skin-to-brain axis. He does not focus on skin alone or home in on only the brain as many others do. “We merge these two worlds,” he said. That approach, he added, requires mastering two sets of techniques, reading two sets of literature and attending two sets of scientific meetings. “It gives us a unique leg up,” he said. It has led to a landmark paper published last year in Cell that laid out the entire neural circuit for pleasurable touch.
Abdus-Saboor has also pioneered a new quantitative measure of pain in mice, a tool he and his team adapted to gather evidence for the transgenerational inheritance of opioid addiction. His results in rodents hint that excessive parental opioid use may alter gene expression in ways that put children at risk for the same.
A recipient of numerous awards for his accomplishments, Abdus-Saboor was named to the inaugural class of the Howard Hughes Medical Institute’s Freeman Hrabowski scholars last May. The award provides up to $8.6 million over a decade to rising-star early-career researchers whose labs foster diversity and inclusion.
Quanta spoke with Abdus-Saboor about his penchant for starting over in science, his zebra fish eureka moment and his hopes for a newly imported naked mole rat colony. The interviews have been condensed and edited for clarity.
To quantify precisely how much pain or pleasure lab animals experience during experiments, Abdus-Saboor explained, he has often had to build new measurement tools from scratch. “I like charting new courses.”
Sasha Maslov for Quanta Magazine
When you were a child, did your parents support your interest in science?
They certainly did. I would start to get animals as birthday presents because they saw how fascinated I was with them. Fast-forward to high school. In ninth grade, my parents allowed me to take over the third floor of our house for the yearlong science fair project I was doing for honors biology. I had hundreds of crayfish everywhere. My parents are not scientists, but they were very supportive of my escapades and adventures in the scientific realm.
What do your parents do?
My mother is chief financial officer at an accounting firm. My dad was an actuary before he retired. So I may have inherited a mathematical bent. To approximate an animal’s pain, we do statistical modeling to condense its behavioral features into a single easy-to-read scale. My dad has come to some of my talks, and although the biology is often over his head, he gets super excited about the math part of my work.
How did college shape your career?
I attended an historically black college, North Carolina A&T. I come from a lineage of people who attended these sorts of universities. My parents attended Howard University. So did my aunt. An uncle attended Virginia State, my grandfather Lincoln University. I don’t know if I had a choice but to attend one of these universities.
Still, I think it was a wise decision. It increased my self-confidence to see people who looked like me really doing well. And the culture of the college is nurturing, not competitive. Faculty members care about you. Students work together and want to see each other succeed.
Sasha Maslov for Quanta Magazine
Early in his career, Abdus-Saboor was drawn to neuroscience, which seemed to be entering a “golden age,” he said. “It seemed like there were still more questions than answers, so there was space for me to make an impact.”
Sasha Maslov for Quanta Magazine
Did you do research in college?
Yes. I knew research experience was important, so for my first month on campus, I went door to door asking faculty for research opportunities. I got hired to work on a pig farm. It’s funny because I don’t eat pork, but I was studying whether a change in the pigs’ diet altered the taste of their meat.
At the time, I was flirting with the idea of becoming a veterinarian. So in my sophomore year, I worked in veterinary hospitals, spaying, neutering and cleaning animals. That’s when I realized that the thrill I felt as a kid with science wasn’t there. I wasn’t in love with that work.
But between junior and senior year, I worked in a molecular biology lab at the University of Pennsylvania, and a lightbulb went off. I thought, “Wow, people get paid to think about big ideas and try to find solutions to problems with importance to human health.” I remember telling my parents, “This is it. I want to get a Ph.D. in molecular biology.”
What led you to study pleasure and pain?
It was a bit of a winding road. I got my Ph.D. at the University of Pennsylvania studying a molecular pathway in roundworms that’s involved in cellular development. The genes for the proteins in this pathway are mutated in at least 30% of human cancers. My work demonstrated how these pathways control the basic type and shape of a cell. I was the first in that lab to study that pathway, so I had to build a lot of tools from scratch. That’s been a theme throughout my career: I like charting new courses.
And the next course you charted took you to neuroscience. Why?
Neuroscience seemed to be in its golden age. People from various disciplines were coming together to study the brain, yet it seemed like there were still more questions than answers, so there was space for me to make an impact. I moved into sensory neuroscience in part because of its logical simplicity: Receptors in the skin become activated, and then you somehow get perception in the brain after a series of relays. Of the sensory systems, touch is the least studied. Some of the big questions are still open.
How did you make up for your lack of knowledge?
At first, I was insecure about my lack of formal training. As a postdoc I had never taken a neuroscience class. At meetings and in conversations with neuroscientists, I often found I couldn’t keep up. I didn’t know the lingo. But I had been meeting regularly with Michael Nusbaum, the director of biomedical research at Penn, after asking him to mentor me. One day in his office, he suggested he tutor me in neuroscience. For two hours a week for over a year, we’d discuss neuroscience papers, starting back in the 1970s and 1980s. I learned neuroscience that way. It emboldened me to say, “OK, I am a neuroscientist.”
I’m African American. Mikey Nusbaum is a white Jewish man from New York City. Sometimes the people in life who support you the most may not have any direct connection to you and your culture.
Though he has sometimes faced racism, Abdus-Saboor appreciates the network of support that has always been there for him. “Sometimes the people in life who support you the most may not have any direct connection to you and your culture,” he said.
Sasha Maslov for Quanta Magazine
How did you come up with your pain scale?
For my work in pain, I took a step back. If we were going to use mice to study pain and potentially develop new painkillers, we first needed to answer the question: How do we know the animal is experiencing pain? Traditionally, researchers look at how often an animal withdraws its paw from a stimulus, but animals move their paws for all sorts of reasons. And because there was no standardization, different labs would decide that the same stimulus was innocuous, painful or very painful depending on the experiment. So I said, “We need to develop a whole new system.”
How did you get the idea for that?
I got the idea from Michael Granato, a Penn neuroscientist whose lab was near ours. He was studying the acoustic startle response in larval zebra fish. I went to a lab meeting in which Roshan Jain, then a postdoc in the Granato lab and now faculty at Haverford College, talked about the use of high-speed videography to capture response movements that are too rapid to appreciate with the naked eye. I realized that we could use the same approach to record an animal’s movements in response to a skin stimulus, and use those movements to approximate the animal’s pain. That opened up a whole new world.
If I hadn’t gone to that meeting with the zebra fish scientist, I would have never gotten this idea. I still go to talks and listen to people talk about worms, flies, fish, yeast, bacteria — you name it — because maybe I’ll learn something I can integrate into the work that we do. The shame of modern science is that everyone is hyperfocused on their system, their approach, their organism, their discipline. It can stifle innovation when people are not broadly trained and don’t step outside their comfort zone.
How did you connect a mouse’s movements to its experience to create a scale for measuring pain?
First, we verified that a stimulus deemed innocuous, like the touch of a soft makeup brush, activated touch neurons in the animal’s skin, and that a needle pricking the skin activated pain neurons. Then we recorded the animal’s response movements to each stimulus. For pain, the animal would grimace, quickly withdraw its paw and shake it vigorously. We gave a numerical value to each type of movement, the speed of withdrawal and the number of paw shakes. We then gave each number a numerical weight, an eigenvalue, based on how important the feature was to the pain level, and then combined the weighted values into a single quantitative measure of pain.
Abdus-Saboor is critical of the current tendency for researchers to focus on their own systems to the exclusion of others. “It can stifle innovation when people … don’t step outside their comfort zone.”
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How do you see this new tool being used?
There are two things we are very excited about. One is studying genetic variability as a driver of pain. The global human population has widely varying pain sensitivities. Some of that is sociocultural, but some of it is in the DNA. For instance, people who don’t feel any pain whatsoever have genetic mutations that underlie that trait. In my lab, we’ve used our pain scale to measure the pain sensitivities of about 20 different mouse strains. We have identified mice that don’t respond much to pain and others that are hypersensitive. We are using genetic mapping approaches to find new genes that may underlie this pain sensitivity.
We are also super excited about how the brain controls the transition from acute to chronic pain. We use our pain scale to measure the pain level in a mouse and then take a snapshot of the mouse’s brain activity using functional magnetic resonance imaging. We image the animals every day to find brain activity patterns that underlie the transition from acute to chronic pain. Once we find them, we can try to change them to alter the course of chronic pain. We’re interested in the emotional as well as sensory components of this pain.
Have you studied touch that is not painful as well?
Yes, in our recent Cell paper, we went from the skin to the brain to explain why some forms of touch are rewarding.
It’s amazing that hadn’t been done before.
The molecular study of touch is still in its relative infancy. The molecular features of the different classes of touch neurons were only identified in the late 2000s. Since then, a lot of the focus has been on discriminative touch, the kind of touch used to discriminate a quarter from a dime based on texture. Social stroking touch has been vastly under-studied.
How did this project get started?
David Anderson’s group at the California Institute of Technology had reported in 2013 that certain cells in the skin responded to gentle touch. But they hadn’t implicated those cells in any natural behavior or made a connection to the brain. I read the paper and decided to try to fill these gaps. In my final year as a postdoc, I genetically engineered mice to have gentle touch neurons that responded to blue light. My plan was to stimulate the neurons with blue light and see what the mice did.
When I started my own lab in 2018, we were ready to start those experiments. I still remember the day the students came into my office to show me what they had found. It was like this eureka moment. When we activated neurons through the skin on the mice’s backs, the animals behaved as if they were being stroked there. That launched the whole project. We did a lot more behavioral tests and traced the pathway for social touch from the skin to the spinal cord to the reward centers in the brain.
“The sky is the limit,” Abdus-Saboor said. He encourages young researchers not to let disappointments bring them down. “Don’t crush your own dreams.”
Sasha Maslov for Quanta Magazine
Does finding this skin-to-brain pathway have any medical implications?
Yes, the skin is a good therapeutic target. It’s accessible and presents a direct highway to the part of the brain that makes us feel good. What if we could turn on these neurons with a skin cream to improve mental health — say, to offset the harm caused by social isolation or to treat anxiety or depression? When I gave a talk about this in December, the psychiatrists and neuropharmacologists in the audience were very enthusiastic about the therapeutic potential.
You have a colony of naked mole rats. What are you doing with them?
Naked mole rats hail from East Africa. They live underground and are essentially blind, relying heavily on touch, using whisker-like hairs to navigate their burrows and interact with each other. Touch occupies an area of their brain three times larger than in other mammals. We believe touch is important for shaping their communal social structure.
We’re also interested in them because mole rats do not feel some forms of pain. For example, they show no pain response to the molecule capsaicin, the active ingredient in hot peppers, which is quite painful to most mammals. They have receptors in their skin that respond to capsaicin, so I hypothesize that the animals have brain pathways that shut down the pain. If we can find and tap into those signals, we might find a new way to block pain.
As a young researcher, what hurdles have you had to overcome, whether scientific, social or cultural?
Overall, I’ve been quite fortunate to have had mentors and colleagues of all races, nationalities and genders who believed in me and supported me. I’ve been more fortunate than some other underrepresented minorities who’ve worked in really challenging environments, and because of that, they’re not here today.
That said, I haven’t gone through unscathed. University police have stopped me and harassed me because they did not think I belonged on the campus. I’ve been stopped in my own building, and authorities have been called on me. Most other Black scientists I know have had very similar experiences. These things happen not just at the university but also in the neighborhood I live in, and when they do, they don’t feel good and can provoke anger and frustration. But I’ve always had a network of people who support me and have helped me push though the relatively few times in my career where I’ve experienced that sort of overt racism.
Do you have advice for aspiring Black scientists?
The sky is the limit. Don’t be embittered if you look around and don’t see a lot of people who look like you, because that’s changing. Surround yourself with good people. Sometimes these folks will look like you, but don’t be surprised if some of your biggest supporters don’t. Be open and make the right connections.
And don’t crush your own dreams. We need people from all backgrounds, all walks of life, because we have challenging problems in front of us. I would encourage Black scientists or any person who’s interested in this work: If you have a love and passion for it, go for it.
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