Part 1: Early Influences and Intellectual Formation

Will: Mark, thank you for taking the time to do this. The goal of this conversation is to document your scientific journey for SSIB. I’d like to understand not just what you worked on, but how your thinking developed, how the field evolved around you, and what shaped your approach to science.

Let’s start at the beginning. What first drew you toward science?

Mark: My father was a doctor, a general practitioner, so I grew up around medicine. We had Netter’s medical illustration books in the house which covered the nervous system, digestive system, endocrine system. They even had a supplement on the hypothalamus.

As a kid, I found those books fascinating. Some of the images were pretty horrific, but I was captivated. So I suspect that growing up in that kind of medical atmosphere influenced me early on.

As a teenager, I became interested in psychology. I read a lot by Freud and about him. When I got to college and discovered that psychology was no longer dominated by Freud, it opened my eyes. I became interested in physiological psychology. I recently dug up my old textbook by Morgan and Morgan and it’s practically entirely underlined. I was fully engaged.

Will: When you got to college, did you already know you wanted to pursue that direction, or did it evolve once you started doing research?

Mark: It evolved. I didn’t even declare a major at first. I considered pre-med briefly, but I got wrapped up in physiological psychology after taking a course.

As an undergraduate at the University of Maryland, I worked in a lab doing grunt work feeding dogs and hosing out the kennel. In that building was Herman Teitelbaum, who was Philip Teitelbaum’s younger brother. He was studying somatosensory cross-hemisphere transfer in cats. I ran his cats and eventually did my honors thesis with him.

At the time, Bart Hoebel had shown that electrically stimulating the lateral hypothalamus in rats at the same site where they self-stimulated would also cause them to eat. The interpretation was that the reward from the stimulation was that from eating and therefore that the same neural substrate mediated both self-stimulation and feeding.

Herman suggested looking at the relationship more systematically. Instead of just showing that stimulation could elicit both behaviors, he proposed correlating the amount of self-stimulation with the amount of eating at the same current and stimulation parameters.

We implanted electrodes in rats and measured how much they self-stimulated over a given period. Then we tested how much they ate when given stimulation at the same parameters.

We found no correlation whatsoever.

Will: That must have been surprising, given how influential the lateral hypothalamus reward model was at the time.

Mark: It was. The stimulation clearly affected feeding, that part replicated. But there was no relationship between how much an animal self-stimulated and how much it ate under the same conditions.

We tried to publish the paper. Herman submitted it to multiple journals, and it was rejected everywhere. I still have the manuscript.

Looking back, that experience probably shaped me. It reinforced the idea that you shouldn’t accept prevailing interpretations without testing them carefully. Sometimes the relationship people assume just isn’t there.

Will: When you were applying to graduate school, what direction did you think you were heading?

Mark: I remember writing in my applications that I was interested in hypothalamic control of food intake and secondarily in taste.

I applied to several places. I got into Syracuse with Matt Wayner. I applied to the Institute of Animal Behavior at Rutgers, where Lehrman was studying reproductive behavior. There were interesting opportunities in multiple directions.

There was even some confusion at Rutgers because there was already another Mark Friedman, and my application got misplaced.

Ultimately, I chose Princeton and went to work with Bart Hoebel.

Will: What drew you specifically to Bart’s lab?

Mark: Bart knew about the work I had done as an undergraduate. But what really happened was that once I was there, I became interested in metabolism.

At the time, there was debate about whether hyperphagia after VMH lesions was due to hyperinsulinemia. I started reading about pancreas, insulin, and metabolic regulation. I discovered that rats could be made diabetic with alloxan, a beta-cell cytotoxin, this was before streptozotocin became standard.

So I designed an experiment in which I induced diabetes, maintained animals on insulin replacement so their intake and body weight were normalized, and then produced VMH lesions to see what would happen.

The first time I did it, I made a mistake. After 30 days of insulin treatment, I gave the long-acting insulin the day before surgery. All the animals were dead the next morning. They became hypoglycemic under anesthesia.

When I told Bart, he said, “Oh yes, we had that problem before. You can’t give insulin the day before surgery.”

I started over.

That experiment became my first publication (in the American Journal of Physiology). Bart helped me write it, but he didn’t put his name on it. He felt it was my idea and my work.

Will: The idea of publishing a single author research paper is amazing, especially compared to authorship norms today. How did that independence affect you?

Mark: It gave me freedom. Bart would ask questions and speculate, for example, what diabetes might do to self-stimulation, but he let me pursue my own ideas.

That independence mattered. It allowed me to follow metabolic questions where they led.

Will: Was that what drew you more deeply into metabolism?

Mark: Yes. There was another key observation from that study:

Untreated diabetic rats are hyperphagic and drink enormous amounts of water and excrete glucose in their urine. Measuring spillage is a messy pain. In those days, high-fat diet was powdered chow mixed with Crisco. Rats didn’t spill that.

So I fed untreated diabetic rats the high-fat diet. What struck me was that they did not become hyperphagic as expected. They ate normal amounts, despite spilling glucose and being unable to utilize it properly. And they remained thin.

At the time, the dominant models were the glucostatic and lipostatic theories of feeding. This preparation didn’t fit either model. That anomaly stayed with me. It pushed me toward thinking more broadly about metabolic control. Specifically, thinking about the use of alternative fuels in the control of intake, which raised the notion of a signal in the final common path for energy generation. Also, it suggested that it isn’t the amount of fat stored that’s being sensed to control intake, but what is done with it in terms of storage and mobilization.

That early observation guided much of my later work and my thinking to this day.

Part 2: Development, Homeostasis, and the Liver ATP Hypothesis

Will: After this early metabolic work, your research path broadened quite a bit. You moved into developmental questions and thirst regulation. How did that transition happen?

Mark: At Princeton, after working with Bart, I moved into Byron Campbell’s lab. At the time, Byron was what became to be called a developmental psychobiologist. He gave his graduate students a great deal of freedom. But he would give very direct feedback. He would say exactly what he thought about your ideas. But he let you pursue them.

In his lab I began working on the development of regulation, especially thirst and milk intake in suckling rats.

We were studying the development of thirst and induced thirst in rats from the earliest weaning age onwards in various ways, making them hypovolemic, injecting hypertonic saline or ligating the vena cava to stimulate the renin angiotensin system. We found that very young rats, right after weaning at 16 days of age, would drink in response to hypovolemia. However, it took longer before they responded to salt loading or vena caval ligation in the same way.

That made me wonder whether suckling itself was regulated partly by a hypovolemic thirst mechanism.

Will: So the question became whether milk intake in pups was being driven by fluid balance rather than just gastric fill?

Mark: Exactly. My dissertation focused on control of milk intake in suckling rats.

At the time, the prevailing idea was that milk intake was largely driven by gastric fill. First, I found that intake was limited by how much milk the mother produces. But if you avoid that by providing pups sequentially with foster mothers that hadn’t nursed for a while after the pups drained their mother, they would continue consuming milk. Although there was some upper limit, they would, continue suckling and, more importantly, suckle more if we made them hypovolemic. That indicated a control of milk intake related to fluid balance that was independent of the mother’s milk supply.

So milk intake was controlled, but not by gastric filling. There was physiological regulation involved.

Will: You then moved to Pittsburgh for your postdoctoral work with Ed Stricker. How did that influence your thinking?

Mark: Working with Ed was formative. He was deeply focused on homeostasis, especially thirst and body fluid regulation.

One of the most elegant studies I did, along with John Bruno, a grad student, and Jeff Alberts a grad student colleague of mine from Princeton who was then at Indiana University, involved maternal recycling of fluids. Mothers lick their pups and ingest the pups’ urine. We injected pups with tritiated water and measured radioactivity in the mothers’ and their littermates’ blood and urine.

We showed that mothers were recycling a significant portion of their fluid intake through the pups. It accounted for roughly one third of their body fluid needs.

If mothers were deprived of pup urine, they drank more water. If they were deprived of water, they licked the pups more. It was a beautifully regulated system.

At about the same time, a group from Australia studying desert animals published similar findings regarding recycling in Science with other species. Their model did not account for exchange between pups. Based on our tracer data, we wrote a letter to the editor pointing out that there appeared to be fluid exchange not only between mother and pups but also among pups, likely through evaporative transfer. We also alerted the authors of our findings and it turned out to solve a missing piece in their model.

It was a satisfying example of how science can work and how physiological regulation can operate at a systems/social level.

Will: That work clearly reflects a strong homeostatic framework. When did the liver begin to enter the picture more centrally?

Mark: The liver work developed from metabolic questions that had been accumulating in my head for years and, of course, I was familiar with Mauricio Russek’s work on hepatic control of food intake.

Earlier, as a postdoc, I had worked with Neil Rowland, another postdoc at Pitt at the time, comparing fructose and ketone body infusions during insulin induced hypoglycemia. Fructose does not significantly enter the brain, whereas ketone bodies do and can serve as a fuel - that alternative fuel issue again.

When animals are made hypoglycemic with insulin, they eat and show a centrally-mediated adreno-medullary response that can be measured from an increase in circulating epinephrine. We found that ketone bodies blocked the epinephrine response at doses that did not block feeding. Fructose blocked feeding, but not the epinephrine response.

That dissociation suggested that peripheral metabolic signals could influence feeding independently of central hypoglycemia sensing.

Years later at Monell, Mike Tordoff and I revisited fructose infusions. We were infusing fructose either through the portal vein or systemically. We saw that portal delivery was more effective at reducing intake early in the infusion, which made sense given the liver is its main site of uptake and metabolism.

We began thinking that what we needed was a liver specific metabolic inhibitor analogous to 2- deoxyglucose, but based on fructose.

Will: And that is where 2,5 anhydromannitol (2,5-AM) came in?

Mark: Yes. Monell had received funding from the Corn Refiners Association to hire carbohydrate chemists. Mike DiNovi and Bob Rafka joined as postdoctoral fellows.

We learned about 2,5-AM, which is a fructose analog (missing the hydroxyl group at the 2-position of the furanose form). They synthesized it for us. The synthesis involved starting from glucosamine derived from chitin. They used to joke that they were starting from crab shells.

Right away we found that giving rats 2,5-AM during the daylight hours caused them to eat, taking a few meals they wouldn’t otherwise take. We went on to find that this effect was due to the 2,5-AM acting in the liver; for example, portal vein infusions were much more effective and cutting the hepatic vagus blocked the response.

In vitro studies in the literature had shown that 2,5-AM depletes hepatic ATP by trapping phosphate. It gets phosphorylated twice and then stops, effectively sequestering phosphate and preventing ATP regeneration. We then went on to see whether this drop in liver energy status was involved in the eating response. Again, harping back to the notion of a final common path in metabolic fuel metabolism providing a signal for feeding control.

Will: What were the key experiments that convinced you this was a meaningful signal?

Mark: First, Nancy Rawson, who was my grad student at the time, was all over this. Through her contacts at Penn, we collaboratively performed NMR studies on livers in anesthetized rats and demonstrated that doses of 2,5-AM sufficient to stimulate feeding reduced hepatic ATP.

Then, Nancy conducted experiments showing that administering sodium phosphate before 2,5-AM treatment prevented both the drop in liver ATP and the feeding response, consistent with the phosphate trapping mechanism of action of the fructose analogue

She also used L-ethionine, a methionine analog that traps adenosine to lower hepatic ATP. It produced an even more pronounced feeding response

That convergence strengthened the interpretation that something tied to ATP availability or production was influencing intake.

Will: You also explored possible transduction mechanisms. What did you find?

Mark: We considered multiple mechanisms. Scharrer and Langhans had suggested sodium pump involvement. Using hepatocytes and NMR with shift reagents, we demonstrated changes in sodium gradients consistent with ATP-dependent sodium pump disruption.

Nancy also measured calcium transients in hepatocytes exposed to 2,5-AM and observed changes that could represent downstream signaling events.

We were trying to understand at a rudimentary level how an energy status changes in the liver might be converted into a neural signal.

Will: Did you also examine normal physiological conditions, such as fasting and refeeding?

Mark: Yes. With Hong Ji, we measured ATP, ADP, and inorganic phosphate, which allowed us to calculate phosphorylation potential (the capacity for ATP production) during fasting and refeeding. Consistent with the literature, hepatic ATP levels dropped after an overnight fast and recovered in parallel with refeeding. The same was true for phosphorylation index and was even more pronounced. Limiting intake during refeeding also limited recovery of ATP and the index.

We also had a line of research going in parallel to the liver ATP work that focused on the control of intake by fatty acid oxidation. This research got us into looking at diet-induced obesity (DIO) and we found that susceptibility to DIO was associated with a reduced capacity for hepatic fatty acid oxidation. These lines came together when we found that the eating response to pharmacological inhibition of fatty acid oxidation was more closely associated with decreased liver energy status than with hepatic fatty acid oxidation. This work culminated in finding evidence that liver energy status was more vulnerable (with respect to recovery from fasting and 2,5-AM injection) in rats susceptible to DIO (obesity-prone animals), That suggested a potential link between energy sensing mechanisms and the development of obesity

But despite its promise, interest in energy sensing and control of intake has faded in the field. There has been subsequent research on central energy sensing based on changes in neuronal AMPK, but that too seems to have faded as well. It’s unfortunate because it gets to the heart of how eating behavior is connected to energy homeostasis, which is a fundamental question. If I could start again, energy sensing in the control of food intake is what I’d study.

Part 3: Field Resistance, Obesity, SSIB, and Advice for the Next Generation

Will: You have been developing this liver centered, metabolism focused framework for decades. When you look back, where do you think the biggest resistance came from? Was it about the data itself, or more about the prevailing way people conceptualized feeding control?

Mark: It evolved over time.

Early on, we were pushing against a very cerebrocentric view of feeding control. That perspective was dominant. The paper I wrote as a postdoc with Ed Stricker was titled, “The Physiological Psychology of Hunger: A Physiological Perspective,” because at that time there really was not much physiological perspective outside the brain and hypothalamus in particular.

Later, the field shifted heavily toward endocrine explanations. A focus on CCK and the discovery of leptin and other hormones changed the landscape. Hormones are tangible. You can hold them in your hand, measure them, inject them, manipulate them directly. That makes them easier to conceptualize than something process-oriented like metabolism.

Then genetics expanded dramatically. The molecular tools have been extraordinary. They have allowed identification and manipulation of specific neurons, which is remarkable. But in terms of explaining the cause of obesity, I am not convinced genetics has provided decisive answers. Others may disagree, but that is my view. After all, we could account for up to 50% of the variance in diet-induced weight gain after a switch to a high-fat/high-carb diet based on fat oxidation. With few rare exceptions, genetic variants account for considerably less.

So the resistance was not necessarily about the data. It was about dominant paradigms.

Will: Can you give an example of how that played out in practice?

Mark: I remember submitting a grant proposing that liver ATP changes might contribute to overeating in obesity. We had pilot data from Zucker rats, VMH lesioned animals, and DIO obese animals suggesting they all had relatively low hepatic ATP.

One reviewer wrote that obesity is multifactorial and asked why we would expect to see a common effect across models.

That comment reflected a conceptual barrier. Multifactorial does not mean there cannot be shared downstream mechanisms. But the assumption was that heterogeneity precluded convergence. (I should also say that “multifactorial” can sometimes mean we just don’t understand it.)

But those kinds of reactions are part of doing science. Everyone has stories like that.

Will: To what extent do you think acceptance sometimes depended on who was reviewing the work or who was in the room?

Mark: That certainly happens. In fact, that might be a deciding factor.

I once gave a talk at an institution where a scientist who happened to be a member of the study section that reviewed many of our grants showed me his office. He had a large light box on his desk, which he told me was for seasonal affective disorder.

As I was standing there, I was amused thinking about when our grants were submitted and reviewed, and how the timing of review might influence enthusiasm. Enthusiasm matters.

That is part of the human side of the system. It has always been there.

Will: If you look at the field today, what do you see as the biggest misconceptions about metabolism and obesity?

Mark: The dominant misconception is that obesity is caused by overeating driven by palatable, rewarding or ultra-processed foods. There is a lot of correlational evidence in humans, but no direct evidence. More telling are studies in mice and rats by Mike Tordoff, Israel Ramirez and others that argue strongly that food palatability alone does not drive intake over a period of time that would result in obesity.

I see it differently and it gets back to the anomalous findings with the fat-fed diabetic rats.

In short, in many cases, there appears to be an inherent metabolic bias toward storing fuels rather than oxidizing them. If you restrict intake, animals still accumulate excess fat. They may not become as obese as ad libitum-fed animals, but they still lay down more body fat relative to controls.

If overeating were the primary cause, then preventing overeating should prevent obesity. That is not what is observed in a range of animal models. What appears to happen is a vicious cycle. A metabolic shift favors storage. That storage creates a relative energy deficit in circulating fuels and energy production, which drives compensatory intake. Increased intake then further promotes storage.

So increased intake contributes, but it may not be the initiating cause.

Will: When you zoom out historically, what do you see as the biggest shifts in the field over your career?

Mark: I once wrote a chapter titled, “Making Sense Out of Calories,” in which I described the field as a pendulum swinging between peripheral and central explanations. A pendulum swings, but it really doesn’t go anywhere.

There have been enormous technological advances. The ability to dissect neural circuits is extraordinary. Endocrine biology and molecular genetics have transformed what we can measure and manipulate.

Yet fundamental questions remain. How do animals regulate calorie intake? Richter was writing about this in the 1940s. It has been more than eighty years. We still do not have a fully satisfying answer.

One encouraging development is increasing attention to central-peripheral loops. Instead of brain versus body, there is greater recognition of dynamic bidirectional communication. I think that is a meaningful conceptual advance.

Will: You were also involved in SSIB from its earliest days. How did the society come into being?

Mark: Before SSIB, ingestive behavior research was presented largely at Eastern Psychological Association meetings. A group of us began meeting informally the night before those meetings. We would gather at a restaurant. Each person would give a five-minute talk about ongoing work. It was intense and interactive.

That informal group eventually evolved into SSIB, largely, if not entirely, through Harry Kissileff’s initiative and hard work.

Will: When you served as president, what did the society most need at that time?

Mark: We needed financial stability. I worked to strengthen industry connections and raise funds.

Will: For trainees navigating today’s scientific environment, what advice feels most important?

Mark: When I trained, people I knew were not thinking strategically about careers in the way they do now. We focused on the next scientific question, the research. Some individuals obtained faculty positions directly out of graduate school. Needless to say, that environment was different.

Today the competition is more intense. Planning matters more.

Still, I believe in following intellectual curiosity. Work with mentors whose thinking you respect.

I learned different things from my mentors. Herman Teitelbaum taught me that you must have a problem. You cannot just accumulate experiments. Bart Hoebel emphasized finding a phenomenon, in a way just the opposite. Byron Campbell said you need a story to tell. Ed Stricker taught me that every word counts and advised minimizing unnecessary committee work.

Karl Popper, a philosopher of science, who’s been a sort of mentor, wrote that our hypotheses die in our stead. That idea stayed with me. You should not be afraid to be wrong. If an idea fails, let it fail and move forward.

Will: Are there other ideas about science that have stayed with you over the years?

Mark: Yes. There’s more from Popper who talks about two approaches to science in his essay, “The Bucket and the Searchlight: Two Theories of Science.” The “bucket” approach is to gather as many facts/observations as you can with the assumption it eventually will all come together as an explanation. The searchlight refers to starting with a theory – a potential explanation – that shows what kinds of observations to make to test the theory. Also, Popper’s idea of the importance of a black swan, by which he meant an anomalous finding like mine with the fat-fed diabetic rats. Those kinds of observations, if not based on a methodological issue, force a change in where to look for an explanation. Finally, in that vein, I’d point to Robert Frost’s poem, “The Road Not Taken”:

Two roads diverged in a wood, and I—

I took the one less traveled by,

And that has made all the difference.

Will: That is a fitting place to end. Thank you, Mark, for taking the time to reflect on your scientific journey and for sharing these insights with the SSIB community.