Perspectives: Home Field Advantage
Director Roger Cone discusses how experts across disciplines tackle complex challenges together at the LSI, and how this collaborative spirit leads to scientific wins
New GLP-1 drugs such as Ozempic and Wegovy have rapidly become household names, hailed by many patients and physicians for their effectiveness in treating obesity and diabetes. These drugs are not a perfect solution for everyone, though; studies estimate that 10% to 20% of patients see little or no weight loss, and half of patients stop taking GLP-1s within a year of starting the medication, many in response to negative side effects.
For more than two decades, Roger Cone, Mary Sue Coleman Director of the Life Sciences Institute, has studied the brain circuitry that regulates energy balances and food intake. Recently, his lab uncovered biological mechanisms that could be leveraged to refine the effectiveness of GLP-1 drugs.
The discovery comes at a time when Cone is concluding his decade-long tenure as the LSI’s director to return to research full time. He has guided the LSI as it expanded its scientific discovery cores, recruited 11 new faculty members, launched new educational programs for both high school and postdoctoral researchers, and navigated a national pandemic and changing federal funding landscape.
Here, Cone reflects on what attracted him to the LSI, how the institute’s unique atmosphere has influenced his own research and what's next for his lab as he transitions into the role of a full-time faculty member.
What do you think makes the LSI unique?
The LSI intentionally recruits people who internalize diversity, who are comfortable talking, thinking and working with people that do very different things to solve big problems.
We have people here doing everything from synthetic organic chemistry to human medical genetics, from the smallest molecules to whole organisms. We have scientists across all different disciplines who are regularly engaging. We can go get a chemical compound to use in our research. We can determine a structure. We can talk to a physician scientist about human genetics and how that is relevant to the process that we’re studying.
To me, that’s what makes the LSI great.
You’ve referred to this method of recruiting LSI scientists as the “best athletes” approach. How does the LSI cultivate an atmosphere where independently successful individuals want to invest in collaborative efforts?
There are two major things that we try to do. One is the type of person that we recruit. We don’t want to just hire the best person in cryo-EM; we want to hire the best person in cryo-EM who wants to collaborate widely, bringing in skills from other areas of expertise to solve difficult problems within their field.
Secondly, we try to create a small, collegial environment. For example, we have regular workshops where faculty members share their research ideas with each other. We create a comfortable environment for them to discuss new, potentially high-risk ideas, and get feedback from a chemist, a geneticist, a medical doctor. That doesn’t happen in a lot of discipline-specific departments. You don’t often have people in widely divergent fields together in one room, focused on your specific question and commenting on how you could better solve this problem using another technique or area of expertise.
Has this approach impacted research within your own lab at the LSI?
Yes, in many ways. For example, I had spent a lot of time working to understand one specific receptor protein in the brain called the melanocortin 3 (MC3) receptor. When looking at receptor function, pharmacology is a great tool, since you can block a receptor and an hour later ask what the effect is. A colleague of mine had published a study describing the only credible molecule that could bind to the MC3 receptor and block its activity. I contacted her and asked if she could send us some, but she did not have any of it and had no plans to make more because it had been so challenging to synthesize.
I walked down two floors and showed the structure to Anna Mapp, a faculty member here who is an expert in synthesizing complex molecules. She looked at it and said, “Oh, yeah, we can make that.” Her lab not only succeeded in making the molecule, but also developed a more efficient route to making it than the published method.
That is just one of many examples of what makes the LSI unique. Someone like me, who has zero chemistry expertise but needs a chemical to solve a problem, can just go down the hall and talk to a chemist, and they’ll collaborate with me because they love to work in different areas.
Our faculty have widely different areas of expertise and skills, and they come together in a single building, breaking down barriers to cross-disciplinary work and collaborating to solve problems. That’s why I came to the LSI, and I’m really looking forward to spending more time pursuing my research in this amazing environment.
Why are the melanocortin receptors important to understand?
Mutations in the melanocortin 4 (MC4) receptor were discovered to be the most common genetic cause of obesity in humans. Leptin is a signal that tells the brain how much energy you have in the form of fat, and it depends on MC4 receptor signaling. A mutation in even one copy of the MC4R gene produced early-onset severe obesity.
In contrast, turning off the MC3 receptor did not provide a satisfying hypothesis as to its role in energy regulation. The animals did show some late-onset modest obesity; but, on the other hand, the animals showed heightened sensitivity to multiple weight loss stimuli. Overall, the animals showed an inability to maintain a proper energy balance. We realized, partially through experiments with the molecule from Anna’s lab, that the MC3 receptor acts as an energy regulator, but in a more complex manner than the MC4 receptors.
If you think about a thermostat, it doesn’t really keep the temperature constant. When the temperature hits a lower boundary, the furnace comes on and raises it. When the temperature hits an upper boundary, the furnace goes off and the temperature starts going back down. As a result, the temperature fluctuates between upper and lower boundaries. We demonstrated that the MC3 receptor functions in much the same way, regulating the upper and lower boundaries of energy balances, in part by blocking the activity of MC4 receptor neurons.
Understanding how the MC3 and MC4 receptors interact to influence the body’s regulation of energy, including the desire to eat and how energy is stored, is essential for addressing a range of metabolic disorders, from obesity to anorexia.
How do the melanocortin receptors interface with the rapid emergence of GLP-1 drugs, such as Ozempic?
GLP-1 is a gut peptide, and its normal role is to signal satiety, or fullness, to the brain. At high levels of GLP-1, nausea occurs. At low levels, nothing occurs. The trick was to figure out how to ramp up GLP-1 levels to inhibit food intake without terrible nausea occurring. They cause a pre-satiation effect. You feel full, you eat less, you lose weight.
The GLP-1 inhibition of food intake requires the melanocortin circuits to work. If you block the melanocortin circuits, you can reduce GLP-1-induced inhibition of feeding. We hypothesized that if we sensitize the melanocortin system, either by removing the inhibitory effects of MC3 or by partially activating MC4 neurons, we can sensitize animals to the weight loss effects of the GLP-1 drugs, making the GLP-1 drugs more effective.
What’s next for your research program as you transition from the directorship back into the role of a full-time faculty member?
We have made several findings over the last few years that I’m really fascinated by and want to solve, and now I will have more time and intellectual energy to do that. I want to understand how sensitizing the melanocortin system can improve the activity of obesity therapeutics. In addition, the activity of the MC4 receptor appears to be linearly related to body weight. We don’t yet understand the mechanism that drives that relationship, and I have a few theories to test. I also hope to further advance our understanding of anorexia, cachexia and other disorders of inadequate nutritional intake, and determine if regulation of the melanocortin circuits can be used to treat some of these disorders.
In my decade as director, I’ve focused on recruiting world-class scientists, keeping our discovery technology at the cutting edge and making these resources accessible to all. Our faculty have widely different areas of expertise and skills, and they come together in a single building, breaking down barriers to cross-disciplinary work and collaborating to solve problems. That’s why I came to the LSI, and I’m really looking forward to spending more time pursuing my research in this amazing environment.