Photo: Gretchen Ertl

Deciphering the cellular mechanisms behind ALS

Professor Ernest Fraenkel has decoded fundamental aspects of Huntington’s disease and glioblastoma, and is now using computation to better understand amyotrophic lateral sclerosis.

Michaela Jarvis | School of Engineering • mit
March 6, 2024 8 minSource

At a time in which scientific research is increasingly cross-disciplinary, Ernest Fraenkel, the Grover M. Hermann Professor in Health Sciences and Technology in MIT’s Department of Biological Engineering, stands out as both a very early adopter of drawing from different scientific fields and a great advocate of the practice today.

When Fraenkel’s students find themselves at an impasse in their work, he suggests they approach their problem from a different angle or look for inspiration in a completely unrelated field.

“I think the thing that I always come back to is try going around it from the side,” Fraenkel says. “Everyone in the field is working in exactly the same way. Maybe you’ll come up with a solution by doing something different.”

Fraenkel’s work untangling the often-complicated mechanisms of disease to develop targeted therapies employs methods from the world of computer science, including algorithms that bring focus to processes most likely to be relevant. Using such methods, he has decoded fundamental aspects of Huntington’s disease and glioblastoma, and he and his collaborators are working to understand the mechanisms behind amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

Very early on, Fraenkel was exposed to a merging of scientific disciplines. One of his teachers in high school, who was a student at Columbia University, started a program in which chemistry, physics, and biology were taught together. The teacher encouraged Fraenkel to visit a lab at Columbia run by Cyrus Levinthal, a physicist who taught one of the first biophysics classes at MIT. Fraenkel not only worked at the lab for a summer, he left high school (later earning an equivalency diploma) and started working at the lab full time and taking classes at Columbia.

“Here was a lab that was studying really important questions in biology, but the head of it had trained in physics,” Fraenkel says. “The idea that you could get really important insights by cross-fertilization, that’s something that I’ve always really appreciated. And now, we can see how this approach can impact how people are being treated for diseases or reveal really important fundamentals of science.”

Breaking barriers

At MIT, Fraenkel works in the Department of Biological Engineering and co-directs the Computational Systems Biology graduate program. For the study of ALS, he and his collaborators at Massachusetts General Hospital (MGH), including neurologist and neuroscientist Merit Cudkowicz, were recently awarded $1.25 million each from the nonprofit EverythingALS organization. The strategy behind the gift, Fraenkel says, is to encourage MIT and MGH to increase their collaboration, eventually enlisting other organizations as well, to form a hub for ALS research “to break down barriers in the field and really focus on the core problems.”

Fraenkel has been working with EverythingALS and their data scientists in collaboration with doctors James Berry of MGH and Lyle Ostrow of Temple University. He also works extensively with the nonprofit Answer ALS, a consortium of scientists studying the disease.

Fraenkel first got interested in ALS and other neurodegenerative diseases because traditional molecular biology research had not yielded effective therapies or, in the case of ALS, much insight into the disease’s causes.

“I was interested in places where the traditional approaches of molecular biology” — in which researchers hypothesize that a certain protein or gene or pathway is key to understanding a disease — “were not having a lot of luck or impact,” Fraenkel says. “Those are the places where if you come at it from another direction, the field could really advance.”

Fraenkel says that while traditional molecular biology has produced many valuable discoveries, it’s not very systematic. “If you start with the wrong hypothesis, you’re not going to get very far,” he says.

Systems biology, on the other hand, measures many cellular changes — including transcription of genes, protein-DNA interactions, of thousands of chemical compounds and of protein modifications — and can apply artificial intelligence and machine learning to those measurements to collectively identify the most important interactions.

“The goal of systems biology is to systematically measure as many cellular changes as possible, integrate this data, and let the data guide you to the most promising hypotheses,” Fraenkel says.

The Answer ALS project, with which Frankel works, involves approximately a thousand people with ALS who provided clinical information about their disease and blood cells. Their blood cells were reprogrammed to be pluripotent stem cells, meaning that the cells could be used to grow neurons that are studied and compared to neurons from a control group.

Emotional connection

While Fraenkel was intellectually inspired to apply systems biology to the challenging problem of understanding ALS — there is no known cause or cure for 80 to 90 percent of people with ALS — he also felt a strong emotional connection to the community of people with ALS and their advocates.

He tells a story of going to meet the director of an ALS organization in Israel who was trying to encourage scientists to work on the disease. Fraenkel knew the man had ALS. What he didn’t know before arriving at the meeting was that he was immobilized, lying in a hospital bed in his living room and only able to communicate with eye-blinking software.

“I sat down so we could both see the screen he was using to type characters out,” Fraenkel says, “and we had this fascinating conversation.”

“Here was a young guy in the prime of life, suffering in a way that’s unimaginable. At the same time, he was doing something amazing, running this organization to try to make a change. And he wasn’t the only one,” he says. “You meet one, and then another and then another — people who are sometimes on their last breaths and are still pushing to make a difference and cure the disease.”

The gift from EverythingALS — which was founded by Indu Navar after losing her husband, Peter Cohen, to ALS and later merged with CureALS, founded by Bill Nuti, who is living with ALS — aims to research the root causes of the disease, in the hope of finding therapies to stop its progression, and natural healing processes that could possibly restore function of damaged nerves.

To achieve those goals, Fraenkel says it is crucial to measure molecular changes in the cells of people with ALS and also to quantify the symptoms of ALS, which presents very differently from person to person. Fraenkel refers to how understanding the differences in various types of cancer has led to much better treatments, pointing out that ALS is nowhere near as well categorized or understood.

“The subtyping is really going to be what the field needs,” he says. “The prognosis for more than 80 percent of people with ALS is not appreciably different than it would have been 20, or maybe even 100, years ago.”

In the same way that Fraenkel was fascinated as a high school student by doing biology in a physicist’s lab, he says he loves that at MIT, different disciplines work together easily.

“You reach out to MIT colleagues in other departments, and they’re not surprised to hear from someone who’s not in their field,” Fraenkel says. “We’re a goal-oriented institution that focuses on solving hard problems.”

Reprinted with permission of MIT News

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