Basic Research How Experiences and Findings Carve Pathways to Future Discoveries

Many trade-offs exist in today’s society. When ordering food, there is a trade-off between quality and price; higher quality foods often cost more. When designing a social psychology experiment, there is a trade-off between the amount of control one has over the experiment and the extent to which results can be applied in the real world. One specific dilemma that researchers in the biological setting often face is the choice between freedom and funding. Choosing freedom allows the researcher to take their research in any direction, but they would need to apply for competitive, difficult-to-obtain grants. On the other hand, choosing funding, which typically involves working for a company, allows for plenty of money obtained from the company, but all research conducted must be consistent with the interests of that company.

Professor Larry Feig’s laboratory has taken the freedom route. Although receiving funding has been a challenge, Feig and his members have taken their research in unexpected directions. The results and experiences of previous research often dictated the next area to explore.

Background

The story of how Feig got involved in neuroscience is unique because it depended heavily on his experiences and projects. He began as a Chemical Engineering major with a focus on Bioengineering, receiving his BS at Columbia University and his MS at MIT. However, at that point, he felt that basic research matched his interests more than engineering-based research, so he secured his PhD in physiology at Harvard Medical School. During his time as a graduate student, he worked in a lab that focused on spermatogenesis and how a protein in the testes drives the production of stem cells. Feig’s exposure to this work has led him to understand how sperm cells play a role in a more recent study involving epigenetic inheritance patterns.

Feig completed his postdoctoral training at the Dana Farber Cancer Institute at around the time that oncogenes were first discovered. Oncogenes are mutated proto-oncogenes; protooncogenes regulate the cell cycle and the process of cell division. Thus, the presence of oncogenes leads to improper regulation of the cell cycle, and ultimately, cancer. Specifically, Feig focused on oncogenes of the Ras protein. When he became a professor at Tufts in 1987, he continued his work on the Ras protein and how it relates to cancer, but then he stumbled upon a protein found in the brain that regulates the Ras protein, called the RasGRF protein. This ultimately got him involved in neuroscience, which is the field that many of his current experiments are in.

Regulation of the Ras Protein

Studying the regulation of the Ras protein is one of Professor Feig’s main projects. At first, the expectation was that determining the mechanism behind the regulation of the Ras protein would lead to breakthroughs in cancer research. Instead, what Feig and his lab team found was that RasGRF (a regulatory protein for the Ras protein) was completely unrelated to the formation of tumors, and it was only expressed in fully differentiated brain neurons. At that point, Feig could have decided to abandon the project because it was not related to cancer, but he decided to study it further primarily because there was not much knowledge about Ras in the brain.

Feig has completed several “knockout” studies on mice that involve blocking the formation of the RasGRF protein. A “knockout” study is a study where the expression of a gene is blocked and the effects are analyzed. When Feig and his team measured the effect of the gene “knockout” on learning and memory, both male and female mice were affected. However, results were different when they measured how subjects responded to stress. “For some reason, which we don't know yet, when you knock out this protein in a study that responds to stress...it only affects adolescent females.” Although the same protein is expressed in males and adult females, it interestingly does not play a role in their response to stress.

Feig’s extensive research on the Ras protein and overall involvement in neuroscience stemmed from previous projects in cancer research. As Feig puts it, “That's what got me into neuroscience. It wasn't that I particularly said, 'I want to study neuroscience;' it was the results we got in the lab that I wanted to follow up.”

Epigenetic Inheritance of Stress

The Feig lab’s second major project is studying the epigenetic inheritance of the social instability stress paradigm. The ideas for this project were developed when studying Ras signaling in the brain, which contributes to learning and memory. At the time, one postdoc working at the lab who happened to be an expert on learning and memory focused primarily on how the environment impacts the brain. He ran studies that exposed adolescent mice that already had a defect in memory and learning to an enriched environment (which involved the presence of more mice, wheels for running on, and more places to explore). When this occurred, not only did those abnormal mice in the enriched environment have a normal learning ability, but their offspring did as well, which indicated some form of epigenetic inheritance (inheritance from outside the genetic code). This led to them asking the following question: would negative experiences such as stress achieve similar results?

The Feig lab’s focus on the social instability stress paradigm has led to the discovery of a unique inheritance pattern. When a male mouse is put under conditions of stress, its female offspring display stress symptoms, while the male offspring do not. When those male offspring mate, their daughters experience stress symptoms. This inheritance pattern can largely be attributed to the possibility that stress changes the micro-RNA content of sperm in the male offspring.

It is important to note that stress symptoms are not necessarily a bad thing. Feig explains, “In some way, it's a good thing that if your parents are living in a stressed environment and they adapt... your offspring are born already adapted.” This would ultimately increase the fitness of the offspring in the unfavorable environment.

“Again, it wasn't like we had some intuition necessarily to go after transgenerational inheritance...a very talented postdoc just tried something and it worked.”

As Feig puts it, “the beauty of basic research is you can really follow where it takes you.” Throughout his journey, the direction of Feig’s research has been through “stumbling upon” something that seemed promising. Much of his work on the Ras protein was due to following up his work in cancer research, and his work in transgenerational inheritance was due to following up his work on the Ras protein and using ideas from his postdoctoral student. Feig’s journey really highlights the fact that there are different ways to do research; one may decide to remain specialized in one field, or one may decide to follow up based on previous experiences and findings. Feig, by choosing the latter, has had a journey in basic research that really took him in unexpected directions.

Figure illustrates the unique inheritance pattern of the social instability

stress paradigm across multiple generations