HHMI award will help Department of Biology faculty unravel the mysteries of precision gene expression across the proteome
Noah Daly | Department of Biology
July 23, 2024
To better understand how cells precisely control the levels of their proteins, Associate Professor Gene-Wei Li utilizes rigorous quantitative analysis to improve our molecular understandings of life. With the support he’ll receive as an HHMI Investigator, Li will explore how genomes are sculpted to allow lifeforms to survive in a competitive environment.
As versatile and durable as cells are, their every function depends on producing precise quantities of proteins. These proteins enable the cells to perform their functions, their organelles to work, and tell the cells when to grow or decompose. Without precise instructions for how much protein they need to generate, organisms would struggle to self-regulate efficiently, rendering them incapable of becoming competitive life forms. These “recipes” for protein production are written into the genetic code of all life. Recent advances in DNA sequencing have identified every protein an organism can produce–every “ingredient” in the genetic cookbook. Despite these significant advances, researchers still don’t know how to read the instructions.
Since opening his lab at MIT in 2015, Associate Professor of Biology Gene-Wei Li has been working, among other things, on quantifying the amount of proteins cells produce and how that process is orchestrated within the cell.
“The goal that we hope to achieve,” Li says, “is to read the genomic sequence and accurately tell you not just what types of proteins are made, but also how many of them will be made.”
Li was recently named a 2024 Howard Hughes Medical Institute Investigator, one of 26 newly appointed Investigators hailing from 19 institutions. Each HHMI Investigator will receive roughly $11 million in support over a seven-year term, potentially renewable indefinitely. This support includes their full salary and benefits, a generous research budget, scientific equipment, and additional resources.
“I feel grateful for the extremely supportive environment in my department,” Li says. “This award is also a recognition for the hard work and risk-taking by my lab’s current and past trainees.”
Other MIT School of Science faculty joining the 2024 cohort include Mary Gehring, Professor of Biology and Core Member and David Baltimore Chair in Biomedical Research at the Whitehead Institute; Steven Flavell, Associate Professor of Brain and Cognitive Sciences and Investigator in the Picower Institute for Learning and Memory; and Mehrdad Jazayeri, Professor of Brain and Cognitive Sciences at the McGovern Institute.
Of the nearly 1,000 researchers who applied to be HHMI investigators this year, successful applicants were selected for their singular accomplishments in scientific research. They receive extensive resources to continue their work at their home institution. HHMI enables scientists to pursue their work with extraordinary freedom, allowing them to expand their current efforts, pivot focus as needed, and execute original ideas.
One of the hallmarks of Li’s lab is the devoted attention he gives to his students. Each member of the lab receives extensive guidance and mentorship, enabling them to pursue careers in science while sharing their ideas and concerns with fellow lab members and Li. For this inclusive culture, Li was honored by MIT as “Committed to Caring” for 2020-2021.
“When scientists create environments in which others can thrive, we all benefit,” says HHMI President Erin O’Shea. “These newest HHMI Investigators are extraordinary, not only because of their outstanding research endeavors but also because they mentor and empower the next generation of scientists to work alongside them at the cutting edge.”
In his lab, Li has emphasized the interweaving of individual achievement and the success of the group, creating a space for lab members to learn from one another, freely question their principal investigator, and ultimately make breakthroughs together.
Discovery through Collaboration
While Li’s lab was built around the question of quantifying a cell’s protein synthesis–that is, the amounts of all the proteins produced in a cell—his background is in physics. He approaches his work by making quantitative and systematic measurements (mainly with high-throughput DNA sequencing tools) and using that information to uncover fundamental molecular mechanisms in gene expression.
The Li lab’s early work utilizing this methodology demonstrated that proteins that go on to form complexes are made in the correct ratios to immediately form complexes with few extra copies.
Li’s team went on to discover that metabolic proteins are synthesized at precise ratios that are conserved across evolutionarily distant species, such as the two bacterial model organisms E. coli and B. subtilis. However, despite their shared output of protein production, the billions of years of evolution gave rise to two completely different ways to control protein quantity.
In 2020, this line of research produced a study that contradicted the longstanding dogma of molecular biology that the machinery of protein synthesis and RNA polymerase work side by side in bacteria, which it does in E coli.
According to Li, two of his graduate student researchers found that, in B. subtilis, the ribosome lags far behind RNA polymerase, a process the lab termed “runaway transcription.” They found that the coordination between transcription and translation is fundamentally different between E. coli and B. subtilis. They then identified bioinformatic signatures, revealing that this kind of uncoupling between transcription and translation is widespread across many species of bacteria. The students, Grace Johnson, a former graduate student in the Department of Biology, and Jean-Benoît Lalanne, a former graduate student in the Department of Physics, were the lead authors of the paper, which appeared in Nature.
“This is very exciting stuff, but all the credit goes to my grad students,” Li chuckles.
Finding the Room to Be Bold
The support from Howard Hughes Medical Institute enables Li and his team the flexibility to pursue the basic research that leads to discoveries.
“Having this award really allows us to be bold and to do things at a scale that wasn’t possible before. The discovery of runaway transcription is a great example of this,” Li says.
Li plans on using the funds made available from HHMI to help determine how functionally related genes differ in their expression and how signals are encoded in the genome at the DNA and RNA levels. According to Li, the collection of high-quality and system-wide data is essential to making discoveries in his field.
“I’m incredibly grateful to HHMI for encouraging us to pursue this work and follow the science wherever it leads us,” he says.
Li and his team are as eager as ever to understand life’s coded cookbook.
“The work of science begins with great people,” Li says. “This award will help ensure our lab continues to be a place where incredible young scientists can work together to achieve miraculous things.”
