FHCC
In April 2022, Fred Hutchinson Cancer Research Center and Seattle Cancer Care Alliance became Fred Hutchinson Cancer Center, an independent, nonprofit organization that also serves as UW Medicine’s cancer program.
Dr. Maria Toro Moreno, a postdoctoral fellow at Fred Hutchinson Cancer Center, was named a Howard Hughes Medical Institute Hanna Gray Fellow. Jointly mentored by evolutionary biologist Dr. Harmit Malik and computational and molecular biologist Dr. Arvind “Rasi” Subramaniam, Toro Moreno studies microproteins. These tiny proteins, made up of fewer than 100 amino acids, have been mostly overlooked in biology. Toro Moreno is working to understand whether certain microproteins defend against infections like HIV and influenza, and whether they can shed light on how new genes arise and evolve.
Toro Moreno is one of 25 “outstanding” young scientists recognized by HHMI for their promise. Hanna Gray Fellows receive up to $1.4 million in financial support over eight years. The funding bridges their postdoctoral training and first years as independent investigators leading their own laboratories. HHMI developed the Hanna H. Gray Fellows Program to increase diversity in biomedical science by recruiting and retaining individuals from groups currently underrepresented in the life sciences and by creating inclusive environments in which all scientists can thrive.
Like all HHMI funding, the award is flexible and allows researchers to change direction as their projects and curiosity dictate.
“The fellowship makes my next steps easier,” Toro Moreno said. “It provides a safety net, which allows me to do riskier research. I have more room to explore.”
Microproteins: Overlooked no longer
Researchers define microproteins as proteins made up of less than 100 amino acids. Proteins are encoded in our DNA, but it’s not always clear when DNA “letters” (the bases that make up the DNA strand) spell out a protein. Proteins aren’t spelled out in a single word of unbroken DNA letters — they’re more like sentences of DNA “words” strung together. Some proteins are long sentences of many words, and some are short sentences of just a few words.
When first studying the DNA of organisms, researchers assumed that gene-like DNA “words” that spelled out fewer than 100 amino acids couldn’t possibly encode real proteins. Even in studies purporting to look at all the proteins or genes within a cell, these stubs were overlooked.
But in the last 10 years, that attitude has changed completely, Toro Moreno said. It’s becoming clear that some small DNA words encode microproteins, and that these tiny proteins could play important roles within our cells. So far, only a few microproteins have been studied in depth, Toro Moreno said, but some common themes have emerged.
“Microproteins seem to act like molecular glue that bind to protein complexes. They’re very sticky,” she said.
By sticking so tightly to their targets, microproteins can either encourage proteins to interact, or block their targets’ activity. But there’s still a lot to learn about what roles microproteins could be playing within cells and how their activity could affect our health, Toro Moreno said.
“These proteins were never accounted for in [molecular] screens or when looking for markers of disease,” she noted. “Microproteins are new raw material for that.”
A window into the origins of genes?
Toro Moreno trained as a chemical biologist interested in interactions between pathogens and their hosts, but her interest in microproteins stretches far beyond their implications for health. Microprotein genes could teach us about how genes evolve, how our interactions with other organisms are recorded in our DNA, and how this record can reveal those interactions.
Some genes that encode microproteins can evolve rapidly. If a gene is changing rapidly, this often means that the protein it encodes is locked in an arms race with another protein. Her co-mentor Malik, an HHMI Investigator, has demonstrated that this occurs with antiviral genes and viruses. As viruses evolve to evade host defenses, those defenses evolve to better block the virus. This sets up a continual cycle of attack and counterattack, and immune genes locked in this cycle change more quickly than genes that encode proteins whose roles change little over thousands or tens of thousands of years.
Toro Moreno wants to know whether the speedy evolution of some microprotein genes documents just such an evolutionary arms race. Do certain microproteins protect against infection? Toro Moreno is focusing on viruses like HIV and influenza as potential microprotein opponents. High-throughput genomics approaches pioneered by Subramaniam will allow her to assess the potential antiviral function of a large repertoire of microproteins encoded in human DNA.
Toro Moreno’s work could also reveal fundamental truths about how new genes form.
The idea is that in some evolutionary arms races, “the pressures are so extreme they could drive the birth of new genes,” she said.
Many microprotein genes found in human DNA are not found in the DNA of other animals. And they’re tiny. Could this mean that they are infant genes? Could studying how they change mean studying how new genes baby-step their way to maturity? Perhaps.
If Toro Moreno is correct, she’ll be uncovering an unrecognized strategy for defense against infection and discovering how new genes are made. And even if her ideas are wrong, there’s still much to learn about these under-appreciated molecules.
“They were unknown unknowns, now they’re known unknowns,” she said.
And ripe for study.
“I am delighted by this award for Maria,” Malik said. “It rewards her scientific ambition, creativity and resilience. Although she is very modest and understated, she was able to convince Rasi and me about this exciting new frontier of biology during her interview. We are delighted to serve as co-mentors to help her establish her independent research program.”
Toro Moreno is the second Hutch Hanna Gray Fellow. Dr. Jeanette Tenthorey was named a fellow in 2018. Co-mentored by Malik and Hutch virologist Dr. Michael Emerman, Tenthorey is finishing the postdoctoral portion of her fellowship.
