Stanford Report - September 23rd, 2021 - by Holly Alyssa MacCormick, Bruce Goldman and Erin Digitale
Stanford University researchers who study three-dimensional structures of biological molecules, aggressive brain cancers and how to heal diseased hearts are among 33 scientists from 21 institutions announced as new Howard Hughes Medical Institute investigators. The Stanford faculty members are Kristy Red-Horse, associate professor of biology at the School of Humanities and Sciences, Rhiju Das, associate professor of biochemistry, and Michelle Monje, associate professor of neurology.
HHMI investigators receive roughly $9 million over a seven-year appointment which may be renewed for additional terms. In addition to covering the researchers’ full salary, benefits and a research budget, the institute covers other expenses, including research space and the purchase of critical equipment. With today’s appointments, Stanford now has 24 HHMI investigators.
“HHMI is committed to giving outstanding biomedical scientists the time, resources and freedom they need to explore uncharted scientific territory,” said HHMI President Erin O’Shea in their announcement of the new recipients. Focusing on “people, not projects” is a guiding principle of the HHMI program which employs scientists as HHMI Investigators, rather than awarding them research grants.
Circumnavigating the heart
Red-Horse’s research focuses on blood vessels of the heart and a special subtype called collateral arteries, which can function as natural coronary artery bypasses. Not everyone has collateral arteries, and their formation and abundance vary from person to person. When they’re present, collateral arteries aren’t typically in use. But if the usual path of blood in the heart becomes blocked, collateral arteries can become active and serve as a detour for the flow of blood.
Red-Horse and her team have been studying how and when collateral arteries form, and whether inducing their growth might pave the way for a therapy for individuals with coronary heart disease.
By studying collateral development in newborn mice, Red-Horse and her team learned that they could make collateral arteries grow in adults by creating a heart blockage and injecting a protein, known as CXCL12. In the future, Red-Horse aims to uncover other proteins and pathways that may help create induced collateral arteries that work as well as the naturally occurring newborn ones.
“Ischemic heart disease is a leading cause of death worldwide. Our group studies how mouse and human embryos construct cardiac blood vessels from scratch. We then use this information to reconstruct them in diseased adult hearts,” said Red-Horse. “The HHMI appointment will allow us to add a new tool to our toolbox – comparative biology, which reveals similarities and differences between species – to discover how some species naturally develop highly protective coronary artery architectures.”
Red-Horse is a member of Stanford Bio-X and a Clark Center resident faculty member, as well as a member of the Cardiovascular Institute and the Institute for Stem Cell Biology and Regenerative Medicine and the Maternal & Child Health Research Institute (MCHRI).
Aggressive brain cancers
Monje’s research targets a group of aggressive and deadly brain tumors. Called gliomas, these tumors arise from the glial cells that surround and support neurons. Gliomas form active electrical connections – synapses – with nearby healthy neurons and use the brain’s normal electrical signals to drive their malignant growth, her team has discovered.
“One of the most lethal aspects of high-grade gliomas is that the cancer cells diffusely invade normal brain tissue so that the tumor and the healthy brain tissue are knitted together,” Monje said. “This is such an insidious group of tumors. They’re actually integrating into the brain.”
In addition to studying malignant glial cells, Monje conducts research on healthy glial cells’ roles in brain development and adaptability. Her lab has discovered that, in the healthy brain, neuronal activity causes changes in glial cells’ formation of a structure called myelin, which coats the long arms of neurons and hastens the transmission of electrical impulses. In a healthy brain, activity-dependent interactions between neurons and myelin-forming glial cells contribute to brain functions like learning and memory.
Monje’s work on understanding healthy and cancerous glia is providing new hope for better glioma therapies, as well as a better understanding of a common side effect of cancer chemotherapy, cognitive impairment known as “chemobrain.”
To treat glioma, interrupting electrical signals from the healthy brain to the cancer can slow tumor growth, her research team has learned. Using mouse models, they demonstrated that blocking a specific protein involved in synapse function halted tumor growth for several months. The team is now conducting a phase 1 clinical trial of an experimental drug that blocks the protein’s function in children with high-grade gliomas. Results are expected in 2024.
Monje is a member of Stanford Bio-X, the Institute for Stem Cell Biology and Regenerative Medicine, the Maternal & Child Health Research Institute (MCHRI), the Stanford Cancer Institute and the Wu Tsai Neurosciences Institute.
Three-dimensional structures of biological molecules
Exposing the three-dimensional structures of biological molecules can reveal valuable insights into how they work. For example, a detailed 3D map of a virus’s RNA could display vulnerable nooks and crannies that might be targets for pathogen-neutralizing drugs. The difficulty is in creating such a map: Most RNA molecules have resisted giving up their structural secrets.
“The dream – and the major goal of my research – has been to be able to take any RNA sequence and rapidly figure out its 3D structure,” Das said.
Das is now close to realizing that dream. His team began by adapting computational methods that had previously been used to predict protein shapes. Bringing these tools together with experimental data from collaborators helped reveal the shapes of entire viruses and key intracellular, RNA-based molecular machines.
Still, the shapes of most RNA molecules remain elusive. So Das and his colleagues turned to an imaging technique called cryo-electron microscopy. The effort finally nailed the structure of the first RNA-only enzyme – 40 years after it was first identified.
Das’s team hopes to build a 3D atlas of all of nature’s RNA molecules.
When the COVID-19 pandemic struck in 2020, Das quickly pivoted to study the new threat, seeking the 3D structures of key segments of coronavirus RNA. He and his lab team have collaborated with other researchers to identify “tantalizing holes and crevices” that could be binding sites for drugs, Das said. They’re now developing antiviral drugs based on those discoveries, as well as probing COVID-19 mRNA vaccines with the goal of improving them, he said.