Stephen Blacklow has biomedical curiosity in his genes.
As the newest Board of Directors member at the Institute for Protein Innovation (IPI) and the Gustavus Adolphus Pfeiffer Professor and chair of the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, Blacklow has spent decades untangling the secrets behind HIV infection, cholesterol regulation and tumor development.
He’s not the first in his family to dedicate his life to treating disease — but he is the first to do so on a molecular level.
In the 1920s, Blacklow’s grandfather made the rounds as a “bag-carrying” town doctor on the outskirts of Boston, a position he held for more than 60 years. His two sons, Blacklow’s father and uncle, would later follow in his footsteps to become physicians.
“In my family, there’s this whole lineage of medicine,” Blacklow says, “I always assumed that interest in science manifested itself in becoming a doctor.”
But as a student at Harvard Medical School, he quickly grew frustrated by the mechanistic questions underlying medicine.
“What is the cause of this disease? Why does it have these symptoms?” he remembers thinking. In the mid-1980s — before in-depth studies of the human genome — “you just didn’t know much. You couldn’t explain anything in detail, certainly not at the molecular level,” he says.
So he added a Ph.D. to his M.D. In Harvard’s Department of Chemistry, he studied enzymes and mechanisms of catalysis with “brilliant, elegant” chemist Jeremy Knowles. After graduating with both degrees in 1991 and completing his residency in pathology at Brigham and Women’s Hospital, he became increasingly engrossed in structural biology questions with significant implications for human health and therapeutic discovery — namely, cell signaling pathways in normal and diseased states.
“The marriage of wanting to work on things that have human relevance with the rigor of chemistry — it’s the merger of those two things that define me as a scientist,” Blacklow says.
From that juncture, Blacklow has spent decades embedded at the forefront of transmembrane receptor and cell signaling research, where biological detail at the atomic scale defines life.
As a postdoctoral fellow at the Whitehead Institute of Biomedical Research, Blacklow worked under the guidance of protein biochemist Peter Kim to successfully uncover the trimeric complex that drove viral and cellular membranes to fuse and initiate HIV-1 infection.
As an early professor at Stanford University and later Harvard Medical School, he drilled into the structure of the low-density lipoprotein (LDL) receptor, a cell surface receptor central to cholesterol uptake. With the help of collaborators, including IPI co-founder Timothy Springer, he built a progressively more granular picture of the mutations and folding defects implicated in familial hypercholesterolemia, a genetic disorder that heightens the risk of coronary artery disease and heart attack.
This work would serve as a jumping-off point for the major question of his career: how the structure and function of the highly conserved Notch signaling pathway correlates to pathogenic states in a variety of genetic disorders and cancers, including leukemia.
The Notch receptor is a single-pass transmembrane protein that plays a role in cell-to-cell communication during embryonic development. But mutations in the mechanotransduction pathway are associated with genetic disorders and cancers, including leukemia, in which the receptor may act oncogenically, at times, or drive tumor suppression.
Alongside Harvard pathologist Jon Aster, Blacklow has steadily pieced together the structural assembly of Notch transcriptional activation complexes. By determining the autoinhibition mechanisms of the deceptively simple receptor and demonstrating how sending cells activate Notch signaling through mechanical force, he’s offered insights into a range of life threatening conditions.
That work, enabled by a talented team of trainees, postdocs and collaborators, has shaped his approach in heading Harvard’s Department of Biological Chemistry and Molecular Pharmacology over the past 10 years.
“Science is a search for fundamental truths that are not bound by hierarchy,” he says. “So if there’s a way to tackle an important question and someone has a good idea, you act on it.”
Today, Blacklow sees the need for a reliable set of reagents to uncover the regulatory mechanisms in Notch signaling and other systems — a problem he thinks IPI can tackle.
“I believe in the purpose of IPI and what it can be,” says Blacklow. “Going well beyond the boundary of providing an antibody repertoire to the scientific community, IPI can be really innovative and creative.”
In protein science, every experiment is ambitious, but there are few places dedicated solely to protein research, Blacklow says. Few labs have the spectrum of tools necessary to build high-quality antibodies and take on non-uniform, shape-shifting complexes — which often act and react in unexpected ways.
But with powerful tools and funding in place, IPI is positioned to produce well-characterized, rigorously-tested antibody reagents. And it can make them openly available, “liberating them from dependence on [the] exorbitant expense associated with acquiring antibodies of uncertain quality,” Blacklow says. He intends to push the Institute to that full potential.
“I see this as an adventure, and I don’t know where it’s going to lead,” he says. “I think that the people involved are at the highest level — these are people with amazing capability. So the opportunity to be a part of the leadership team for something with the kind of potential that exists is a big part of why I’m here.”
The Institute for Protein Innovation is pioneering a new approach to scientific discovery and collaboration. As a nonprofit research institute, we provide the biomedical research community with synthetic antibodies and deep protein expertise, empowering scientists to explore fundamental biological processes and pinpoint new targets for therapeutic development. IPI’s mission is to advance protein science to accelerate research and improve human health.For more information, visit https://proteininnovation.org/ or follow us on social media, @ipiproteins
Source: Stephen Blacklow, stephen_blacklow@hms.harvard.edu