Jeff Hoch felt a strong pull to his career – quite literally.
As a professor of molecular biology and biophysics in UConn’s School of Medicine, Hoch uses nuclear magnetic resonance (NMR) to study protein structure and dynamics.
These magnets are massive. NMR spectrometers weigh several tons and stand 10 feet tall or more. This technology works in the same way as magnetic resonance imaging (MRI), but on a much finer scale.
NMR spectroscopy places the nucleus of an atom in a magnetic field. When exposed to this field and excited with a pulse of radio-frequency energy, each part of a protein produces a specific frequency of radiation which scientists use to build a picture of the molecule.
A Lifelong Love Affair
Hoch started working with NMR as an undergraduate doing summer research at Boston University and continued as a research assistant after graduation.
“It’s been a lifelong love affair,” Hoch says. “I got a taste for magnetic resonance as a probe of matter over that summer.”
When Hoch began working with NMR, the technology was primitive, yet it was developing quickly.
“It keeps you young,” Hoch says. “You perpetually remain a student because the field evolves constantly and very rapidly, so we’re always learning.”
Much of the research Hoch performed on computational NMR methods early in his career have become much more relevant recently. More researchers now have access to the kind of computational power necessary to use them.
“It’s no longer limited to the province of people who have access to room-sized super computers,” Hoch says. “Now people with laptops can make use of these methods.”
After receiving his Ph.D. from Harvard University, Hoch worked at the Rowland Institute for Science for 23 years. With the passing of its founding director Greg Mullen, Hoch came to UConn to lead the Gregory P. Mullen NMR Structural Biology Facility.
“His legacy has gone on to expand and have even broader impacts,” Hoch says.
The facility has become a useful resource for researchers throughout New England.
“We’re turning UConn Health into a mini powerhouse,” Hoch says.
Unlocking Latent Knowledge
Hoch serves as the director for the Biological Magnetic Resonance Data Bank (BMRB), a massive depository for NMR data. The center was originally established in 1980 at the University of Wisconsin, Madison. When the founding director retired, Hoch took over. The center is now moving to Farmington.
The bank allows scientists to validate or extend results from completed studies.
It’s the great untapped potential. There is latent knowledge sitting there on a scale that’s almost unimaginable, and it’s only latent because of our inability to draw those connections. — Jeff Hoch, School of Medicine
“There’s a real push these days in making data more open and accessible,” Hoch says. “We really have a responsibility to make sure the results of taxpayer-funded research are open and accessible to everyone.”
NMR has clinical applications as it can help identify the quantity of various biomarkers in biofluids like blood plasma, urine, or spinal fluid. This can help clinicians diagnose patients and identify how they are responding to treatment.
While technologies such as mass spectrometry can also be used and are more sensitive to detecting the kind of molecules in biofluids, NMR is better at providing an output of the quantity of these molecules.
“We’re hoping to make BMRB much more useful for people working in clinical applications of NMR like diagnostics and drug discovery,” Hoch says.
Hoch is also the director of NMRbox, a resource for NMR software.
Hoch is addressing problems with data federation, or the aggregation of data from disparate sources.
There is an extraordinary amount of information about protein structure and dynamics available, but they exist in different locations making it difficult to identify connections between the various sources.
Developing a single database would be unwieldly and quickly become outdated. Instead, Hoch is developing virtual tools that can parse through these data sources for researchers.
Through a grant funded by UConn’s Office of the Vice President for Research, Hoch is collaborating with colleagues from the Department of Cell Biology and the Center for Cell Analysis and Modeling.
“It’s the great untapped potential,” Hoch says. “There is latent knowledge sitting there on a scale that’s almost unimaginable and it’s only latent because of our inability to draw those connections. My hope is we can develop tools to unlock latent knowledge that’s already been collected.”
While they will be directed to NMR applications, these tools could be used across fields as all disciplines struggle with the challenges of data federation.
The Unexpected Wonders of Basic Science
In his own lab, Hoch studies how proteins interact with their environments and carry out their biological functions.
“Proteins are not rigid,” Hoch says. “They fluctuate over many length scales and time scales.”
One protein Hoch studies is prolactin, which is important for lactation and blood vessel formation.
While studying prolactin, Hoch was getting results unlike any other protein he had ever researched. He realized these anomalies were the result of metal impurities in the solution they used to prepare the molecule.
Hoch’s lab then purposefully added metals to the solution to see how prolactin interacts with them. They discovered prolactin has two metal binding sites on opposite sides of the molecule. Scientists previously thought there was only one.
“It was kind of serendipity,” Hoch says. “We weren’t looking for that at all. It’s just one of those things that just fell out of a chance observation.”
This breakthrough explains why prolactin can create large aggregates. When metal attaches to prolactin, it attracts another to join. The second metal-binding site on the other side of the molecule is free to bind to another prolactin.
By contrast, with human growth hormone, which is similar to prolactin in many ways, the metal binding sites on two copies of the protein are buried at the interface. This means when two of them bind, the metal-binding site is unavailable for further binding, so they cannot create these aggregates.
This is an important discovery for Hoch’s larger goal of understanding interactions between prolactin, which floats in the bloodstream, and the receptors to which it binds on cell surfaces.
Hoch is also studying proteins from SARS-COV-2, the virus that causes COVID-19. His lab is working to annotate the function of these proteins to gain a better understanding of how the virus operates.
While Hoch does not study drug development directly, his work lays the groundwork for it. Most drugs target proteins, so knowing the structure and dynamics of these proteins is critical.
“Basic science is about understanding biology and life and matter without a specific application in mind,” Hoch says. “But it turns out it’s exceedingly important that we have basic science in hand for any application down the line.”
This approach to science allows Hoch to explore and discover in ways applied science does not.
“You find nature is full of surprises you wouldn’t have found if you were only looking at applied science,” Hoch says.
