A coin toss led Marie Heffern to inorganic chemistry.
As an undergraduate student at University of Southern California, Heffern knew she wanted her science to mean something. The field of forensics seemed like a space where one could have an impact, and Heffern had cold-emailed the crime laboratory director of the Los Angeles County Sheriff’s Department.
“I said, ‘Can I go to coffee with you, so I can figure out how to have a career in forensics?’” the now UC Davis associate professor of chemistry recalled. “And he agreed to meet with me!”
By the end of the meeting Heffern learned that if she wanted to pursue the forensic sciences, she needed a Ph.D. degree. And if she wanted to be competitive as a graduate school applicant, she needed undergraduate research experience.
It just so happened an opportunity waited in her email inbox. A graduate student in the chemistry department was seeking an undergraduate student for a summer project.
“I showed up at this grad student’s office and there’s only one other undergrad there,” Heffern said. “I kid you not, the grad student goes, ‘Heads or tails?’ I don’t remember which one I called, but I won the coin toss and that’s how I got the position.”
The research project involved advancing the chemical components underlying organic light-emitting diodes, a premium display technology. It wasn’t forensics, but the experience opened Heffern to the rules-free world of inorganic chemistry.
“In organic chemistry, you learn the octet rule and that carbon can’t have more than four bonds,” Heffern said. “In inorganic chemistry, it’s the opposite. If there are rules, they’re meant to be broken and I just kind of saw it as this big playground.”
In a class that followed, Heffern learned about the field of bioinorganic chemistry, which analyzes the role metals play in the health of biological organisms. She was fascinated by the therapeutic potential of metals, that you could tune their reactivity to do something biology doesn’t normally do.
“Because of that, you can potentially use it as a medicine,” Heffern said. “That was actually originally why I got into inorganic chemistry.”
What are metal micronutrients and why do they matter?
Today, the Heffern Lab in the College of Letters and Science at UC Davis studies the relationship between the metal micronutrients naturally in our bodies, how nutritional intake impacts those metal micronutrients, and how that relates to the pathology and diagnostic biomarkers for endocrine disorders, such as diabetes, liver disease and cancer.
“We really do try to give voice and hold up a microphone to the models in our body in a way that goes beyond basic science,” Heffern said. “We do a lot of really cool, intricate research in the lab, but then you have diseases that happen in real people and we don’t have a way of connecting those two when it comes to the metal chemistry.”
Metal ions are fundamental to life. Across all biological organisms, copper, iron and zinc, among other metal ions, signal and activate numerous biological processes, from aiding in oxygen transport and kickstarting immune function to acting as scaffolding for proteins and maintaining nerve signaling. But the nuances of these interactions aren’t well understood.
“There’s a big hole, not just in academia but in industry, of the impact metals have in biology,” Heffern said. “We have to bridge what we understand about how models behave in our biological systems and how that can apply to questions that are clinically applicable.”
How metal micronutrients influence health and disease
Many metal-mediated interactions occur inside the cell, but the Heffern Lab is particularly interested in the extracellular environment, the spaces outside and between the cells.
“We believe that it is home to a lot of communication between tissues in our body, but then on the flip side, some of that information goes into our blood and can be used as potential biomarkers that we otherwise ignore,” Heffern said.
Heffern and her colleagues have learned that macronutrients in our diets, such as sugars and fats, affect the metal populations in our blood in ways that can’t be ascertained with current clinical technologies.
“If you get a blood draw, one of the things they’ll test you for iron, but those markers are not actually looking directly at iron,” Heffern said. “You’re looking at proteins that are supposed to be proxies for your iron levels and what we’ve learned is that those proxies are not entirely accurate for anything besides a genetic disorder.”
Heffern and her lab have developed tools more capable of ascertaining the metal micronutrient balance in blood, allowing them to observe how diet affects that balance and how that balance relates to health and disease.
Creating the new field of “metalloendocrinology”
In one project, the team is focusing on how metal micronutrients affect C-peptide, a byproduct of insulin production in the pancreas and a biomarker for diabetic diseases.
Heffern and her colleagues have found that C-peptide levels, or more accurately, the interpretation of them in a clinical setting, are influenced by other components in the blood, specifically an abundant carrier protein called albumin and the metal micronutrient copper.
“If you do your standard clinical immunoassay of C-peptide,” Heffern said, “the quantification of C-peptide is artificially inflated when you have copper and albumin there together.”
That is a concern, she added, because many diabetic patients actually have excess amounts of copper and excess amounts of albumin floating around.
Such nuanced interactions can drastically affect diagnostics and clinical interpretation. Heffern and her colleagues have conducted similar metal micronutrient characterization research on other hormones, such as oxytocin and glucagon-like peptide-1, or GLP-1.
“We know that Ozempic works in a large cohort of individuals, but there’s a large percentage that are actually non-responders,” Heffern said. “We’ve been investigating these contexts to ask whether one of the components that’s missing is the interaction of metals that we don’t otherwise pay attention to.”
Heffern and her colleagues have coined this hormone-focused, metal micronutrient research as “metalloendocrinology.”
Research existing in the complexity of biology
Accomplishing sound “metalloendocrinology” research requires a holistic view of the body, one that accounts for its numerous cellular and extracellular complexities.
“There’s one big issue, which is that we don’t have the technology to study this in a very comprehensive way,” Heffern said. “And we do everything in aqueous, biologically relevant environments.”
Heffern is developing and refining the tools that can provide that view.
A recent award from Agilent Technologies, a scientific instrumentation company, is also making a difference. Using a suite of advanced instrumentation provided by the company, Heffern and her colleagues will analyze metal-peptide-protein interactions in complex cellular and extracellular environments. Additionally, the team hopes that those observations will help build a predictive framework that can inform and advance drug design and formulation.
“Let’s live in the complexity of the cellular environment and see what happens,” Heffern said.
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