Yehia Mechref is a Horn Distinguished Professor in the Department of Chemistry & Biochemistry.
Yehia Mechref understands the frustrations of research: the way even small questions can take years to answer, and how each answer can prompt a dozen new questions.
He also understands the vast rewards such research can reap.
As a Horn Distinguished Professor in Texas Tech University's Department of Chemistry & Biochemistry, associate vice president of research and innovation and director of the Center for Biotechnology & Genomics, Mechref has spent his entire career engaged in these kinds of pursuits – and he wouldn't have it any other way.
In part, it's because research is his passion. But of equal measure is another factor: His line of research could improve the trajectory for an increasingly large portion of the world's population.
‘Doing big things'
Mechref's work began during his postdoctoral research position at Indiana University. On his first day in the lab of renowned chemist Milos Novotny, Mechref was handed a small vial and instructed to analyze its contents; his report was expected within a few months.
“The protein in that vial was by far the most complex glycoprotein I'd ever received,” Mechref recalls. “And the idea was, nothing had been done in order to characterize the sugars associated with this protein. I had to actually learn new techniques from A to Z and repurpose my knowledge in analytical chemistry down a completely different road.”
Two and half decades later, that's Mechref's specialty, and his research is supported by an R01 research grant from the National Institutes of Health (NIH) that has been renewed twice – an unprecedented achievement at Texas Tech.
“I'm nationally and internationally known for what I do, because it wasn't just a matter of doing small things that advanced the field; we were doing big things that were advancing the field,” Mechref said, “and the entire scientific community was recognizing it.”
That recognition came because Mechref was one of the only – if not the only – chemists pursuing his line of research.
“The area I'm working in is challenging, and I'm using the word ‘challenging' just to soften the blow; it's actually very difficult,” Mechref chuckled. “But that's the beauty of research: you pick something challenging, and you advance it, making it less challenging.”
Breast cancer-brain metastasis
Mechref specializes in studying the sugars throughout the human body. These are not the kind of sugars you might use in your coffee, he notes – they're biological sugars that decorate cells and proteins. To accurately examine these proteins, glycoproteins and glycans, he has become an expert in biological applications of mass spectrometry and tandem mass spectrometry.
“Professor Mechref's research lies in a critical area of basic biological chemistry,” said Joseph A. Heppert, vice president for research and innovation. “Glycans are an incredibly important component of the cellular recognition pathways that regulate basic biological function and make all life possible. But glycans are also critically important to the success of dangerous pathogens and play a role in cellular malfunctions that represent major threats to human health.
“Understanding the pathways that allow cells to create glycans and unraveling the puzzle of how they function in biological systems can help us promote their beneficial function in healthy cells and selectively interfere with their role in diseases that threaten human life. Dr. Mechref's peers consider his research to be of the highest quality, as witnessed by the sustained level of federal support for his work, and I celebrate his repeated success in obtaining NIH grants that will continue this important research.”
Through the lens of these biological sugars, Mechref began studying cancer eight years ago by focusing on the blood-brain barrier, a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from crossing into the extracellular fluid of the central nervous system, where neurons reside.
“The blood-brain barrier is supposed to protect the brain from toxins,” Mechref explained. “It works like a filtration system to make sure no toxins make it to the brain, so you can get physically ill, but mentally, you are still sound.”
In theory, it's an excellent way for our bodies to protect our brains from infection. But in practice, it doesn't always work that way. Of particular concern are cancer cells, which can metastasize, spreading from one area of the body to another. For some reason, cancer cells are able to cross the blood-brain barrier. And unfortunately for people with cancer, chemotherapy drugs are not.
“Chemotherapy for brain cancer doesn't work,” Mechref said. “You can introduce the drug through the blood, but the blood-brain barrier is going to prevent it from getting into the brain.”
Using his knowledge of biological sugars, Mechref has been working to determine the distinctive sugar signature of breast cancer cells that can cross the blood-brain barrier versus those that cannot.
“We got lucky because we have cancer cell lines that are what we call ‘brain-seeking cancer cell lines,' so they only go to the brain,” Mechref says. “We looked at the sugar content, genomics and proteomics, and there seems to be a specific signature for those that we believe is responsible for ensuring that they have the ability to cross the blood-brain barrier.”
Neurodegenerative diseases
Unlocking the inner workings of cancer isn't Mechref's only ongoing project. The methods he uses to do that work also enable potentially life-changing research in other areas.
Expanding upon his use of mass spectrometry and tandem mass spectrometry, Mechref now is developing additional methods to enhance and advance glycan analyses for many different diseases.
“We will still be looking at the breast cancer-brain metastasis, but now we are expanding it and using our technology to look at traumatic brain injuries (TBI), Alzheimer's disease and neurodegenerative diseases,” he said. “We are looking at the development and association between TBI, Alzheimer's disease and also mild cognitive impairment, which is a prelude for Alzheimer's. We are an aging nation, and I think we need to focus our attention now on how to attend to the neurodegenerative diseases associated with that.”
Thus, the decision to expand the research was simple, Mechref says.
“Our research is diverse in that we can repurpose what we do for so many different areas,” he said. “Although our focus is looking at the sugars, we know the sugar contents are critical in so many biological and biomedical processes. So, simply, we are taking the technology we've been developing for many years and seeing if it can help us understand the development and progression of other diseases.”
More big things ahead
Part of Mechref's desire to study neurodegenerative diseases was due to an overall lack of progress in that area. For 15 years, most research in the area has focused on amyloid beta, a microscopic brain protein fragment that accumulates in the brain, disrupting communication between brain cells and eventually killing them. The problem is, after all that time, researchers still don't know if that amyloid beta aggregation is a cause of the diseases or an effect. If it's an effect, that means some other mechanism is the cause, and any treatment focusing on amyloid beta would treat only the symptoms, not the disease.
So, to Mechref, the next steps are clear: they need to be able to identify the sugars, and the proteins holding those sugars, that contribute to the effects seen in TBI and Alzheimer's disease.
“Once we identify those, we will be able to go back and look at the mechanisms of their association,” he said. “Then, if we can define that mechanism of association, we'll be able to get closer to a target for therapy.”
The work is ongoing and, like all research, Mechref doesn't exactly see an endpoint.
“There's no completion,” he said. “You set goals and you set tasks to fulfill what you want to do. But with research, if you say, ‘This is the conclusion,' then you are setting yourself to have a very limited vision of what you can do.”
