Why is this Scientist so Excited?

Scientists are justifiably cautious when they talk about their research. “Possibly,” “presumably,” “probably,” they say. “Our research suggests . . . .” So, when a scientist gets excited, and that excitement spreads to those around her, it gets your attention.

“This is a great paper!” exclaimed geneticist Dennis Guberski ’75, ’83G, after evaluating the research of Jeanne Hardy, associate professor of chemistry at UMass Amherst. “Fantastic! I read academic papers every day of my life, and I can’t wait to shake her hand.” Guberski is president of Biomere Biomedical Research Models Inc., based in Worcester, Massachusetts.

Hardy’s research, which focuses on a key protein linked to neurological disorders, such as Alzheimer’s disease, won the inaugural Mahoney Life Sciences Prize at UMass Amherst this spring. Guberski was one of the expert judges on the award panel. The $10,000 prize recognizes scientists from the College of Natural Sciences whose work significantly advances connections between research and industry. The prize will be awarded annually to one faculty member who is the principal author of a peer-reviewed paper about original research.

The prize was established by three alumni brothers: Richard Mahoney ’55, ’83H, William Mahoney ’55, and Robert Mahoney ’70, all chemistry majors, who went on to become leaders in their industries and serve as high-level campus advisers.

Richard Mahoney, former president and CEO of Monsanto, shares Guberski’s appreciation of Hardy’s work and the research of the nine other Mahoney prize finalists. “I was delighted to learn about this research, and I’m impressed by the scope of the translational research at CNS,” he said. “It’s important to be relevant.”

For her part, Hardy is understandably enthusiastic about many developments at UMass: the research that resulted in the Mahoney Prize, her “super-awesome” students, the “amazing” support of the Massachusetts Life Sciences Center, and the “game-changing” Synapt G2 mass spectrometer in the new Institute for Applied Life Sciences.

Hardy’s excitement over their discoveries is palpable as she explains the research behind the winning paper she wrote with Kevin Dagbay ’15G, ’17PhD. The Hardy lab has been intensively investigating a group of 12 human proteins known as caspases, which are active in programmed cell death and inflammation. “They are really powerful because they can cut up other proteins and change life or death outcomes,” Hardy says.

“Have you ever seen a picture of an Alzheimer’s patient’s brain?” she asks. “Huge regions of the brain have holes that look like Swiss cheese. If you analyze critical Alzheimer’s proteins of the brain, like tau, you’ll see that much of it has been cleaved by caspase-6 [C6]. The idea is that if we block the activity of C6, it will be an effective treatment for Alzheimer’s and other neuro-degenerative disorders, such as Huntington’s disease.”

Research over the last decade in the Hardy lab had revealed much about the function of C6. Next, explains Hardy, “We wanted to know how the structure of C6 changes. We recognize that if we can understand the protein’s motions in molecular detail, then we can develop targeted drugs to control C6 function.”

This is where the new mass spectrometer came into play. Using this equipment, purchased with a grant from the Massachusetts Life Sciences Center, Dagbay collected more than 25,000 pieces of data that allowed Hardy’s team to define the molecular motions during the maturation process of C6.

“Our capacity to do experiments has dramatically increased with the acquisition of the mass spec and other equipment,” says Hardy, eagerly conveying the delight she takes in the new tools. “The speed and reproducibility of our experiments is so much higher than before. We have facilities that are equal to or better than the country’s biggest and best research centers. And, thanks to the foresight of the campus administration, we have amazing core facility directors who keep the equipment running and train users. We all recognize that it is the support we’ve had from both campus and state leadership that has made our research life this outstanding!”

Now that Hardy’s lab has crucial insight into the structure and dynamics of C6, the next step is to take advantage of those changes in structure to develop Alzheimer’s disease therapies. “The elegance of this therapeutic approach lies in its simplicity,” remarks Guberski. “This may be the pivotal paper to cure Alzheimer’s.” 

“But every new drug is a moon shot, and now it’s up to the engineers,” he continues. Cautions Hardy, “We have to go over a billion hurdles on our way to make a difference for people with neurodegeneration—funding, partnerships, testing . . .”

The drug development process takes many years, and there will be many “possiblies,” “presumablies,” and “probablies” along the way, but now, at prize time, excitement is appropriate, even in the lab. Hardy says: “We all have personal investment and pride in our research. We work on science that can impact human diseases. That’s what continues to motivate us to do to this work.”

NINE UMASS Leaders in Applied Life Sciences

How can we detect rare biomolecules in a reliable, inexpensive way?

Min Chen has invented an innovative nanopore for finding the “needle in the haystack”: rare biomolecules in complex samples. This technology has broad applications for detecting targets such as pathogens, cancer biomarkers, and contaminants in media such as blood, soil, and food. Chen’s nanopore is flexible, with a highly sensitive dynamic interface. It is also much simpler to engineer than existing nanopores, so it may be rapidly produced. Chen is already collaborating with Oxford Nanopore Technologies to develop this new class of nanopore into industry-ready detectors.

How can we treat human infection without stimulating antibiotic resistance in bacteria?

Peter Chien looks at the specific features that make pathogenic bacteria infectious, so that we can inhibit bacterial virulence selectively. This approach will allow us to treat infections without putting pressure on noninfectious bacteria to evolve antibiotic resistance and let us eliminate virulent bacteria without harming potentially useful microbes. All known human pathogens require proteases, which are enzymes that break down proteins, to be infectious, but these proteases are often dispensable for normal growth. Chien has uncovered how one highly conserved family of these proteases selects certain proteins to break down at certain times, which will allow us to find ways to block this activity.

How can we reduce human exposure to pesticides?

Lili He has developed an innovative method that informs the safe and effective application of pesticide. Chemical pesticides are widely used and play an essential role in agriculture production, but there is increasing evidence that exposure to pesticide is associated with human health problems. He’s method allows us to tell how deeply pesticide has penetrated into plant tissue, where it is difficult to remove by washing. The method has attracted the attention of BASF Corporation, which is using the technology to study new pesticides, in order to develop strategies to formulate and apply the pesticides safely and effectively.

How can we sustainably produce sophisticated electronic materials?

Derek Lovley has redesigned electronic materials using bacteria to produce nanowires that are highly functional in an environmentally friendly way. The microorganism Geobacter naturally produces electrically conductive protein filaments. Lovely has designed synthetic genes that enable Geobacter to produce copious quantities of protein nanowires that are very thin and that can sense specific chemicals or that have finely tuned conductivity for specific types of sensors. This research has established a new field of “e-biologics,” including a start-up company of that name.

How can we support a strong immune system response in cases of illness?

Leonid Pobezinsky has gained insight into how to help the immune system work at its full capacity to fight disease. T-killer cells are the most potent killer cells involved in the immune response to viruses and tumors. Unfortunately, under pathological conditions such as chronic viral infections or cancer,T-killer cells often lose their functionality, making it very difficult to treat these diseases. Pobezinsky has discovered a molecular switch that turns T-killer cells on or off, opening up the possibility for designing therapies that improve T-killer cell performance. Pobezinsky recently received a large industry grant to explore these translational possibilities.

How can we improve treatment of genetic diseases?

Vince Rotello has developed a strategy that will help the CRISPR gene editing tool realize its full potential for treating genetic diseases. CRISPR molecules enter a cell nucleus and can make precise changes to problematic genetic code. However, the current method of CRISPR therapy creates major problems of unwanted gene editing and immune responses because the CRISPR genes remain in the host cells after they are delivered. Rotello has demonstrated a novel alternative approach that overcomes these limitations, thereby enabling the powerful capabilities of CRISPR system. The research has been patented, and two industrial partnerships have been generated to apply the technology for both therapeutic and agricultural use.

How can we ensure that protein-based drugs reach their targets?

Thayumanavan has developed a novel and practical strategy for delivering protein- and antibody-based drugs into cells so that they function as intended. In this strategy, polymers self-assemble to form a sheath around the protein, analogous to “shrink-wrapping” the protein. The sheath protects and preserves the protein’s structure and function and releases the protein upon entry into the cell. In addition to the applications for protein therapeutics and devices, the technology can be used to design reagents for basic biochemical research. Thayumanavan is currently working with industry partners toward both applications, in part through his start-up company, Cyta Therapeutics.

How can we ensure that protein-based drugs are safe and effective?

Richard Vachet has developed an innovative method to perform quality control on protein-based drugs. In order to be safe and effective, protein-based drugs must maintain their proper three‐dimensional (3-D) structure. The Vachet lab developed an approach based on chemical labeling and mass spectrometry that is more rapid and provides much more structural resolution than commonly used techniques. The approach is the subject of a pending patent, and a company called QuarryBio has recently licensed this technology. Our lab is collaborating with QuarryBio on ways to further extend this method to make it more readily available for pharmaceutical companies to use.

How can we provide sufficient nutrients to crops without damaging the environment?

Dong Wang seeks to address one of the “grand challenges of engineering”: to restore balance to the global nitrogen cycle. Specifically, he researches the symbiosis between legumes and nitrogen-fixing bacteria, which allows legumes to provide their own supply of nitrogen. He has discovered a key protein that enables this symbiosis and has found that this protein is present in nonlegume plants. Together, these insights could simplify the task of expanding the range of crops that fix their own nitrogen. Developing those plants would reduce the need for man-made fertilizers, thereby reducing the extensive damage they cause to ecosystems.