The National Institutes of Health (NIH), which is the primary funding agency for biomedical research in the United States, is using a venture capital-style approach to find and fund unconventional studies that hold potential to transform the medical field.

This week, three UW-Madison faculty members were awarded a total of more than $6.8 million as NIH New Innovator Awards, and one faculty member was awarded an NIH Transformative Research Award. Both grant programs are offered by the NIH High-Risk, High-Reward Research Program.

Each of the three New Innovator projects tackles a stubborn problem by wielding techniques from different disciplines.

Assistant professor of neuroscience Darcie Moore, PhD is using novel approaches to determine why aging stem cells become less effective at regeneration.

Professor of medicine Nasia Safdar, MD, PhD, is leading a team of health care researchers and systems engineers to create a computational model that fights the spread of Clostridium difficile (C diff), a gastrointestinal germ that persists stubbornly in hospitals.

And assistant professor of biochemistry Srivatsan “Vatsan” Raman, PhD is using high-throughput experiments and computational tools to define the rules by which proteins switch between active and inactive states.

In addition, the Morgridge Institute’s Jan Huisken, PhD, professor of biomedical engineering, who has won an NIH Transformative Research Award to develop a complete cellular blueprint of zebrafish development.

Moore, Safdar, and Raman were each selected for an NIH New Innovator Award, which are unique grants for early-career researchers. Unlike standard NIH R01 grants, they do not require preliminary data. They also pay out the entire amount in the first year of each five-year project so work can move forward swiftly.

With three NIH New Innovator Awards in 2018, University of Wisconsin-Madison is tied for second place among all public universities in the nation for this type of grant.

Professor of neuroscience Cynthia Czajkowski, PhD, who was appointed in September as Associate Vice Chancellor for Research in the Biological Sciences, is proud of their success in competing for these awards. She explains that this accomplishment is a natural outcome of steps the university has taken in recent years to promote cutting-edge, high-impact research.

“Having three UW faculty members awarded highly competitive NIH Director's New Innovative Awards speaks to the success of our campus-wide efforts to recruit the best and brightest early-career research investigators to UW-Madison,” says Czajkowski.

There are parallels between the strategies that NIH and UW-Madison are using to spark such investigations. Money for the NIH High-Risk, High-Reward Research Program is drawn from the NIH Common Fund. Established by the NIH Reform Act of 2006, this pool of funding is set aside for cross-disciplinary research that addresses emerging scientific opportunities and pressing biomedical challenges.

Similarly, in 2015 UW-Madison launched the UW2020 Initiative, which uses proceeds from the university’s technology transfer office to fund multidisciplinary teams of researchers who are proposing highly innovative and groundbreaking research that hasn’t yet received federal grants. Moore and Raman are among UW2020 co-investigators. In 2017, the university also established strategic funding for the UW Microbiome Initiative; Safdar is among 12 principal investigators supported by that program.

“We’re putting an emphasis on stimulating creative, high risk, high-impact research,” says Czajkowski.

Not All Stem Cells Are Equal: Understanding the Toll of Aging on Neural Stem Cells

Moore’s study will examine the role neural stem cells, which can generate specialized nervous system cells, play in aging.

Specifically, it will focus on why neural stem cells segregate certain proteins unevenly between their two daughter cells when they divide.

Her initial discovery of this asymmetry occurred during her postdoctoral fellowship in Zurich, Switzerland. Moore was investigating a diffusion barrier she identified in dividing cells.

“We found polyubiquitinated proteins, or proteins destined for degradation, were segregated to only one daughter cell after the cell divided, and we have subsequently identified many other cargoes that behave similarly,” she said.

Her research team found that in neural stem cells from old mice, this diffusion barrier becomes weaker and the cells are less able to compartmentalize proteins that cause cellular aging. Because aged neural stem cells divide less and make fewer neurons, this may contribute to dysfunction.

Her research focuses on why neural stem cell proliferation and new neuron production decrease in the brain with age.

Her team will perform novel genetic screening experiments to determine the mechanisms of asymmetric cargo segregation, use automated microscopy to identify segregated cargoes and further assess their roles, and determine how these processes function in the adult brain.

“Understanding how neural stem cells function normally, as well as in disease and with aging, will help us to identify ways to therapeutically target them to improve their numbers, potentially improving cognitive function,” Moore said.

There are far-reaching implications for human health, according to Moore.

“These findings are critical to developing future therapeutic technologies,” she said. “If you don't set the foundation, you can't build a house.”

Computer-based Simulation Helps Hospitals Stop Germ Transmission

As an epidemiologist and infectious disease physician, Safdar has seen far too many patients suffer from C diff infections, which causes debilitating, difficult-to-treat diarrhea. It affects half a million Americans each year.

C diff can also be fatal, causing 29,000 deaths in the U.S. and costing over $1 billion annually.

In a cruel twist of fate, the bacterium that causes it — Clostridium difficile — thrives in hospitals.

“It got the name because it's difficult to culture in the laboratory, but its spores are resistant to almost any disinfectant you can think of,” says Safdar.

Many interventions have been tried in hospitals, including rapid testing and treatment when cases are first suspected, using rigorous cleaning protocols, requiring health care workers to suit up in protective gear, and emphasizing correct hand hygiene techniques.

“Unfortunately, the effects of these interventions have been highly variable and modest,” says Safdar. They don’t address all of the ways that the germ spreads. Many also rely on perfectly sustained human behavior, which is an unrealized goal. Nationally, studies show that only 48 percent of health care workers continually follow correct hand hygiene technique; the rate is far lower among hospital visitors.

Safdar is collaborating with a team that includes professors of engineering Oguzhan Alagoz, PhD and Pascale Carayon, PhD to take a systems engineering approach.

In 2015, they created a computational model to simulate C diff transmission in a hospital ward over time. The team will strengthen the simulation model with more data sets from an acute-care hospital, a veteran’s hospital, and a children’s hospital.

Hospital types have unique factors, she explains. In a children's hospital, for example, visitor hand hygiene may be more critical because visiting parents and siblings may stay overnight in the patient’s room, use shared areas like kitchens, and help the patient with tasks like feeding and toileting.

“The goal is to create a simulation model that can be generalized. Every hospital is different, so we want a hospital representative to be able to enter parameters about their facility and predict which steps will be most effective for reducing C diff infections at their site.”

Sensing a Switch: Defining the Rules and Playbook of Protein Function

“Allosteric proteins are nature’s switches,” Raman, explaining that allostery is a fundamental property of all proteins. “Allosteric proteins regulate many essential cellular processes required for life.”

When a protein switches between “off” and “on” states, there can be dramatic consequences for gene expression. And just like a broken light switch plunges a room into darkness, unresponsive allosteric proteins can be responsible for many diseases because they can no longer effectively regulate activities inside a cell.

Almost half of all current drug targets are allosteric proteins, says Raman, and yet little is understood about how allostery itself works. His laboratory aims to decipher the fundamental rules governing the process by using high-throughput analyses methods and machine learning to look for patterns among different allosteric proteins, probing the role of every amino acid.

If successful, computer modeling could allow Raman’s team to predict the impact of a mutation in an allosteric protein, and how to alleviate any detrimental effects.

“The broader vision of my laboratory is to develop these tools to advance precision medicine,” Raman says. “Every day we sequence the genomes of patients with diseases, but we have no clue which protein mutations affect function, and how they do so. Wouldn’t it be great if we could create a ‘lookup table’ or a database of mutations that a physician could use to interpret a patient’s genome?”

While deducing these molecular rules could prove challenging, Raman believes that they would hold value for applications in biomedicine and biotechnology. Additionally, drug discovery projects informed by allostery data could lead to more specific drugs with fewer side effects, he says.

Resources:

• "2018 NIH Director’s awards for High-Risk, High-Reward Research program announced," National Institutes of Health, October 2, 2018