A big lift from tiny wings

AT THE UNIVERSITY OF PITTSBURGH School of Medicine, researchers Dr. Michael Palladino and Dr. Elias Aizenman work across the hall from one another. But once they enter their respective labs, it’s as if they enter different worlds.

Palladino is known as “the fly guy” for the fruit flies he uses in his biochemical research, while Aizenman, a neural cell biologist, uses mice in his work on complex neurological diseases. Different research, different subjects.

That changed in February 2016, when Aizenman was ready to test a potential treatment method for a range of diseases —Parkinson’s, Alzheimer’s, Huntingdon’s and amyotrophic lateral sclerosis, also known as Lou Gehrig’s. The new concept uses a “silent gene” programmed to recognize the release of zinc, an early-stage indicator of cell death. Before testing the concept on mice, Aizenman, professor of neurobiology, wanted to experiment on fruit flies, which have a much shorter life cycle, so he ventured across the hall.

“Let’s do it,” said Palladino.

With a 2016 New Initiative Award grant of $300,000 from the Charles E. Kaufman Foundation, a supporting organization of The Pittsburgh Foundation, the two Pitt scientists are moving forward. Kaufman, a respected chemical engineer, left $50 million to the Foundation, $40 million of which is dedicated to funding basic science research and interdisciplinary projects. Since 2013, the Foundation has awarded 43 Kaufman grants totaling $9.1 million. Palladino and Aizenman discussed the importance of the Kaufman grant to their work and why a fly is the perfect research specimen.

DR. MICHAEL PALLADINO: My mom was diagnosed with Alzheimer’s disease about a year ago. It’s frustrating and sad. I have been in the field for a long time, but it’s hard to anticipate what it is going to be like [when it affects you personally]. She’s not forgetting names, but she’ll get very nervous and not sleep well for days, or even weeks.

DR. ELIAS AIZENMAN: I think all these diseases are appearing more because we’re getting older. I don’t think we were meant to live this long. Before, you reproduced, you died and the clan moved on.

PALLADINO: When I first started here 14 years ago, research funding was actually pretty good. It’s just been a constant slide since then. In the last eight years or so, it’s been tough.

AIZENMAN: [President] Clinton doubled the NIH [National Institutes for Health] budget, and that was a good period. And then we had two wars and a slash in taxes, and things started to get tough. Obama stabilized the system, prevented it from getting really bad. Now we don’t really know where we stand. All the indications are that the current administration wants to slash funding. We are constantly writing grant [applications].

PALLADINO: It’s not what we signed up for, this perpetual begging for money. It slows down the science. It used to be you locked yourself in the office for a month or two, wrote a grant or two, and one of them would get funded, and you could work in the lab for a year or two. Now, you end up spending too much time writing grants and not enough time in the lab being as creative as you could. It hamstrings what you can do. You end up writing the grant that can be funded, so you let what you think can be funded guide your thinking, not your creativity. That’s the risk. There aren’t enough people branching out into novel areas.

AIZENMAN: The Kaufman grant is great. It is paying for part of the salary for people in both of our labs. And what’s nice is that it will lead to something else — another grant proposal. The Kaufman grant will allow us to generate preliminary data, and when you write an NIH grant, you need very strong preliminary data. The stronger you go in, the better.

PALLADINO: The Kaufman grant enabled us to hire full-time people in the lab and not just limp along. It brings some kind of validation. It’s a step in the right direction.

AIZENMAN: This is exactly the kind of collaboration I’m looking for. A lot of people say, “Yeah, yeah, that sounds interesting,” and then nothing happens. I’m not a fly person, so I really couldn’t do it myself. Michael saw that the idea was really good. And he contributed some interesting modifications to the idea. Eventually, we want to translate it to mammalian systems and eventually to people.

PALLADINO: I think that’s the strength of the fly model. Instead of a research course of two years in a rodent model or 60 or 70 years in humans, it’s all sort of compressed down to a month, a month and a half, with a fly. Our mutants only live four to six weeks, so we can measure changes in characteristics such as cell death, behavioral function and longevity every three or four days. We can understand very quickly the dynamic progressive dysfunction that happens over the lifespan of these animals.

AIZENMAN: We aren’t in it for the fame or money or anything like that. We really are interested in basic discovery and curing disease. And I’m hoping by the time I retire, preferably before I die, that one of those strategies, not necessarily from my lab, not necessarily from Michael’s lab, but one of these strategies that people have been working so hard over many years will actually protect neurons from dying. Because we have nothing right now…You never know who’s going to make the next big discovery.

About the Research

Neurodegenerative diseases such as Parkinson’s, Huntington’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS) are known for wreaking havoc on the human brain. Scientists have identified the source of the degeneration — progressive death of neurons within the brain leading to widespread loss of neurological function — but they have not yet found a way to stop the process of cell death or the suffering it causes.

At the University of Pittsburgh School of Medicine, Elias Aizenman, professor of neurobiology, and Michael Palladino, professor of pharmacology and chemical biology, are in the early stages of studying a potential intervention.

Aizenman has studied neurodegenerative diseases for the last 30 years. He identified a complex process preceding cell death — once injured, brain cells activate a “signaling cascade” in which each step triggers the next until the cell finally dies. For the past three years, he has studied the role of zinc and activation of a potential potassium channel as a means of interrupting the cascade.

Last year, Aizenman began collaborating with Palladino, known as “the fly guy” for his expertise in the genetics of fruit flies. Fruit flies have a much shorter life cycle than the mice typically used in medical research, allowing researchers to run through test cycles much more rapidly.

Funded through the New Initiative Research Grants from the Charles E. Kaufman Foundation, their research uses a “silent gene” that recognizes the release of zinc, one of the early signals in the cascade. Once activated, the gene product blocks the loss of potassium within the cell, thwarting the process before cell death can occur.

Instead of imminent death, an injured cell would be re-programmed to trigger its own defense.

If the silent gene method is effective with fruit flies, the researchers hope for a successful outcome with mice and, one day, a cure for people with neurodegenerative disease.

INVESTIGATOR AWARDS

Locus-specific regulation of pericentric satellite sequences	Dawn Carone, Ph.D. Assistant professor, department of biology, Swarthmore College
Singlet fission:  Deriving fundamental insights from computation	Noa Marom, Ph.D. Assistant professor, department of materials science and engineering, Carnegie Mellon University
Four-dimensional quantum Hall physics with light	Mikael Rechtsman, Ph.D. Assistant professor of physics, Pennsylvania State University
Deconstructing the molecular basis of  condensin-mediated chromatin folding	Eric Joyce, Ph.D. Assistant professor, department of genetics,  Perelman School of Medicine, University of Pennsylvania

INITIATIVE AWARDS

Pollen as the next viral frontier: Unrecognized threat to food security and native biodiversity	Tia-Lynn Ashman, Ph.D. Distinguished professor of ecology and evolution, University of Pittsburgh James Pipas, Ph.D. Herbert W. and Grace Boyer Chair in Molecular Biology, University of Pittsburgh
Defining the glycan-specificity and mechanisms of action for antitumor lectins	James Marden, Ph.D. Professor of biology, Pennsylvania State University Scott Medina, Ph.D. Assistant professor of biomedical engineering, Pennsylvania State University
Protecting quantum wires for quantum computing	Michael Hatridge, Ph.D. Assistant professor of condensed matter physics, University of Pittsburgh Roger Mong, Ph.D. Assistant professor of condensed matter physics, University of Pittsburgh
Reconstitution and dissection of chromosome segregation	Ekaterina Grishchuk, Ph.D. Associate professor of physiology, Perelman School of Medicine, University of Pennsylvania Ben E. Black, Ph.D. Associate professor of biochemistry and biophysics, Perelman School of Medicine, University of Pennsylvania

Original story appeared in Report to the Community 2016-17