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Jefferson Researcher Explores Cell Death Controls and Effects

01/18/19

Emad S. Alnemri’s breakthrough work may yield a powerful new way to kill cancer

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BY ROBIN WARSHAW

Programmed cell death, or apoptosis, is a fundamental process in all animals. Caused by the molecular triggering of biochemical reactions encoded within cells, apoptosis enables the digits of a human hand to emerge from a cell mass, protects the body from autoimmune diseases by removing certain white blood cells that could attack it, and even kills some transformed cells before they become cancer.

Impaired regulation of this cellular “suicide” can affect everything from embryonic development to the appearance and progression of devastating conditions such as cancer and Alzheimer’s disease.

Discovering the basic mechanisms, pathways, and controls of cell death is important for exploring approaches to treatment. “If you understand how the machine works, then you can fix it,” says Emad S. Alnemri, PhD, Thomas Eakins Endowed Professor in the Department of Biochemistry and Molecular Biology at Thomas Jefferson University.

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“We are trying to find out every piece of this apoptotic machinery, to know what is going on in there, what the players are and how we can manipulate them,” says Alnemri, who is also a researcher at the Sidney Kimmel Cancer Center at Jefferson Health (SKCC).

Alnemri has led many projects during his 27 years at Jefferson, including investigations of caspases, protease enzymes that break down proteins to trigger apoptosis and inflammation. Caspases cleave or split cellular proteins, which dismantles cells and generates inflammatory cytokines.

Guided by the discovery of the first death protease in the nematode worm by H. Robert Horvitz, PhD, of MIT, Alnemri decided to look in human cells to see if they have a similar death protease. He discovered caspase-3, which he calls “the workhorse of all cell death.” That finding was followed by the discovery of six more human caspases, including caspase-8 and caspase-9, known as initiator caspases, which split and activate caspase-3. Further research showed how mitochondria release molecules that jump-start caspase-9 into stimulating caspase-3 to kill the cell.

“We’ve looked at each caspase and found its function. We’ve characterized the important mechanisms that regulate cell death in human cells, what triggers them, and what’s upstream of them,” Alnemri says. “Now, although it has been more than 22 years since the discovery of caspase-3, we’re still discovering new things that this caspase does.”

Alnemri came to the United States in 1985 after graduating summa cum laude from the University of Jordan with a master’s degree in biochemistry. He joined the lab of Gerald Litwack, PhD, at the Temple University School of Medicine, where he received his PhD in biochemistry and molecular biology. He decided to stay in the United States because, at the time, there were few advanced research opportunities in Jordan. “And I love research,” he says.

In 1991, when the SKCC was established, Alnemri came to Jefferson. Since 1995, his research has been well funded by
private and NIH grants.

His discoveries have helped advance the cell death field. Alnemri has authored or co-authored about 180 peer-reviewed publications, holds more than 20 patents, and has mentored more than 30 trainees. His work has been cited more than 66,000 times, according to Google Scholar. In 2013, he was identified as one of the top 400 highly influential biomedical researchers evaluated from 1996 to 2011.

Two years ago, he and a team of Jefferson researchers found that the protein DFNA5, when split and activated by caspase-3, can form pores in the cell’s plasma membrane. This releases danger signals that prompt immune action. “We believe that this protein plays an important role in the ability of dying cells to stimulate the immune system,” Alnemri says.

He recently received $3 million from the National Institutes of Health (NIH) and $300,000 from the Dr. Ralph and Marian Falk Medical Research Trust to study DFNA5 further. Researchers have already found that DFNA5 is silenced, or turned off, in many cancers. Alnemri and his team will look at DFNA5’s role as an immune system stimulator to kill cancer cells. Learning to control its activity could lead to advances in cancer immunotherapy.

The research looks promising, Alnemri says, because a similar protein, gasdermin D, also makes pores in the cell membrane when activated by inflammatory caspases during bacterial infection. This causes infected immune system cells to swell and burst, releasing potent immune signaling mediators and substances that could lead to septic shock.

Some of the Jefferson research on DFNA5 was described in a 2017 study published in Nature Communications. The researchers collaborating with Alnemri on that work included Teresa Fernandes-Alnemri, PhD, research assistant professor in the Department of Biochemistry and Molecular Biology at Jefferson. Teresa and Emad are married, and their daughter Diana was also on the team. Now a first-year student at SKMC, at the time the study was published she was an undergraduate at Pennsylvania State University, where her honors research project was focused on inflammation.

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The Alnemris’ older daughter, Angela, is a second-year SKMC student, while their son, Ahab, is an undergraduate neuroscience major at the University of Pennsylvania. “All three are interested in medicine and research,” says Alnemri, with understandable pride.

His lab is also researching the activity and regulation of inflammasomes, molecular complexes of proteins that trigger responses by activating inflammatory caspases 1, 4, and 5. Alnemri notes that inflammasomes cause pyroptotic or inflammatory cell death, a form of programmed cell death that differs from apoptosis.

His work on inflammasomes started more than a decade ago when he characterized pyrin, a protein that forms an inflammasome complex involved in familial Mediterranean fever disease. He later discovered the AIM2 inflammasome, reporting his findings in successive papers in Nature and Nature Immunology.

“We are trying to find out how inflammasomes are regulated during infection and during sterile inflammation,” Alnemri says. “If we figure that out, you can develop therapeutics that target important steps in the inflammasome pathways and use these therapies to treat inflammatory disease.”