Progeria protein discovery

New characteristics linked to premature aging disease.

Glavy Lab team at work in the chemical biology program lab at Stevens

Dr. Joseph Glavy at Stevens Institute of Technology studies the smallest and most basic elements of life. The Assistant Professor of Chemical Biology runs the Glavy Lab, where advanced student scientists study the nuclear pore complexes (NPCs) in cells, observing the minutest mechanisms of life as they unfold during mitosis. The Glavy Lab's formal purpose is to study the NPC at the molecular level in the pursuit of the unknown or unexpected in the well-studied but not always well-understood nuclei of living cells.

His team has uncovered a disease-related protein outside of its known range and published the results in the August 2010 issue of Cell Cycle. The article's co-authors, Dr. Simarna Kaur, Tommy White, and Amanda DiGuilio are current or recent students of Stevens Institute of Technology. For these scientists, being a student was no barrier to impacting ground-breaking medical science research.

The NPC is a supramolecular assembly that provides gateways for molecular trafficking between DNA with a cell's nucleus and the cytoplasm within the cell membrane walls in eukaryotic cells. Protein, RNA, ions, and other small molecules are transported through the NPC on their way into the nucleus. The composition of the NPC is about thirty proteins, called nucleoporins (Nups), which are arranged quasi-symmetrically and in subcomplexes that break apart during mitosis in some cells.

Dr. Glavy investigated interactions within the NPC of mammalian cells while a post-doctoral researcher at Rockefeller University in New York City. Unlike other living cells, the mammalian cell NPC breaks down around DNA during mitosis, allowing specific Nup subcomplexes to be isolated and studied in the lab, but also leaving room for something to go wrong in the reorganization of the nucleus . Focused on the very specific Nup 107-160 subcomplex, the Glavy Lab had been looking for what might go wrong during mitosis.

Chemical Biology program lab resultsBut rather than genetic mutations, the lab discovered something far more important within Nup 107-160: the Werner Helicase Interacting Protein 1 (WHIP). WHIP's moniker derives from its interaction with Werner protein, which maintains genome stability and conversely is responsible for the progeria disease Werner's Syndrome. This adult-onset disease causes premature aging and increased susceptibility to other old-age diseases such as cancer, heart disease, and diabetes.

The initial discovery of WHIP within the NPC, when it had been associated with the Werner protein, prompted further exploration to deduce the role of WHIP during mitosis. The scientists isolated the NPC subcomplex and used immunofluorescence and immunoblotting to detect the presence and movement of WHIP during mitosis. They discovered WHIP interacting within the NPC autonomous of Werner protein, demonstrating a novel relation.

In addition to its connection with gene-stabilizing Werner protein, WHIP may play an independent, unique role in the cell cycle. Beyond supporting DNA replication, WHIP may also function to detect genetic damage. The authors look forward to future work that will further understanding of this protein's role in maintaining genome stability, and in completing some of that important work themselves.

Life in the Glavy Lab

Dr. Simarna Kaur, chemical biology graduate program studentThe Glavy Lab hosts undergraduate, graduate, and post-doctoral research at Stevens in the field of biochemistry and chemical biology. Dr. Kaur, now a research scientist with Johnson & Johnson, was conducting post-doc work at her alma mater and managing students in the Glavy Lab during the period of discovery. Tommy White is a Ph.D. candidate in Chemical Biology and Amanda DiGuilio is an undergraduate Chemistry major at Stevens.

Dr. Kaur earned her B.S., M.S., and Ph.D. at Stevens, at every step taking advantage of the amalgamation of chemistry and biology that the school offers. She points to this unique approach as fuel for her lasting interest in science and a platform for opportunities as a professional in multiple industries. Dr. Kaur also brought junior scientists up-to-speed on processes in the Glavy Lab, enabling them to perform high-level research.

"The experience of training new students has come in handy for my professional life," reports Dr. Kaur. "At Johnson & Johnson, I'm supervising the work of another researcher in addition to managing multiple projects of my own. My experiences in graduate school and especially in the lab have prepared me for the demands of an industrial career."

Tommy White, student in chemical biology graduate program Tommy and Amanda, the tireless student research scientists, share crowded desk space in the lab with petri dishes, beakers, perpetually-nodding sample rockers, and sheets of western blot membranes. Formerly a laboratory diagnostic technician for Siemens, Tommy started his Ph.D. program at Stevens as a part-time student. The flexible yet challenging program allowed Tommy to transition from industry professional to professor-in-training with the full support of both his Siemens VP and the faculty at Stevens. Rather than run patient tests for doctors and hospitals, Tommy now studies the most basic components and cause of disease as a full-time Ph.D. candidate with dreams of becoming an academic.

As an undergrad, Amanda has already had a productive research career. She has participated twice in the Stevens Technogenesis summer program and traveled on scholarship to the European Molecular Biology Laboratory in Heidelberg, Germany, where she worked in the lab of Dr. Martin Beck, a leading expert in cryo-electron tomography. This process allowed the researchers to analyze samples without destroying their structure. Amanda continues to work in the Glavy Lab and has been invited for future training with Dr. Beck.

Their success in the lab has come at a price: Tommy spends 14-15 hours there every day. But like Dr. Glavy's commitment to basic science, Tommy recognizes the importance of this fundamental labor.

"Everyone has good ideas, but nothing works the first time at the bench," Tommy says. "Ninety percent of the hard science is problem solving—doing everything required to go from idea to experiment to article about the results."

"Even though our discovery is new, the process is not a novelty," adds Dr. Glavy. "Original exploration is the result of good biochemists looking at specific interactions."

Dr. Glavy reiterates his simple but powerful message. "If you do the basics well, then you'll have opportunities like this emerge."

The dedication to science has paid off for everyone involved. Tommy and Amanda will be published scientists before receiving their intended degrees; Amanda as an undergrad. Dr. Kaur's post-doc was a mere six months long, yet also earned her an author credit; this is in addition to her other peer-reviewed papers and book, Cystic Fibrosis Transmembrane Conductance Regulator: Regulation by Rab GTPases, published by Lambert.

"I learned how to transition from a graduate student to an independent researcher by working with Dr. Glavy," reports Dr. Kaur. "He strongly encourages his students and post-docs to think independently and develop their own ideas. This transitional experience of doing independent research has helped me in my industrial career."

The Next Steps for the Glavy Lab

It may be years before the Glavy Lab's insights into WHIP can be turned into therapies for sufferers of Werner Syndrome and other progeria diseases, but this new look into the workings of the body creates hope for future treatments and other advances in biology and medicine.

"Cell biology is a growing, multi-disciplinary field that is establishing a foundation of knowledge for the future," says Dr. Glavy. "We are beginning to establish tangible relations between biology and disease and advancing towards an understanding of gene repair and expression that might help with drug development in the future."

For more information about this research and other activities in health care at Stevens, please contact Dr. Peter Tolias.