More than two decades after the 1991 war in the Persian Gulf, over a quarter of the 700,000 veterans who served are still suffering from chronic fatigue, memory loss, joint pain, insomnia and stomach problems. These veterans for years struggled to convince doctors that their issues were more than psychological, and so far, none have received relief.
The cluster of unexplained symptoms are characteristic of Gulf War Illness, now an official diagnosis recognized by the Veterans Administration. Researchers suspect a combination of toxins could be linked to the illness — including pesticides, anti-nerve agent pills and sarin gas — added to genetic factors and the physical stressors of war.
Though the U.S. Department of Defense has allocated significant dollars to Gulf War Illness research, scientists still only loosely understand the multi-symptom disorder, and animals offer an imperfect disease model for further study.
Now, with DOD funding, a team of researchers from Drexel University and Boston University are generating a bank of stem cells — derived from cells taken directly from the blood of veterans suffering from Gulf War Illness — that could hold answers to this 25-year-old medical mystery. This paradigm shift in the study of Gulf War Illness was just published in the journal Neurology.
Using blood cells obtained from 300 veterans in the Gulf War Illness Consortium, Drexel College of Medicine researchers will genetically modify them into human induced pluripotent stem cell lines (hiPSC). This means the cells will behave like embryonic stem cells and, once treated with different growth factors, will have the ability to form practically any other type of adult cell, including various types of neurons. (The journal cover above features neurons that have been differentiated from pluripotent cell lines in the Peter Baas Laboratory.)
Since the cells will continue to divide, they can be made available to any interested researcher to study the mechanisms of Gulf War Illness and to test potential treatments.
“The GWI research community does not have very good model systems in which to test hypotheses and potential therapeutics. These cell lines represent an important shift toward an experimental model that will be much more useful for understanding this disease,” said Peter Baas, PhD, a professor in the Department of Neurobiology and Anatomy at Drexel University College of Medicine. “We see this as an urgent situation. These veterans are not getting any younger.”
Japanese researcher Shinya Yamanaka, who won the Nobel Prize for his work in 2012, pioneered the extraordinary process of reprogramming adult cells to an embryonic-like state.
Though originally intended for clinical application, using hiPSC lines to cure sick patients has proved challenging. However, these cells have become a critical tool for investigating human disease and testing new treatments. In diseases ranging from Parkinson’s to Amyotrophic Lateral Sclerosis, hiPSC lines offer a cutting-edge, invaluable method for studying illness, without the ethical concerns of cells derived from embryos.
The Drexel and BU researchers will be the first group in the world to use hiPSC lines derived directly from Gulf War veterans, comparing those who did or did not get sick after serving.
Studying patient-derived cells offer a number of major advantages to understanding the origins of this disease, according to Liang Qiang, PhD, a research assistant professor in the College of Medicine and the expert who supervised the conversion of somatic cells from GWI veterans into pluripotent cell lines.
Since hiPSC are human cells, they have human proteins and pathways that may not be reflected in animal models. And most importantly, Qiang said, these cells are derived from the patients themselves, which means they harbor the wide array of genetic factors that may contribute to the disease.
“The big advantage of using patient-derived calls is that many diseases cannot be traced to just one gene being mutated, but rather are due to the complex interactions of genes. Susceptibility of these disease may also be based on epigenetic factors, which cannot be looked at in animal models,” Qiang said. “These cell lines will preserve the complete genetic composition of those affected by the disease.”
The cell lines will be used to identify how alterations in axonal transport, microtubule functioning and neuroinflammation may contribute to GWI symptoms. For instance, Baas’ research group found that microtubules — cylinder structures that give shape to cells and power their movements — could be a prime target for treating this disease in a study recently published in the journal Traffic.
Because pluripotent cell lines are essentially immortal, they can be used for study an unlimited number of times, including to be compared against results of parallel studies on other neurodegenerative diseases.
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