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Office of Neuroscience Research > WUSTL Neuroscience News > Pursuing a precision paradigm

Pursuing a precision paradigm



From the WashU Newsroom...

Of the top-grossing domestic movies of 2017 to date, three of the Top 5 feature superheroes: ­Wonder ­Woman; Guardians of the Galaxy, Vol. 2; and ­Spider-Man: Homecoming. Similarly, in 2016, five of the Top 10 ­movies focus on adventure and heroes, including ­Captain ­America: Civil War and Batman v Superman: Dawn of Justice. Studying the genre, examples emerge at the top of movie lists year after year. In these films, the “heroes” venture out and engage in great and noble deeds against incredible odds on ­behalf of a group, ­population or civilization.

The battle between good and evil is a consistent theme in art and considered a timeless and universal element of the ­human condition — not unlike the age-old battle between health and disease.

Cancer, Alzheimer’s, multiple sclerosis, inflammatory ­bowel disease, diabetes, heart disease and more are formidable foes. Yet in their quest to conquer these debilitating, sometimes life-threatening adversaries and save lives, the ­Washington ­University Medical Center and its bold team of ­physicians and research scientists are starting to wield new, more ­precise weaponry.

As these bright, committed men and women stand on the threshold of a revolution in medicine, they are primed to ­confront new obstacles and venture down new pathways in their pursuit of precision therapies designed for individual patients.

The vision: imagining what science can do

David Perlmutter, MD, might question the label “hero,” yet he focuses his highly ­developed skills on behalf of society. Among his proficiencies is transformational leadership. As executive vice chancellor for medical affairs and dean of the School of Medicine, he directs a vast organization: hundreds of ­brilliant physicians, physician-scientists and research ­scientists; the No. 1 program in the country training MD/PhDs (the ­physician-scientists of tomorrow); the No. 1 Alzheimer’s disease research center; the No. 3 cancer center; and leading departments and centers in genomics, immunology, ­microbiology, pediatrics and more.

Perlmutter also possesses keen ­vision. He sees the future of medicine right now: a “precision paradigm,” supporting the personalized treatment of patients, rather than the ­current standards of care that guide treating all patients with the same condition. By leveraging the medical school’s ­incredible strengths today, Perlmutter is ­positioning his team to make an even greater impact on human health tomorrow...

...The dream: fixing mutations and altering pathways

Jeff Milbrandt, MD, PhD, is a dreamer. One of the medical school leaders who first recognized the need for using DNA ­sequencing in the clinical arena, he now heads the James S. McDonnell ­Department of Genetics. Milbrandt, the James S. McDonnell ­Professor of Genetics, says that we’re living in the “fanciful era” now — an era of genome editing, in which ­researchers have the power to alter genes. Further, they’re able to generate induced pluripotent stem cells (iPSC), taking skin cells or cells from blood or urine and transforming them into stem cells. These stem cells can then be converted into almost any cell in the body, providing a system for studying how ­specific mutations lead to cell malfunction and cause disease.

To do this, scientists use CRISPR technology — a powerful editing tool that allows them to easily alter DNA ­sequences and modify gene function. In addition to editing cell lines and generating iPSCs, they can create model systems to explore and screen for thousands of drugs to see if any ­reverse a specified mutation. This is all happening now.

“In the next five years,” Milbrandt says, “we’re going to go from cataloguing mutations — and saying, ‘This mutation is ­causing this particular problem’ — to ­fixing the mutation using CRISPR. Then we’re going to inject these CRISPR components, in the form of a virus, into your body and basically, magically, fix the mutation.”...

...In his own work, Milbrandt studies peripheral ­neuropathy, a condition that develops as a result of damage to the ­peripheral nervous system. Symptoms range from muscle tingling and weakness to pain and paralysis. This condition can be inherited or induced by diabetes or chemotherapy ­treatment for cancer. ­Chemotherapy is helping save more and more lives, yet at the same time, more folks are affected by the painful ­neurological side effects of their treatment.

Using the latest technologies, ­Milbrandt and ­collaborator Aaron ­DiAntonio, MD, PhD, the Alan A. and Edith L. ­Profe­ssor of ­Developmental ­Biology, are working to understand the exact pathways that lead to the root cause of neuropathy: axonal degeneration. They have found the central executioner of this ­destructive ­process and have good leads on small-­molecule drugs that might work in neuropathy, but they are also testing whether gene therapy with viruses can fix the degeneration directly.

“As we delve more deeply into the fundamental ­pathways that are being altered by these diseases, we start to see ­commonalities,” Milbrandt says. “For instance, the axonal degeneration that happens in neuropathy also happens in Alzheimer’s, Parkinson’s, MS and other diseases. By dreaming big and discovering a way to block that sort of degeneration, we could possibly impact all these disorders.”...

...The struggle: advancing Alzheimer’s treatment

Another major concern for physician-­scientists is the aging population. The ­average lifespan in the U.S. for a male in 1912 was 51.5 years, whereas in 2012 it was 76.4. For women, the ­increase jumped from 55.9 years to 81.2. We’re ­living longer because we’re surviving cancer, heart disease and other disorders. That’s the good news. The bad news, ­however, is that with an ­increase in ­longevity has come an increase in the ­diseases that ­occur more commonly with age — the ­diseases of the brain — which currently have no great treatments.

Overseeing the department charged with untangling the mysteries of ­neurological ­disorders, including neurodegenerative ­diseases, is David Holtzman, MD, the ­Andrew B. and Gretchen P. Jones ­Professor of Neurology, the ­Charlotte and Paul ­Hagemann ­Professor of Neurology, head of the Department of Neurology at the medical school, and neurologist-in-chief at Barnes-Jewish Hospital. Under his direction is a deep bench of resolute ­researchers working on Alzheimer’s, ­frontotemporal dementia, Parkinson’s, ALS, MS, stroke,­ ­subarachnoid ­hemorrhage and more.

The most common neurodegenerative disease is Alzheimer’s disease, in which both age and genetics play a role. In the neurology department’s Charles F. and Joanne Knight Alzheimer’s Disease Research Center, led by John Morris, MD, the ­Harvey A. and Dorismae Friedman ­Distinguished Professor of Neurology, researchers have determined a number of genetic markers that are risk factors or causative for certain forms of the disease. In addition, in studies of early-onset Alzheimer’s disease, there is a huge research effort in the Dominantly Inherited Alzheimer Network (DIAN) and treatment unit, led by Randall Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology. These studies are determining the ­biomarkers and time course of the disease, both before and after the onset of symptoms, as well as testing novel treatments.

“In terms of personalized medicine for early onset, ­individuals are being identified and put in novel clinical ­trials based on family history and specific genetic ­information,” Holtzman says. And for late-onset Alzheimer’s, the most ­common form, Holtzman says the center is identifying people before they’re symptomatic, trying to determine whether ­researchers can predict the onset of symptoms. Some individuals are in clinical trials based on their biomarkers.

“Many individuals in our various clinical research studies are having their genome sequenced completely by ­researchers such as Carlos Cruchaga, PhD, associate professor of ­psychiatry,” Holtzman says. “And that’s providing important information about new genetic factors that lead to the disease, as well as ­identifying new targets for treatment.”

Discussing innovations, Holtzman says that researchers are making advances in better diagnostics that are not as expensive as PET scanning or as invasive as spinal tap. “It needs further development,” Holtzman says, “but there’s a blood test that may enable screening of people for whether or not they’re ­developing the pathology of Alzheimer’s.”...

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