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.”
Milbrandt says that although some ethical concerns remain, progress is inevitable. He says he can visualize incredible advancements on the horizon — a day when someone with muscular dystrophy will walk, or when someone with retinitis pigmentosa will see. “This is not futuristic stuff anymore,” he says. “It will soon be reality.”
To position the medical school at the leading edge of this work, Milbrandt and others have created the Genome Engineering and iPSC Center to assist other investigators in using CRISPR genome engineering for their studies. (To learn more about centers playing pivotal roles in the medical school’s efforts in precision medicine, see related content: “Building the foundation for discovery.”)
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.
“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.”
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
In the last 20 years, mortality from cancer — the No. 2 leading cause of death today in the United States — has decreased by 25 percent. And, according to
Tim Eberlein, MD, director of Siteman Cancer Center, that drop in mortality is going to accelerate, because researchers are “now at the threshold of being able to control the disease instead of the disease controlling us.”
With that goal in sight, Siteman has established very large, robust programs in leukemia, lymphoma, myeloma, breast cancer, lung cancer, brain cancer and more. And it has outlined four major strategic initiatives in collaboration with other departments to advance care: genomics, immunology/immune therapies, technology and imaging, and prevention.
Regarding the first initiative, researchers at Washington University have made a massive effort since the sequencing of the human genome to identify genomic information associated with cancers. Eberlein estimates that nearly 99 percent of the mutations associated with human cancer have been identified. Siteman Cancer Center and the Elizabeth H. and James S. McDonnell III Genome Institute led this global effort. (See related story above, “Undaunted explorer” to learn more about the work of Timothy Ley, MD, who inspired and collaboratively led the team that sequenced the first cancer genome in 2008, and the challenges he has faced and insights he has gleaned in treating patients with acute myeloid leukemia ever since.)
“We realize now that cancer is thousands of different diseases,” says Eberlein, who is also the Bixby Professor of Surgery and head of the
Department of Surgery at the School of Medicine. “So Patient A’s breast cancer, for example, may be very different from Patient B’s breast cancer, even if the two cancers look the same under a microscope, are the same size or are in the same breast. These differences are based on molecular and genetic markers that cause the cancer to behave in different ways.”
Eberlein says the question now is, How do scientists apply that knowledge to diagnose and treat the next individual patient who walks through the door?
Siteman’s second initiative centers on immunology and targeted immune therapy. For years, researchers — including
Robert Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor of Pathology and Immunology and director of the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs — have been studying how to turn on a patient’s immune system to make it recognize and destroy cancer cells, as well as how to control the process so it doesn’t also destroy normal cells and normal function.
“Genomic analysis on breast cancer patients’ tumors, for example, has shown there are different mutations that are signatures to individual patients,” Eberlein says. Researchers collect these unique mutations, create a vaccine that targets them and then administer it to individual patients to stimulate their immune system to recognize the specific mutations. “This is more precise in destroying diseased cells than radiation or even surgery, and there is less damage to healthy tissue,” Eberlein says.
Today, researchers are conducting such trials in breast and brain cancers, and they’re in various stages of development in head and neck, lung, lymphoma, melanoma, pancreas, prostate and retinal cancers. “And we don’t do this research in silos,” Eberlein says. “We gather experts in these various areas and discuss developments as a group: ‘What did you learn in studying brain cancer, and how could we apply that in breast cancer, and vice versa?’ Cross-fertilization is a strength of Siteman’s, and it helps accelerate how fast we can do these kinds of studies.”
The third initiative encompasses technology and imaging. For example, Siteman has the ability to detect cancer cells through photo-acoustic imaging. And it can insert an individual gene into a normal cell to study its impact, if any, on cell growth and division. Siteman also has invested heavily in understanding the molecular mechanisms of various pathways in cancer.
Again, how does exploring pathways promote progress toward precision medicine?
Eberlein explains that “as we study these pathways, we’re beginning to realize that some of them drive the growth of cancer cells. So we’re beginning to develop drugs and interventions that interrupt these pathways.”
“In lung cancer, for example, we identified a mutation that also occurs in a minority of colon cancers. We have a drug for this subset of colon cancers that we never would have thought to use for lung cancer before we discovered this similarity.”
Tim Eberlein, MD
To further explain, Eberlein hypothesizes two patients, Patient A and Patient B, who have the same leukemia. If each patient’s cancer is promoted by a different pathway, each cancer will respond differently to the same drug therapy, if at all.
There’s another benefit of discovering these pathways. “In lung cancer, for example, we identified a mutation that also occurs in a minority of colon cancers,” he says. “We have a drug for this subset of colon cancers that we never would have thought to use for lung cancer before we discovered this similarity.”
The discovery is another example of how understanding the biology of the disease and the molecular and genetic information of the pathways can inform physicians on how to treat certain patients in a very personalized way.
“These developments aren’t going to happen in 50 years,” Eberlein says. “They’re happening right now.”
One of the most ambitious developments in Siteman’s plan to save lives and help communities is conceivably through its fourth initiative: prevention.
The BJC HealthCare organization has collaborative relationships with eight other health-care systems — not hospitals, but entire systems that together cover much of Missouri and the southern half of Illinois. The region includes four of the top six counties in the country for cancer deaths. And Siteman, recognized as a Comprehensive Cancer Center by the National Cancer Institute since 2005, is proposing to these systems a collaborative and mutually beneficial arrangement: Siteman would provide effective, evidence-based cancer prevention programs and help oversee them in exchange for access to their patients’ genomic and clinical information. The goal is twofold: advise the other systems on how to care for their patients and build a large, relational database at Siteman. Such a database would help researchers develop algorithms for managing different populations and individuals who have breast cancer, lung cancer, prostate cancer and more.
Eberlein clarifies how this database would help personalize treatment. In early breast cancer, for example, stage one/stage two breast cancer, the vast majority of female patients are treated with lumpectomy and radiation therapy, and some have a mastectomy. After these treatments, 80 percent of women with early breast cancer are cured of their disease. Twenty percent, however, have a risk of recurrence.
“Until very recently, if their tumors were bigger than a centimeter, we would treat almost 100 percent of these women with multidrug-regimen chemotherapy,” Eberlein says. “But if I had a massive database, I could compare, say, Mrs. Smith’s genetic signatures computationally to those of all the other women in the database to see if she had a match for recurrence. If she didn’t, we could provide her with statistical validation and say, ‘You won’t need multidrug-regimen chemotherapy.’ If she did have a match for recurrence, we might have to say to her, ‘Mrs. Smith, you match the type of woman who has a high risk of having recurrence, so we recommend aggressive chemotherapy.’”
Although it’s going to take time to work through all the various mutations and pathways in all the types of cancer, Eberlein is excited about what’s happening already. “One of the first major impacts of precision medicine is that it’s going to show us which patients we should not be treating aggressively,” he says, which will lead to a reduction both in unnecessary treatment and in costs of health care.
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.”
The blood-based screening test, discovered in Bateman’s lab, aims to detect certain forms of amyloid beta, which collects in brain amyloid plaques, that are thought to contribute to Alzheimer’s disease and its progression in people before they become symptomatic.
A promising future
Regarding new therapies, one treatment, developed in Holtzman’s lab a few years ago, is now in Phase II clinical trials. It’s an antibody to tau, which in some people collects into toxic tangles that damage brain cells and contribute to neurodegenerative diseases. (See related content,
“A promising future,” to learn more about doctoral students contributing to such discoveries in Holtzman’s lab.) And another researcher, Tim Miller, MD, PhD, the Clayson Professor of Neurology, has made a discovery on antisense oligonucleotide treatment for tau, trying to prevent disease onset or halt disease progression, that will soon enter trials.
Further, researchers are making major new discoveries on what’s called the innate immune system, studying how cells in the brain — microglial cells — figure in modulating innate immunity, both to better understand Alzheimer’s and to develop treatments. “These cells can create, decrease or increase inflammatory reaction in the brain,” Holtzman says. “And we have some of the best people in the world working on this, trying to understand which molecules to modulate to turn the cells on or off.”
One molecule, called TREM2, was discovered about 15 years ago by
Marco Colonna, MD, the Robert Rock Belleveau, MD, Professor of Pathology and Immunology. “We didn’t know then that it was connected with Alzheimer’s,” Holtzman says. “But four years ago, it was discovered that mutations in that gene put an individual at higher risk of getting the disease.” Since then, researchers in Colonna’s lab; Holtzman’s lab; the lab of Laura Piccio, MD, PhD, associate professor of neurology; and others have been trying to better understand TREM2’s role in the inflammatory response, trying to figure out whether to turn that on or off as a treatment.
In a recent study from Holtzman’s lab published in Nature, it was shown that the most important genetic risk factor for Alzheimer’s disease,
APOE, appears to modulate brain injury in part through modulating the brain’s innate immune response. Holtzman says the big-picture issue is that inflammation is definitely involved in Alzheimer’s disease. Therefore, researchers are trying to determine how and when to alter that inflammatory response to best effect a change in progression at the individual level. The next challenge: making progress
Looking toward the future on all these fronts, Dean Perlmutter says, “This is hard stuff and why Washington University needs to be at the forefront of what I call ‘the next huge challenge.’
“We’re in an era where medical researchers do sequencing, get big data, analyze it statistically, and then say, ‘OK, this is the gene that causes the disease.’ And many research centers will continue to do that,” Perlmutter says. “But our vision here is to take that sequence variant, put it into biological systems that are faithful and tractable models, and try, first, to understand whether the variant is truly causing the disease (exactly how and why) and, second, to use that knowledge to develop new diagnostics and therapeutics.”
Questions remain: How much effort will it take? And how much time? According to those on the front lines, it will take a massive effort and require lots of resources. And, as with any epic battle, it will require perseverance and incredible dedication and focus.
“But we’re making progress so much faster now than even 10 or five years ago, and that feels very different,” Skip Virgin says. “It feels as if we can run now, whereas before we were only crawling.”
Terri Nappier is editor of Washington magazine.
Pursuing a precision paradigm appeared first on The Source.
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