Category Archives: Genetic Medicine

ScienceDaily (Mar. 19, 2012) Research from a Kansas State University professor may make it easier to recover after spinal cord injury or to study neurological disorders.

Mark Weiss, professor of anatomy and physiology, is researching genetic models for spinal cord injury or diseases such as Parkinson's disease. He is developing technology that can advance cellular therapy and regenerative medicine -- a type of research that can greatly improve animal and human health.

"We're trying to build tools, trying to build models that will have broad applications," Weiss said. "So if you're interested in neural differentiation or if you're interested in response after an injury, we're trying to come up with cell lines that will teach us, help us to solve a medical mystery."

Weiss' research team has perfected a technique to use stem cells to study targeted genetic modifications. They are among a handful of laboratories in the world using these types of models for disease. The research is an important step in the field of functional genomics, which focuses on understanding the functions and roles of these genes in disease.

The researchers are creating several tools to study functional genomics. One such tool involves developing new ways to use fluorescent transporters, which make it easier to study proteins and their functions. These fluorescent transporters can be especially helpful when studying neurological disorders such as Parkinson's disease, stroke and spinal cord injury.

"People who have spinal cord injury do not experience a lot of regeneration," Weiss said. "It is one of the problems of the nervous system -- it is not great at regenerating itself like other tissues."

The researchers want to discover a way to help this regenerative process kick in. By studying signals from fluorescing cells, they can understand how neural stem cells are reactivated.

"We want to try and make these genetic markers, and then we can test different kinds of treatment to see how they assist in the regenerative process," Weiss said.

Weiss' stem cell research has appeared in two recent journals: Stem Cells and Development and the Journal of Assisted Reproduction and Genetics. His research has been funded by the National Institutes of Health and university funds, including the Johnson Cancer Research Center.

Weiss' seven-member research team includes a visiting professor, two full-time researchers, a graduate student and three undergraduates. He has also been collaborating with researchers from the University of Kansas Medical Center.

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Genetic research develops tools for studying diseases, improving regenerative treatment

ScienceDaily (Mar. 19, 2012) A growing body of evidence underscores the importance of human gut bacteria in modulating human health, metabolism, and disease. Yet bacteria are only part of the story. Viruses that infect those bacteria also shape who we are. Frederic D. Bushman, PhD, professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania, led a study published this month in the Proceedings of the National Academy of Sciences that sequenced the DNA of viruses -- the virome -- present in the gut of healthy people.

Nearly 48 billion bases of DNA, the genetic building blocks, were collected in the stools of 12 individuals. The researchers then assembled the blocks like puzzle pieces to recreate whole virus genomes. Hundreds to thousands of likely distinct viruses were assembled per individual, of which all but one type were bacteriophages -- viruses that infect bacteria -- which the team expected. The other was a human pathogen, a human papillomavirus found in a single individual. Bacteriophages are responsible for the toxic effects of many bacteria, but their role in the human microbiome has only recently started to be studied.

To assess variability in the viral populations among the 12 individuals studied, Bushman's team, led by graduate student Samuel Minot, looked for stretches of bases that varied the most.

Their survey identified 51 hypervariable regions among the 12 people studied, which, to the team's surprise, were associated with reverse transcriptase genes. Reverse transcriptase enzymes, more commonly associated with replication of retroviruses such as HIV, copy RNA into DNA. Of the 51 regions, 29 bore sequence and structural similarity to one well-studied reverse transcriptase, a hypervariable region in the Bordetella bacteriophage BPP-1. Bordetella is the microbe that causes kennel cough in dogs.

BPP-1 uses reverse transcriptase and an error-prone copying mechanism to modify a protein to aid in entering and reproducing in a wide array of viral targets. Bushman and colleagues speculate that the newly discovered hypervariable regions could serve a similar function in the human virome, and microbiome, by extension.

"It appears there's natural selective pressure for rapid variation for these classes of bacteriophages, which implies there's a corresponding rapidly changing environmental factor that the phage must be able to quickly adapt to," says Minot. Possible reasons for change, say the authors, include evading the immune system and keeping abreast of ever-evolving bacterial hosts -- a kind of mutation-based host-pathogen arms race. Whatever the case, Minot says, such variability may be helping to drive evolution of the gut microbiome: "The substrate of evolution is mutation."

Evolutionary analysis of the 185 reverse transcriptases discovered in this study population suggests that a large fraction of these enzymes are primarily involved in generating diversity. Now, Minot says, the challenge is to determine the function of the newly discovered hypervariable regions, and understand how their variability changes over time and in relationship to disease.

"This method opens a whole new world of 'diversity-generating' biology to discover what these clearly important systems are actually doing," he says.

In addition to Bushman and Minot, co-authors are Stephanie Grunberg (Department of Microbiology); Gary Wu (Division of Gastroenterology); and James Lewis (Department of Biostatistics and Epidemiology), all from Penn.

The research was supported by grants from the National Institutes of Health, Pennsylvania Department of Health, and the Crohn's and Colitis Foundation of America.

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Genetic variation in human gut viruses could be raw material for inner evolution

Public release date: 19-Mar-2012 [ | E-mail | Share ]

Contact: Marla Paul marla-paul@northwestern.edu 312-503-8928 Northwestern University

CHICAGO --- A genetic pathway previously known for its role in embryonic development and cancer has been identified as a target for systemic sclerosis, or scleroderma, therapy. The finding, discovered by a cross-disciplinary team led by John Varga, MD, John and Nancy Hughes Distinguished Professor of Rheumatology at Northwestern University Feinberg School of Medicine, was recently published in the journal Arthritis & Rheumatism.

"We showed, for the first time, that the Wnt signaling pathway is abnormally activated in scleroderma patients," said Varga, who is also a physician at Northwestern Memorial Hospital. "This is significant for three reasons. First, it gives a better picture of scleroderma and fibrosis in general. Second, it provides a strategy for assessing disease severity, progression, and activity. And third, it opens a door for the design of treatments that aim to block the Wnt pathway and restore its normal controlled activity."

Varga's laboratory collaborated with a pulmonary team at Northwestern, along with teams at Case Western Reserve University and Dartmouth University on the discovery.

Researchers studied skin and lung biopsies from scleroderma patients and found that the Wnt pathway was 'turned on', in contrast to healthy individuals where the pathway was 'turned off.' Varga said this activation may be due to loss of Wnt inhibitors that normally serve as 'brakes' on the pathway to prevent its activation.

The team also examined what the pathway does using fibroblasts and stem cells from healthy people. They found Wnt causes fibroblast activation and blocks the development of fat cells (adipocytes), which directly contribute to scar formation and tissue damage seen in scleroderma.

Scleroderma is a chronic autoimmune disease in which the body's immune system attacks itself. It causes progressive thickening and tightening (fibrosis) of the skin and also can lead to serious internal organ damage and, in some cases, death. Scleroderma affects an estimated 150,000 people in the United States, most frequently young to middle-aged women.

"Scleroderma is a complex and poorly understood disease with no cure," said Varga. "Our findings suggest that treatments targeting the Wnt signaling pathway could lead to an effective treatment."

Varga said Northwestern researchers next plan to conduct multi-center preclinical studies to evaluate treatments that block the Wnt pathway in animal models and measure Wnt activity in additional scleroderma biopsies to see if it can be clinically useful as a biomarker.

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New genetic path for scleroderma

ScienceDaily (Mar. 18, 2012) A multinational research team led by scientists at Duke-NUS Graduate Medical School has identified the reason why some patients fail to respond to some of the most successful cancer drugs.

Tyrosine kinase inhibitor drugs (TKI) work effectively in most patients to fight certain blood cell cancers, such as chronic myelogenous leukemia (CML), and non-small-cell lung cancers (NSCLC) with mutations in the EGFR gene.

These precisely targeted drugs shut down molecular pathways that keep these cancers flourishing and include TKIs for treating CML, and the form of NSCLC with EGFR genetic mutations.

Now the team at Duke-NUS Graduate Medical School in Singapore, working with the Genome Institute of Singapore (GIS), Singapore General Hospital, and the National Cancer Centre Singapore, has discovered that there is a common variation in the BIM gene in people of East Asian descent that contributes to some patients' failure to benefit from these tyrosine kinase inhibitor drugs.

"Because we could determine in cells how the BIM gene variant caused TKI resistance, we were able to devise a strategy to overcome it," said S. Tiong Ong, MBBCh, senior author of the study and associate professor in the Cancer and Stem Cell Biology Signature Research Programme at Duke-NUS and Division of Medical Oncology, Department of Medicine, at Duke University Medical Center.

"A novel class of drugs called the BH3-mimetics provided the answer," Ong said. "When the BH3 drugs were added to the TKI therapy in experiments conducted on cancer cells with the BIM gene variant, we were able to overcome the resistance conferred by the gene. Our next step will be to bring this to clinical trials with patients."

Said Yijun Ruan, PhD, a co-senior author of this study and associate director for Genome Technology and Biology at GIS: "We used a genome-wide sequencing approach to specifically look for structural changes in the DNA of patient samples. This helped in the discovery of the East Asian BIM gene variant. What's more gratifying is that this collaboration validates the use of basic genomic technology to make clinically important discoveries."

The study was published online in Nature Medicine on March 18.

If the drug combination does override TKI resistance in people, this will be good news for those with the BIM gene variant, which occurs in about 15 percent of the typical East Asian population. By contrast, no people of European or African ancestry were found to have this gene variant.

"While it's interesting to learn about this ethnic difference for the mutation, the greater significance of the finding is that the same principle may apply for other populations," said Patrick Casey, PhD, senior vice dean for research at Duke-NUS and James B. Duke Professor of Pharmacology and Cancer Biology.

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Genetic variation in East Asians found to explain resistance to cancer drugs

15-03-2012 14:59 What is the relationship between implementation guidelines and reimbursement? Are payers the ultimate gatekeeper? Is it worth educating healthcare providers and patients? • Appropriate uses of genetic testing • Evidence-based guidelines and flexibility • Clinical management of new technology • Best practices (eg, breast cancer) Moderator: Robert Green, Harvard Medical School Robert McCormack, Veridex/J&J Thomas Musci, Novartis Diagnostics Greg Feero, Maine - Dartmouth Family Medicine Residency and NHGRI Deborah Heine, Claire Altman Heine Foundation

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Integrating new genetic testing technologies into clinical pathways - Video

15-03-2012 12:52 Personalized Medicine: trends and prospects for the new science of genetic testing and molecular diagnostics Overview of new working paper -- Mapping the Future of Genetic Testing and Molecular Diagnostics: A payer's perspective on integrating personalized care into clinical practice Review of results of survey of consumers and physicians about genetic testing Deneen Vojta, UnitedHealth Group

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Personalized Medicine, UnitedHealth Group - Video