The Digital Future of Molecular Medicine: Rethinking FDA Regulation - Part II
Manhattan Institute Event- May 15, 2013 Speakers: Linda Avey, John Crowley, Andy Palmer, Karen Gutekunst, Paul Howard.
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The Digital Future of Molecular Medicine: Rethinking FDA Regulation - Part I
Manhattan Institute Event- May 15, 2013 Speakers: Peter Huber, Dr. Andrew von Eschenbach, Paul Howard.
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The Digital Future of Molecular Medicine: Rethinking FDA Regulation - Part III
Manhattan Institute Event- May 15, 2013 Speakers: Newton Crenshaw, Vicki Seyfert Margolis, Marty Kohn, Susan Winckler.
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The Digital Future of Molecular Medicine: Rethinking FDA Regulation - Part IV
Manhattan Institute Event- May 15, 2013 Speakers: Paul Howard, Mark Levin.
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Newswise Professor Jonathan Stamlers latest findings regarding nitric oxide have the potential to reshape fundamentally the way we think about the respiratory system and offer new avenues to save lives. It may be time to rewrite the textbooks.
Scientific dogma has the respiration process involving only two elements oxygen and carbon dioxide. Specifically, the delivery of oxygen from lungs to tissues, and the removal of the waste product, carbon dioxide, through exhaling.
Recently published online in the journal Proceedings of the National Academy of Sciences (PNAS), Stamler and colleagues demonstrate that nitric oxide is essential for the delivery of oxygen to the cells and tissues that need it.
Stamler, MD, a Professor of Medicine at Case Western Reserve University School of Medicine and Cardiologist at University Hospitals Case Medical Center, led a team that showed that nitric oxide must accompany hemoglobin to enable blood vessels to open and then supply oxygen to tissues.
Doctors have long known that a major disconnect exists between the amount of oxygen carried in the blood and the amount of oxygen delivered to the tissues. Until now, they had no way to explain the discrepancy. The new findings show that nitric oxide within the red blood cell itself is the gatekeeper to the respiratory cycle nitric oxide makes the cycle run.
The bottom line is that we have discovered the molecular basis of blood flow control in the respiratory cycle loop, Stamler said. Its in the hemoglobin protein itself, which has the ability to deliver the nitric oxide together with oxygen. The simplified textbook view of two gases carried by hemoglobin is missing an essential element nitric oxide because blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system.
Stamlers previous research had revealed that the respiratory cycle was more than an oxygen and carbon dioxide exchange proposition. Stamler and colleagues also had shown that red blood cells carry and release nitric oxide, but had not yet explained the exact physiologic ramifications of nitric oxide release.
In this most recent research, investigators uncovered the key role of nitric oxide in controlling the blood flow in small vessels within tissues responsible for delivering oxygen (known as blood flow autoregulation) a process whose molecular basis had been a longstanding mystery in medicine. Investigators specifically examined the respiratory cycle in mice lacking the one amino acid site that carries nitric oxide in their red blood cells. Low and behold, blood flow autoregulation was eliminated entirely the animals could not oxygenate tissues.
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OXFORD, England (PRWEB) April 09, 2015
Personalized medicine pioneer Jonathan Knowles, PhD has been named as the PMWC United Kingdom 2015 Honorary for his distinguished work advancing both the science and broader recognition of the personalized medicine field. Knowles career in personalized medicine stretches over several decades in both commercial and academic settings.
Dr. Knowles served as Roche President of Group Research and a Member of the Executive Committee. During his twelve years with the company, he helped focus efforts on key disease biology and in-depth understanding of molecular pathology of disease. Under his leadership, Roche developed and implemented a strategy for developing highly effective therapies based on personalized healthcare. His long-held passion for individualized medicine is exemplified by his role as Founding Chairman of the Innovative Medicines Initiative Board (IMI). This 5.5 billion public - private partnership facilitates innovative partnerships among key stakeholders to foster and drive innovation in medicine. He also held positions on the Board of Directors for Roche subsidiaries, Genentech and Chugai.
Prior to Roche, Knowles was the head of the Glaxo Institute in Geneva and Head of European Research for Glaxo Wellcome where he launched work on DNA Colony Sequencing technology which enables one of todays leading next generation DNA sequencing platforms.
In addition to his work in the commercial arena, Professor Knowles has made a significant impact in academia. He is currently a Visiting Professor at the University of Oxford; Professor Emeritus at EPFL, Lausanne; a Member of the European Molecular Biology Organization; and a visiting Scholar at Pembroke College, Cambridge. Knowles also held a Distinguished Professorship in Personalized Medicine at FIMM (Institute for Molecular Medicine Finland) at the University of Helsinki from 2010 to 2014.
In 2011, Knowles was appointed as a Trustee of Cancer Research UK, one of the worlds leading cancer research organizations and as a board member of A*Star, the leading state research organization in Singapore. He is currently Executive Chairman at two UK-based cancer immunotherapy companies, Immunocore, Ltd. and Adaptimmune, Ltd. Dr. Knowles also serves as a non-executive member of numerous biotech companies and on the international science advisory boards of several public organizations.
Precision medicine holds the potential to eradicate many of the seemingly incurable diseases that today cause untold human suffering. We are beginning to see progress thanks to contributions of individuals, like Jonathan Knowles, who has been a leader in advancing the science and in promoting the concept of personalized medicine for most of his career. I would like to congratulate Jonathan for receiving the PMWC United Kingdom 2015 Honors. Jonathan Sheldon, PhD, PMWC 2015 UK Program Chair and Global Vice President, Oracle Health Sciences.
Past recipients of The Personalized Medicine World Conference Honors include Leroy Hood, Co-inventor of the first DNA sequencer, George Church, Co-developer of the Human Genome Project, Brian Druker the Co-inventor of the blockbuster drug, Gleevec and more. The Personalized Medicine World Conference United Kingdom 2015 will be held at the Oxford University Museum of Natural History April 15-17 in Oxford, England. The award reception ceremony for Jonathan Knowles will be held April 15 from 7:00 to 8:30 pm. See program: http://2015uk.pmwcintl.com/program.php
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Personalized Medicine World Conference (PMWC) to honor Jonathan Knowles
Discovery could lead to treatment focus on red blood cell dysfunction in cardiovascular diseases and blood disorders
Professor Jonathan Stamler's latest findings regarding nitric oxide have the potential to reshape fundamentally the way we think about the respiratory system - and offer new avenues to save lives. It may be time to rewrite the textbooks.
Scientific dogma has the respiration process involving only two elements -- oxygen and carbon dioxide. Specifically, the delivery of oxygen from lungs to tissues, and the removal of the waste product, carbon dioxide, through exhaling.
Recently published online in the journal Proceedings of the National Academy of Sciences (PNAS), Stamler and colleagues demonstrate that nitric oxide is essential for the delivery of oxygen to the cells and tissues that need it.
Stamler, MD, a Professor of Medicine at Case Western Reserve University School of Medicine and Cardiologist at University Hospitals Case Medical Center, led a team that showed that nitric oxide must accompany hemoglobin to enable blood vessels to open and then supply oxygen to tissues.
Doctors have long known that a major disconnect exists between the amount of oxygen carried in the blood and the amount of oxygen delivered to the tissues. Until now, they had no way to explain the discrepancy. The new findings show that nitric oxide within the red blood cell itself is the gatekeeper to the respiratory cycle - nitric oxide makes the cycle run.
"The bottom line is that we have discovered the molecular basis of blood flow control in the respiratory cycle loop," Stamler said. "It's in the hemoglobin protein itself, which has the ability to deliver the nitric oxide together with oxygen. The simplified textbook view of two gases carried by hemoglobin is missing an essential element - nitric oxide - because blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system."
Stamler's previous research had revealed that the respiratory cycle was more than an oxygen and carbon dioxide exchange proposition. Stamler and colleagues also had shown that red blood cells carry and release nitric oxide, but had not yet explained the exact physiologic ramifications of nitric oxide release.
In this most recent research, investigators uncovered the key role of nitric oxide in controlling the blood flow in small vessels within tissues responsible for delivering oxygen (known as "blood flow autoregulation") - a process whose molecular basis had been a longstanding mystery in medicine. Investigators specifically examined the respiratory cycle in mice lacking the one amino acid site that carries nitric oxide in their red blood cells. Low and behold, blood flow autoregulation was eliminated entirely - the animals could not oxygenate tissues.
Initially, investigators found low oxygen levels in the animals' muscles at baseline, despite the animals' red blood cells carrying a full load of oxygen. When the mice were then stressed to bring on slight oxygen deprivation (hypoxia), the blood flow to their organs dropped precipitously. The lack of oxygen should have prompted a spike in blood flow to send more oxygenated blood to tissues and cells. Instead, the reduced blood flow and ensuing oxygen shortfall triggered heart attacks and heart failure in these nitric oxide-deficient animals.
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Basis established for nitric oxide joining oxygen and carbon dioxide in respiratory cycle
We age in part thanks to "friendly fire" from the immune system -- inflammation and chemically active molecules called reactive oxygen species that help fight infection, but also wreak molecular havoc over time, contributing to frailty, disability and disease. The CD33rSiglec family of proteins are known to help protect our cells from becoming inflammatory collateral damage, prompting researchers at the University of California, San Diego School of Medicine to ask whether CD33rSiglecs might help mammals live longer, too.
In a study published April 7 by eLife, the team reports a correlation between CD33rSIGLEC gene copy number and maximum lifespan across 14 mammalian species. In addition, they found that mice lacking one CD33rSIGLEC gene copy don't live as long as normal mice, have higher levels of reactive oxygen species and experience more molecular damage.
"Though not quite definitive, this finding is provocative. As far as we know, it's the first time lifespan has been correlated with simple gene copy number," said Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine and member of the UC San Diego Moores Cancer Center. "Since people also vary in number of CD33rSIGLEC gene copies, it will be interesting to see if these genes influence variations in human lifespan as they do in mice."
Varki led the study, along with Pascal Gagneux, PhD, associate professor of pathology.
The CD33rSIGLEC genes encode siglec receptors that bind sialic acids -- sugar molecules found on many cells. These siglec receptors stick out like antennae on the outer surface of immune cells, probing the surface of other "self" cells in the body. When sialic acids bind siglec receptors, they transmit the message to the inside of the cell. This signal relay puts a brake on immune cell activation. In this way, the CD33rSiglec receptors help dampen chronic inflammation and reactive oxygen species in the body.
Different mammal species carry different numbers of the CD33rSIGLEC genes in their genomes. In this study, Varki, Gagneux and colleagues surveyed 14 different mammalian genomes, including those of elephants, dogs, monkeys and humans, and found that CD33rSIGLEC gene number correlates with maximum lifespan. In other words, species with more copies tend to live longer, even when the researchers controlled for other factors, such as body mass, adjacent genes and shared evolutionary history.
To dig deeper, Varki, Gagneux and team turned to a mouse model. They discovered that mice that were missing one CD33rSIGLEC gene and experienced inflammation early in life showed signs of accelerated aging (gray hair, disorientation, thin skin), had higher levels of reactive oxygen species and did not live as long as normal mice.
"The higher CD33rSIGLEC gene number can be thought of as an improved maintenance system that co-evolved in mammals to buffer against the effects of many infectious episodes fought off by the immune system of long-lived mammals," said Gagneux.
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The above story is based on materials provided by University of California, San Diego Health Sciences. The original article was written by Heather Buschman, PhD. Note: Materials may be edited for content and length.
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More anti-inflammatory genes mean longer lifespans for mammals
A particular molecular pathway permits stem cells in pediatric bone cancers to grow rapidly and aggressively, according to researchers at NYU Langone Medical Center and its Laura and Isaac Perlmutter Cancer Center.
In normal cell growth, the Hippo pathway, which controls organ size in animals, works as a dam, regulating cell proliferation. What the researchers found is that the transcription factor of a DNA binding protein called sex determining region Y box 2, or Sox2 for short, which normally maintains cell self-renewal, actually releases the floodgates in the Hippo pathway in osteosarcomas and other cancers, permitting the growth of highly aggressive, tumor-forming stem cells.
Results from the study are to be published in the journal Nature Communications online April 2.
"This study is one of the first to identify the mechanisms that underlie how an osteosarcoma cancer stem cell maintains its tumor-initiating properties," says senior study investigator Claudio Basilico, MD, the Jan T. Vilcek Professor of Molecular Pathogenesis at NYU Langone and a member of its Perlmutter Cancer Center.
In the study, the investigators used human and mouse osteosarcomas to pinpoint the molecular mechanisms that inhibit the tumor-suppressive Hippo pathway. The researchers concluded that Sox2 represses the functioning of the Hippo pathway, which, in turn, leads to an increase of the potent growth stimulator Yes Associated Protein, known as YAP, permitting cancer cell proliferation.
"Our research is an important step forward in developing novel targeted therapies for these highly aggressive cancers," says study co-investigator Alka Mansukhani, PhD, an associate professor at NYU Langone and also a member of the Perlmutter Cancer Center. "One possibility is to develop a small molecule that could knock out the Sox2 transcription factor and free the Hippo pathway to re-exert tumor suppression."
Mansukhani adds that the research suggests that drugs such as verteporfin, which interfere with cancer-promoting YAP function, might prove useful in Sox2-dependent tumors.
The study expands on previous work in Basilico's and Mansukhani's molecular oncology laboratories at NYU Langone and on earlier work by Upal Basu Roy, PhD, MPH, the lead study investigator, who found that Sox2 was an essential transcription factor for the maintenance of osteosarcoma stem cells.
The NYU group has shown that, i addition to playing a role in osteosarcoma, Sox2 operates in other tumors, such as glioblastomas, an aggressive type of brain cancer.
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Key mechanism identified in tumor-cell proliferation in pediatric bone cancers
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Newswise Chicago, IL, Northfield, IL, Bethesda, MD, Alexandria, VA - The American Society for Clinical Pathology (ASCP), the College of American Pathologists (CAP), the Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) today released a draft of a clinical practice guideline on the use of molecular marker testing for patients with primary or metastatic colorectal carcinoma. This evidence-based guideline will help establish standard molecular marker testing, guide targeted therapies, and advance personalized care for these patients. The draft guidance document, Guideline on the Evaluation of Molecular Markers for Colorectal Cancer Workgroup Draft Recommendations Summary, (#CRCOCP) is now available online for public comment through April 22, 2015.
The draft guidance is designed to identify opportunities for improving patient outcomes. By bringing together four key organizations, all with substantial interest in treatment of colorectal cancer, we have addressed multiple elements of the patient care continuum, said Wayne W. Grody, MD, PhD, UCLA School of Medicine, project co-chair on behalf of ASCP. While we didnt focus on a selected set of molecular markers, we considered the overall plan-of-care from collection of tissue samples to diagnostics, treatment, and follow-up.
The co-chairs, one from each of the four organizations, utilized the expertise of more than 25 specialists in a variety of disciplines, including pathologists and oncologists as well as patient advocates, to draft the guidance document. The multi-disciplinary perspective has resulted in a thorough set of draft recommendations that streamline processes and contribute to improving patient outcomes. While other colorectal cancer biomarker guidelines have been published, they tend to focus on one marker or a small panel of markers for one specific clinical use, unlike the collaborative multidisciplinary approach for this guideline, said Stanley R. Hamilton, MD, FCAP, AGAF, The University of Texas MD Anderson Cancer Center, project co-chair on behalf of CAP. This guideline addresses all current molecular markers that can impact treatment decisions for patients with colorectal cancer. To date, there isnt an evidence-based guideline thats quite as all-encompassing and patient-centered as this one.
Input from stakeholders, including scientists, clinicians, government agencies, other non-profit organizations, patients, patient advocates, and members of the public is critical to the release of a final set of recommendations for the care of patients with colorectal cancer. Anyone who may be affected by or play a role in the application of the guideline is encouraged to provide comments, said Antonia R. Sepulveda, MD, PhD, FASCP, FCAP, Columbia University, project co-chair on behalf of AMP. From the onset, we have adhered to the Institute of Medicines Standards for Developing Trustworthy Clinical Practice Guidelines, which includes a dedicated external review period.
The final guidance document is targeted for publication later this year. Given the rapid evolution of the field, we have future proofed the document with a research section that acknowledges molecular markers and tests on the horizon, said Carmen Allegra, MD, University of Florida Health Cancer Center, project co-chair on behalf of ASCO. We intend to review these recommendations regularly and will update the guidance document as necessary.
Editors Note: The draft recommendations and references provided here represent time-limited information and are not to be distributed, used, or considered as an accurate representation of the Colorectal Cancer Molecular Marker Guideline group's work product(s) after April 22, 2015.
About the American Society for Clinical Pathology: Founded in 1922 in Chicago, ASCP unites more than 120,000 anatomic and clinical pathologists, residents and fellows, medical laboratory professionals and students to accelerate the advancement of laboratory medicine to better improve patient care through knowledge, collaboration and global community. ASCPs mission is to provide excellence in education, certification, and advocacy on behalf of the patients, pathologists, and laboratory professionals across the globe. To learn more, visit http://www.ascp.org. Follow us on Twitter at http://www.twitter.com/ascp_chicago and connect with us on Facebook at http://www.facebook.com/ASCP.Chicago.
About the College of American Pathologists As the leading organization with more than 18,000 board-certified pathologists, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. The CAPs Laboratory Improvement Programs, initiated 65 years ago, currently has customers in more than 100 countries, accrediting 7,600 laboratories and providing proficiency testing to 20,000 laboratories worldwide. Find more information about the CAP at cap.org. Follow CAP on Twitter: @pathologists.
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Angelina Jolie told the story yesterday of her decision to have her ovaries and fallopian tubes surgically removed to reduce the risk of ovarian cancer due to the faulty BRCA1 gene she was born with. This follows a similar decision to undergo a double mastectomy in 2013 to reduce the even higher risk of breast cancer the mutant BRCA1 gene bestows.
As a human being, its hard not to feel enormous sympathy with her for facing such a decision a thoroughly 21stCentury decision that no-one ever had to face until the advent of molecular medicine. For centuries humanity has had to face the many adversities of life head on, but for the most part without much forewarning and even less hope of intervention.
The knowledge that certain mutations in this BRCA1 gene confer such high risks of cancer (as much as 87% chance over a lifetime for breast cancer and 50% for ovarian cancer) has the potential to be empowering or frightening (and perhaps both at the same time) in equal measure.
The interventions are hugely invasive. The surgeries themselves are major, and come with short-term risks. The hormonal imbalances that will result can change not only health but also the person. But perhaps hardest of all to quantify is the psychological and emotional impact.
In addition to sympathy for having to face such a decision, Ms Jolie also deserves admiration for her self-awareness and the clarity of her thinking that has allowed her to make such a clear choice the right choice uniquely for her. Not everyone is blessed with such gifts.
That matters because we all of us are going to face these kind of decisions much more frequently in the future.
We hear from all sides about the benefits of personalized medicine the product of refined molecular diagnostics that offer a glimpse into the future health of the individual. But Ms Jolies experience of personalized medicine highlights some of the challenges that also remain.
The biggest hurdle seems to be one of education. The default state of humans is to be pretty bad at understanding risks and the output of all precision medicine algorithms is precisely that: an estimate of individual risk. While science can make the estimate more accurate, what it cannot provide is the calibration of what that risk estimate means to the individual. A 50% risk of ovarian cancer over a lifetime sounds, on the face of it, like a death sentence. But it needs some context. First and most importantly we have to remember we are all born with a death sentence. The only questions are when and how. Something like 33% of everyone alive today will suffer cancer in their lifetime.
Of course, BRCA1 mutations carry a material risk of an early death and no doubt that influenced Ms Jolies decision (as it would likely have done for most of us). But the important point is that properly understanding the implications of the genetic diagnosis is a complex education process. It cannot be nicely packaged up into a single number or a simple decision.
And BRCA1 carries one of the larger risks associated with any single genetic marker. As molecular diagnostics are refined (as they are being at an impressive rate), that picture will become more complex still and the decisions facing the patient ever more challenging.
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What Angelina Jolie's Very Personal Medicine Tells Us About Personalized Medicine
CRISPR-Cas9 is a powerful new tool for editing the genome. For researchers around the world, the CRISPR-Cas9 technique is an exciting innovation because it is faster and cheaper than previous methods. Now, using a molecular trick, Dr. Van Trung Chu and Professor Klaus Rajewsky of the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch and Dr. Ralf Khn, MDC and Berlin Institute of Health (BIH), have found a solution to considerably increase the efficiency of precise genetic modifications by up to eightfold (Nature Biotechnology: doi:10.1038/nbt.3198)**.
"What we used to do in years, we can now achieve in months," said gene researcher and immunologist Klaus Rajewsky, indicating the power of this new genome-editing technology. CRISPR-Cas9 not only speeds up research considerably - at the same time it is much more efficient, cheaper and also easier to handle than the methods used so far.
The CRISPR-Cas9 technology allows researchers to transiently introduce DNA double-strand breaks into the genome of cells or model organisms at genes of choice. In these artificially produced strand breaks, they can insert or cut out genes and change the genetic coding according to their needs.
Mammalian cells are able to repair DNA damage in their cells using two different repair mechanisms. The homology-directed repair (HDR) pathway enables the insertion of preplanned genetic modifications using engineered DNA molecules that share identical sequence regions with the targeted gene and which are recognized as a repair template. Thus, HDR repair is very precise but occurs only at low frequency in mammalian cells.
The other repair system, called non-homologous end-joining (NHEJ) is more efficient in nature but less precise, since it readily reconnects free DNA ends without repair template, thereby frequently deleting short sequences from the genome. Therefore, NHEJ repair can only be used to create short genomic deletions, but does not support precise gene modification or the insertion and replacement of gene segments.
Many researchers, including Van Trung Chu, Klaus Rajewsky and Ralf Khn, are seeking to promote the HDR repair pathway to make gene modification in the laboratory more precise in order to avoid editing errors and to increase efficiency. The MDC researchers succeeded in increasing the efficiency of the more precisely working HDR repair system by temporarily inhibiting the most dominant repair protein of NHEJ, the enzyme DNA Ligase IV. In their approach they used various inhibitors such as proteins and small molecules.
"But we also used a trick of nature and blocked Ligase IV with the proteins of adeno viruses. Thus we were able to increase the efficiency of the CRISPR-Cas9 technology up to eightfold," Ralf Khn explained. For example, they succeeded in inserting a gene into a predefined position in the genome (knock-in) in more than 60 per cent of all manipulated mouse cells. Khn has just recently joined the MDC and is head of the research group for "iPS cell based disease modeling". Before coming to the MDC, he was on the research staff of Helmholtz Zentrum Mnchen. "The expertise of Ralf Khn is very important for gene research at MDC and especially for my research group," Klaus Rajewsky said.
Concurrent with the publication of the article by the MDC researchers, Nature Biotechnology published another, related paper on CRISPR-Cas9 technology. It comes from the laboratory of Hidde Ploegh of the Whitehead Institute in Cambridge, MA, USA.
Somatic gene therapy with CRISPR-Cas9 is a goal
The new CRISPR-Cas9 technology, developed in 2012, is already used in the laboratory to correct genetic defects in mice. Researchers also plan to modify the genetic set up of induced pluripotent stem cells (iPS), which can be differentiated into specialized cell types or tissues. That is, researchers are able to use the new tool to introduce patient-derived mutations into the genome of iPS cells for studying the onset of human diseases. "Another future goal, however, is to use CRISPR-Cas9 for somatic gene therapy in humans with severe diseases," Klaus Rajewsky pointed out.
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MDC researchers greatly increase precision of new genome editing tool
Hopital Tenon, Paris- Personalised health care in Urology: from innovation technologies to practice
The translation, from bench to bedside, of knowledge in molecular medicine as well as in technologies for functional imaging and surgical procedures into personalised medicine improve the quality...
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Newswise PHILADELPHIA - Researchers at the Perelman School of Medicine at the University of Pennsylvania describe the first set of genes important in learning in a zebrafish model in the journal Neuron this week. Using an in-depth analysis of one of these genes, we have already revealed an important relevant signaling pathway, says senior author Michael Granato, PhD, a professor of Cell and Developmental Biology. The proteins in this pathway could provide new insights into the development of novel pharmacological targets.
Over the last 20 years, zebrafish have become great models for studying development and disease. Like humans, zebrafish are vertebrates and over 80 percent of human genes bearing disease descriptions are also present in zebrafish. As such, this animal model has become increasingly popular to study human diseases such as cardiovascular conditions or tumor formation.
Zebrafish have also become an ideal model for studying vertebrate neuroscience and behavior. In fact, Granato developed the first high-throughput behavioral assays that measure learning and memory in fish. Normal fish startle with changes in noise and light level by bending and swimming away from the annoying stimuli. They do eventually habituate and get used to the alterations in their environment, he explains. However, fish mutants fail to habituate -- they never get used to their surroundings and always flinch at the loud noises.
In nature, this startle response is important for avoiding predators, but is flexible in how the fish use it in different situations, notes first author Marc A. Wolman, PhD, a postdoctoral fellow in the Granato lab who is now an assistant professor at the University of Wisconsin. Past data from the Granato lab indicate that learning and memory defects are reversible with acute pharmacologic treatments and are therefore not hard-wired, as might be expected for a defect in the development of nerves. Habituation represents a fundamental form of learning, yet the underlying molecular genetic mechanisms are not well defined. In humans, deficits in habituation are associated with a variety of neuropsychiatric disorders, including schizophrenia, autism, Tourettes, and obsessive-compulsive disorder.
Years in the Making To find these genetic needles in the chromosome haystack, the team started four years ago by introducing small, point mutations into the zebrafish DNA. These are changes that affect only one or two DNA building blocks at a time. They then bred mutant fish for three generations to obtain fish whose genomes contain two copies of a mutant gene. These mutants were then exposed to the startle response test. Using a camera and software to eliminate human observer bias, they recorded how the mutants reacted to a loud noise. Most fish larvae habituated and stopped reacting to the noise stimulus. Some of the mutants, did, however, fail to habituate and continued to respond to the noise.
A genome-wide genetic screen, coupled with whole genome sequencing, identified 14 different mutations in zebrafish that failed to habituate. One of these 14 contained a mutation in the vertebrate-specific gene pregnancy-associated plasma protein-aa (pappaa). This gene encodes an enzyme that cleaves other proteins and works outside the cell. It is known to increase the availability of the hormone IGF at the cell surface, thereby enhancing receptor signaling for the IGF pathway. (A role of the PAPPAA enzyme in or on neurons had not been described; however, IGF is known to be an important molecule in pathways that determine long-term memory.)
At first we didnt think it was important in learning, but we found that pappaa is expressed by startle-circuit neurons, explains Granato. The team verified the involvement of the IGF pathway by rescuing mutant behavior to normal by adding an activator of downstream molecules that interact with the IGF receptor. Mutants that were treated this way, when put back in the startle test, reacted normally and habituated to the loud noise. Also, when the team used an inhibitor of the IGF receptor in normal zebrafish larvae, these fish showed the same behavior in the startle test as the pappaa mutants. This all indicates that the pappaa gene promotes learning by acutely and locally increasing IGF availability to the cell.
Our experiments found the first functional gene set for habituation learning in a vertebrate and identify PAPPAA-regulated IGF signaling as a novel mechanism regulating this type of behavior, says Granato. A mammal pappaa gene exists but its function is as yet unknown. In future studies we hope to capitalize on the identification of pappaa and the other 13 genes we isolated to identify pharmacological treatments that enhance learning and memory.
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Genomewide Screen of Learning in Zebrafish Identifies Enzyme Important in Neural Circuit
"To build a premier virus, gene, and cell therapy program and to translate promising therapeutics from bench to bedside in a timely manner."
In mid-July, 2009, Eva Galanis, M.D., a professor of oncology, became the second person to lead the Department of Molecular Medicine. Dr. Galanis succeeds Stephen Russell, M.D., Ph.D., who came to Mayo Clinic from Cambridge University in 1998 to establish the Gene and Virus Therapy Program, which eventually led to the Gene and Virus Therapy Ph.D. track at Mayo Graduate School, and the creation of the Department of Molecular Medicine.
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Mayo Clinic is targeting cancer on the molecular level - by changing the genetic makeup of diseased cells. Gene therapy changes the DNA of cancer cells so that they die, while virus therapy uses the destructive power of viruses to kill cancer cells. "Viruses are professional gene delivery vehicles," said Dr. Stephen Russell, leader of the Gene and Virus Therapy Program of the Mayo Clinic Cancer Center. "We're now able to harness that."
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A significant landmark for the Molecular Medicine Department was July 12, 2004, when a patient with ovarian cancer received an intraperitoneal infusion of a recombinant measles virus that was designed, constructed, preclinically tested, and manufactured by gene therapy investigators at Mayo Clinic. This is the first time that a genetically engineered measles virus has ever been tested in human subjects.
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Researchers at the Max Delbrck Center for Molecular Medicine (MDC) Berlin-Buch and Charit - Universittsmedizin Berlin, Campus Berlin-Buch, have succeeded in generating cells of the immune system to specifically target and destroy cancer cells. The research findings of Matthias Obenaus, Professor Thomas Blankenstein (MDC and Charit), Dr. Matthias Leisegang (MDC) and Professor Wolfgang Uckert (Humboldt-Universitt zu Berlin and MDC) as well as Professor Dolores Schendel (Medigene AG, Planegg/Martinsried) have now been published in Nature Biotechnology online (doi:10.1038/nbt.3147)*.
The immune system of the body is trained to distinguish between "foreign" and "self" and to recognize and destroy exogenous structures. In cancer, however, the immune system appears to be quite docile in its response. While it is capable of detecting cancer cells because they often bear characteristics (antigens) on their surfaces that identify them as pathologically altered cells, usually the immune system does not mount an attack but rather tolerates them. The reason: The cancer cells are endogenous to the body, and immune cells do not recognize them as foreign, as they would pathogens. The researchers want to break this tolerance in order to develop therapies against cancer.
T cells are the linchpin in the attack of the immune system. On their surface they have anchor molecules (receptors) with which they recognize foreign structures, the antigens of bacteria or viruses, and thus can target and destroy invaders. Cancer researchers and immunologists are attempting to mobilize this property of the T cells in the fight against cancer. The objective is to develop T cells that specifically recognize and attack only cancer cells but spare other body cells.
Now Matthias Obenaus, Professor Blankenstein, Dr. Leisegang, Professor Uckert and Professor Schendel have developed human T cell receptors (TCRs) that have no tolerance toward human cancer antigens and specifically recognize the antigen MAGE-A1, which is present on various human tumor cells. Instead of directly using human-derived TCRs, which do not mediate substantial anti-tumor effects, the scientists took a "detour" over a mouse model.
First, the researchers transferred the genetic information for human TCRs into the mice, thus creating an entire arsenal of human TCRs (Nature Medicine, doi: 10.1038/nm.2197). When the humanized mouse T cells come into contact with human cancer cells, they perceive the tumor antigens as foreign - like viral or bacterial antigens. Thus, the T cells can specifically target, attack and destroy the tumor cells.
The researchers subsequently isolated the human T-cell receptors of these mice, which are specifically targeted toward the tumor antigen MAGE-A1. Then they transferred the T-cell receptors into human T cells, thereby training them to recognize the cancer cells as foreign.
Some people possess T cells which naturally recognize MAGE-A1 on tumor cells, but only in the Petri dish. In studies using an animal model, only the human TCRs derived from mice were shown to be effective against the tumor. The TCRs from human T cells ignored the tumor completely. The comparison with the tweaked human TCRs from the mouse model shows that the TCRs of patients cannot recognize the tumor antigens sufficiently; they are too weak. "The fact that our TCRs from the mouse are better is a strong indication that the T cells of a human are tolerant toward MAGE-A1," said Matthias Obenaus and Professor Blankenstein.
Using the T-cell receptors they developed, the researchers are planning an initial clinical trial with patients with MAGE-A1 positive multiple myeloma, a malignant disease of the bone marrow.
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*Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice Matthias Obenaus1, Catarina Leito1,7, Matthias Leisegang1, Xiaojing Chen1, Ioannis Gavvovidis1 Pierre van der Bruggen2,3, Wolfgang Uckert1,4, Dolores J Schendel5 & Thomas Blankenstein1,6 1Max Delbrck Center for Molecular Medicine, Berlin, Germany. 2Ludwig Institute for Cancer Research, Brussels, Belgium. 3De Duve Institute, Universit Catholique de Louvain, Brussels, Belgium. 4Institute of Biology, Humboldt University, Berlin, Germany. 5Medigene AG, Planegg/Martinsried, Germany. 6Institute of Immunology, Charit Campus Buch, Berlin, Germany. 7Present address: Institute for Molecular and Cell Biology, Porto, Portugal.
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Researchers in Berlin tweak the immune system to target cells bearing tumor antigens
The kidney carries out vital functions by continuously filtering the blood and excreting waste products into the urine. This is achieved by a complex system of tubules which transports the urine and regulates its composition. PhD student Annekatrin Aue, Dr. Christian Hinze and Professor Kai Schmidt-Ott of the Max Delbrck Center for Molecular Medicine (MDC) have now discovered how parts of these kidney tubules establish an inner space (lumen) and form a tight barrier against adjacent structures. The epithelial cells which line the tubules coordinate these processes through a novel molecular signaling pathway (Journal of the American Society of Nephrology, doi: 10.1681/ASN.2014080759)1.
The starting point of the MDC researcher's analyses was the transcription factor grainyhead-like 2 (Grhl2). As the research group led by Professor Schmidt-Ott discovered a few years ago, Grhl2 regulates the formation and structural integrity of epithelial cells lining the inner and outer surfaces of the body. Now, the researchers have shown that this gene regulator also plays a role in the kidney.
The studies, which were funded by the German Research Foundation (DFG) and the Urological Research Foundation, revealed that Grhl2 is primarily expressed in the renal collecting duct and in its embryonic precursors, the nephric duct and the ureteric bud. The collecting ducts form particularly tight, impermeable segments of the nephron, which is the basic structural unit of the kidney. The kidney filters around 1700 liters of blood every day, producing about 180 liters of primary urine. However, after passing through the tubular system only one to two liters of urine are excreted, while the remaining vital components are reabsorbed. The collecting ducts carry out the fine-tuning of the urinary composition, thereby ensuring life-sustaining processes like blood pressure regulation and body water homeostasis.
To determine the function of the Grhl2 transcription factor in the kidney, the researchers investigated cell cultures of collecting duct cells and nephric ducts of mouse embryos deficient for this factor. The result: If Grhl2 is missing, the barrier function of these epithelial cells is significantly reduced and lumen expansion is defective.
Furthermore, the MDC researchers found that the transcription factor Grhl2 does not work alone. It teams up with and regulates another transcription factor, ovo-like 2 (Ovol2). This tandem controls a gene that is important for the sealing of epithelial cell clusters (claudin 4), thus ensuring an impermeable barrier, as well as another gene (Rab 25), which controls cellular trafficking of constituents between the cell and the internal environment of the lumen. Hence, the researchers could elucidate a novel molecular signaling pathway in the kidney.
Barrier formation and lumen expansion are essential components for normal kidney development and function. However, they also participate in kidney pathology, such as cystic kidney diseases, which lead to an uncontrolled expansion of the tubular lumen. Further research must demonstrate whether the insights obtained by the MDC researchers are of clinical importance.
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1A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion Annekatrin Aue*, Christian Hinze*, Katharina Walentin*, Janett Ruffert*, Yesim Yurtdas*?, Max Werth*, Wei Chen*, Anja Rabien?, Ergin Kilic, Jrg-Dieter Schulzke**, Michael Schumann** and Kai M. Schmidt-Ott* *Max Delbrueck Center for Molecular Medicine, Berlin, Germany Experimental and Clinical Research Center, and Departments of Nephrology, Urology, Pathology, and **Gastroenterology, Charit Medical University, Berlin, Germany; and ?Berlin Institute of Urologic Research, Berlin, Germany #Corresponding author: Prof. Dr. Kai M. Schmidt-Ott, MDC, email: kai.schmidt-ott@charite.de
A micrograph of the kidney can be downloaded from the Internet at: https://www.mdc-berlin.de/44046890/en/news/2015
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Cells have two different programs to safeguard them from getting out of control and developing cancer. One of them is senescence (biological aging). It puts cancer cells into a permanent sleep so they no longer divide and grow in an uncontrolled way. Now the research group led by Professor Walter Birchmeier (Max Delbrck Center for Molecular Medicine, MDC, Berlin-Buch) has discovered that an enzyme known to be active in breast cancer and leukemia blocks this protection program and boosts tumor growth. They succeeded in blocking this enzyme in mice with breast cancer, thus reactivating senescence and stopping tumor growth (EMBO-Journal, DOI 10.15252/embj.201489004)*.
The enzyme Shp2 belongs to a group of enzymes called tyrosine phosphatases. These enzymes are major cell growth regulators. Shp2, for example, plays an essential role in early embryogenesis and is also known to play a role in cancer. Some years ago researchers showed that Shp2 is upregulated in 70 percent of invasive breast cancers. These forms of breast cancer are particularly aggressive. Recent studies with human breast cancer cell lines have also shown that Shp2 mediates survival signals in cancer cells.
Reason enough for MDC cancer researcher Professor Birchmeier, who for years has been studying signaling in cancer, to further investigate this enzyme with his research team colleagues Dr. Linxiang Lan and Dr. Jane Holland. Also, current evidence shows that senescence may play an inhibitory role in breast cancer.
The MDC researchers therefore studied mice which carried the breast cancer gene PyMT. This oncogene rapidly initiates breast cancer, which also metastasizes. The researchers noted that the enzyme Shp2 is very active in these mice. They were able to show that Shp2 initiates a signaling cascade. Within this cascade Shp2 turns on different signaling molecules, but turns off the tumor suppressor genes p27 und p53. As a result, the senescence protection program is also shut off.
The question of interest was whether or not senescence can be turned on again. Is it possible to target Shp2 directly and shut it off? Using a small molecule, researchers of the biotech company Experimental Pharmacology and Oncology (EPO), based on the Berlin-Buch campus as is the MDC, were able to shut down the Shp2 gene in the mice with breast cancer. In this way they were able to reactivate the senescence program and stop the growth of the breast cancer cells. The small molecule was developed by the Leibniz-Institut fr molekulare Pharmakologie (FMP) in Berlin-Buch. However, it is still an experimental drug and has not been licensed for use in human patients.
The next step was to find out which role Shp2 and its target genes play in human patients with breast cancer. Dr. Balzs Gyrffy of Semmelweiss University in Budapest, Hungary, a longtime collaborator of Professor Birchmeier, looked at the retrospective data of almost 4,000 patients. After analyzing the data, he and his collaborators in Berlin are convinced that the activity of Shp2 and its target genes can predict the outcome of breast cancer: The less active Shp2 is, the higher the chance for the affected women to stay relapse-free after having undergone a successful breast cancer therapy.
"Our data suggest that senescence induction by inhibiting Shp2 or controlling its targets may be useful in therapeutic approaches to breast cancer," the researchers conclude. Cancer cells in the senescence mode secrete messenger molecules of the immune system (cytokines), enabling the body's defense system to identify these sleeping cancer cells and destroy them.
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*Shp2 Signaling is Essential to the Suppression of Senescence in PyMT-induced Mammary Gland Cancer in Mice Linxiang Lan1, Jane D. Holland1, Jingjing Qi1, Stefanie Grosskopf1, Regina Vogel1, Balzs Gyrffy2,3, Annika Wulf-Goldenberg4, Walter Birchmeier1,*
1 Cancer Research Program, Max Delbrck Center for Molecular Medicine (MDC) Berlin, Germany 2 MTA TTK Lendlet Cancer Biomarker Research Group, Budapest, Hungary 3 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary 4 Experimental Pharmacology & Oncology (EPO), Berlin, Germany
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MDC cancer researchers identify new function in an old acquaintance