Category Archives: Gene Medicine

New York Times

Scientists Discover a Key to a Longer Life in Male DNA New York Times But large-scale surveys of people's DNA have revealed few genes with a clear influence on longevity. It's been a real disappointment, said Nir Barzilai, a geneticist at Albert Einstein College of Medicine. Researchers are having better luck following ...

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Scientists Discover a Key to a Longer Life in Male DNA - New York Times

Precision medicine is more hype than reality right now but, at the same time, the incredible potentialit holds for the future is even greater than all the buzz teases today.

Thats what I came away with from the Precision Medicine Summit in Boston this week.

Lets look into the distant future: A patient walks into a hospital to meet with clinicians who run tests and pinpoint a biomarker for, say, Alzheimers. Then a gene surgeon does some on-the-spot genome editing. The patient walks out with that Alzheimers-free-for-life feeling.

Primary care andgenome sequencing will come to the forefrontto identify which patients can benefit in a future where genome editing is widespread, said Ross Wilson, principal investigator at the University of California Berkeleys Institute for Quantitative Biosciences.

Just how widespread can precision medicine get? Well, Eric Dishman, who spearheads the NIHs All of Us program said the program is starting off with the goal of attracting 1 million American participants but is already thinking about how toscale that into the billionsglobally.

Getting genomic data into an EHR The grand vision is to democratize research and apply more brainpower per problem to the most vexing medical issues.

Before we can get there, though, a lot has to happen to hammer out data gathering and sharing capabilities, retool the healthcare system so its much more adaptable to change and ultimately modernize IT infrastructure to support precision medicine and all the data that entails.

Robert Green, MD, a medical geneticist and physician-scientist at Brigham and Womens Hospital and Harvard Medical School predicted skirmishes,if not all-out war, over genetic and genomic screening practices: with clinicians and patients on one side, calling for as much information as they can possibly get, versus public health officials and others, warning about the unforeseeable consequences of over-screening.

Among the reasons that people are refusing to participate in genetic testing is fear of discriminationby life, disability or long-term care insurance companies, according to Mayo Clinic Department of Laboratory Medicine and Pathology attorney Sharon Zehe. She added that the whole scenario puts providers in an awkward position because even among patients who are willing to undergo screening, many dont want that data to live in their medical records.

Not that getting genetic data into a medical record is exactly easy. One of the fascinating accounts at the conference was Washington University genetics fellow and bioinformaticist Nephi Walton explaining how it took nine months working with Epic to include genetic results into the EHR. You can make a human in that time, Walton said to laughter from the audience as he turned to a slide with a baby picture.

Precision medicine architecture emerging While its true that todays EHRs and IT infrastructure are not ready for the big data needs of precision medicine and I saw that thesame thing is true about population healthlast month at least one architecture is emerging.

Indeed, the strategy of harnessing FHIR standards, with mobile phones as middleware and a common data repository outside the EHR, is an apt way to manage the demands of precision medicine, said John Halamka, MD, CIO of Beth Israel Deaconess Medical Center. The idea is to maximize what patients already have in their homes.

That approach also gives patients more controlover who can and cannot share their data, including researchers, which India Hook-Barnard, director of strategy and associate director of precision medicine at University of California, San Francisco, said it is both the right thing to do and sound science.

But even the architecture Halamka described and giving patients more control over data sharing will not conquer all precision medicine challenges, of course. Michael Dulin, MD, director of the academy for population health innovation at the University of North Carolina Charlotte said simply dumping a whole heap of genomic data on top of the already broken healthcare system, replete with huge variances and medical errors, may actually yield worse outcomes than we have today.

We have to use technology, we need AI, Dulin said. We cannot do this without it.

Walton noted that first we need simple artificial intelligence and machine learning algorithms just to clean up healthcares messy data so its suitable for more sophisticated AI tools.

Becoming'precision health' What was perhaps the boldest prediction to emerge from the conference came from Bryce Olsen, global strategist for Intels Health and Life Sciences unit: Patients will start asking for precision medicine in the second half of 2017 though many of them will not even realize what theyre requesting.

Patients are going to demand that doctors get a better understanding of underlying drivers of disease and defects in their tumor. Were going to see this for cancer first, Olsen said. Doctors that dont have good answers will see patients bounce.

Ill add one more to the mix: Precision medicine, in both term and concept, will be supplanted by the phrase precision health and, yes, this is distinct from how Im seeing digital health become digital medicine.

Precision health, said Megan Mahoney, chief of primary care in Stanfords population health division, is a fundamental shift to a more proactive and personalized approach that empowers people to live healthy lives.

Twitter:SullyHIT Email the writer:tom.sullivan@himssmedia.com

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Precision medicine: Hype today but the promise is even bigger than we think - Healthcare IT News

ByMolly Wood and Paulina Velasco

June 16, 2017 | 3:00 PM

In 2012, Jennifer Doudna, along with a small group of scientists, invented a ground-breaking technology to edit DNA known as Crispr. Scientists are still experimenting with it.

Crispr has been in the news recently because a group of scientists released a much-debated study arguing that editing genes can lead to many unintended, unpredictable consequences. In the controversial case, the scientists edited genetic blindness out of a group of mice and said they found two thousand unintended consequences. The scientific community is split on the results, and Doudna said it's hard to conclude anything from the study. But she knows the possible dangers of gene editing, and she warned about them in aWired article in May.

Marketplace's senior tech correspondent Molly Wood spoke withDoudna at the Wired Business Conference in New York earlier this month and asked Doudna whatconcerns her the most about her revolutionary new technology?

The following is an edited transcript of their conversation.

Jennifer Doudna: I guess I worry about a couple of things. I think there's sort of the potential for unintended consequences of gene editing in people for clinical use. How would you ever do the kinds of experiments that you might want to do to ensure safety? And then there's another application of gene editing called gene drive that involves moving a genetic trait very quickly through a population. And there's been discussion about this in the media around the use of gene drives in insects like mosquitoes to control the spread of disease. On one hand, that sounds like a desirable thing, and on the other hand, I think one, again, has to think about potential for unintended consequences of releasing a system like that into an environmental setting where you can't predict what might happen.

Molly Wood: How important is the accessibility? You know, you could buy a Crispr kit online for $150. What does that kind of accessibility lead to, either in terms of opportunity or problems?

Doudna: I think it's mostly a really good thing in the sense that it makes the science more tangible. I honestly feel that things that break down the barriers between scientists and technologists and everybody else, in a way, is a good thing. Although it's easy to use this technology for those that have some training in molecular biology, its actually not going to be very easy to do anything that would be particularly dangerous in my opinion.

Wood: How do you think this technology could change the way we practice medicine? I mean, if we're really talking about potentially curing genetic diseases, it seems like a whole industry will be affected by that.

Doudna: I think it's a fascinating question, and I've been thinking about this a lot and having a number of discussions with folks that work in the pharmaceutical industry to think about really changing the paradigm for how we do human therapeutics, at least for certain types of disease. Imagine that you had a technology or a treatment that allowed, rather than having someone take a pill every day for the rest of their life, that you had a treatment that you could do once and cure them. It also brings along a lot of other issues. Who pays for that? How do you price such a thing? How do you get insurance companies to cover it? Even if there won't be easy answers, I think the first step is really just to realize that that's the moment that we're in right now.

Wood: One of the things I find fascinating is the intellectual property part of the conversation to what extent people might try to patent genetically modified versions of organisms or plants or even human genes?

Doudna: It's very difficult to patent genes. But I think youre touching on an important point. I think the real value of a technology like this that really allows research to move at a much faster pace than it has in the past, is that it opens up opportunities for applications that I think will lead to incredible commercial opportunities and creative things to make products that couldn't have been generated in the past. And along with that, of course, goes all of the issues regarding regulation and pricing and things like that.

Wood: Jennifer, on that question of regulation and pricing, do you have a sense of what body might end up being in charge of that? Because it's really a global issue on some level, right?

Doudna: It is. But I think a lot of it will come down to initial regulatory approval. If we're talking about agricultural products in the U.S. we're talking about the U.S. Department of Agriculture. We might be talking about the Food and Drug Administration, certainly for therapeutics. Of course that affects pricing and valuations, because if there is an onerous regulatory pathway for things, then that adds to the cost of developing them. So this is why I think it's actually very important that scientists be engaging right now with these agencies to set up appropriate regulations, but also not ones that are so onerous that it really prevents development of important products.

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Crispr inventor worries about the unintended consequences of gene editing - Marketplace.org

June 15, 2017

Researchers at the Stanford University School of Medicine have discovered an unexpected layer of the regulation of gene expression. The finding will likely disrupt scientists' understanding of how cells regulate their genes to develop, communicate and carry out specific tasks throughout the body.

The researchers found that cellular workhorses called ribosomes, which are responsible for transforming genes encoded in RNA into proteins, display a never-before-imagined variety in their composition that significantly affects their function. In particular, the protein components of a ribosome serve to tune the tiny machine so that it specializes in the translation of genes in related cellular pathways. One type of ribosome, for example, prefers to translate genes involved in cellular differentiation, while another specializes in genes that carry out essential metabolic duties.

The discovery is shocking because researchers have believed for decades that ribosomes functioned like tiny automatons, showing no preference as they translated any and all nearby RNA molecules into proteins. Now it appears that broad variation in protein production could be sparked not by changes in the expression levels of thousands of individual genes, but instead by small tweaks to ribosomal proteins.

'Broad implications'

"This discovery was completely unexpected," said Maria Barna, PhD, assistant professor of developmental biology and of genetics. "These findings will likely change the dogma for how the genetic code is translated. Until now, each of the 1 to10 million ribosomes within a cell has been thought to be identical and interchangeable. Now we're uncovering a new layer of control to gene expression that will have broad implications for basic science and human disease."

Barna is the senior author of the study, which will be published online June 15 in Molecular Cell. Postdoctoral scholars Zhen Shi, PhD, and Kotaro Fujii, PhD, share lead authorship. Barna is a New York Stem Cell Robertson Investigator and is also a member of Stanford's Bio-X and Child Health Research Institute.

The work builds upon a previous study from Barna's laboratory that was published June 1 in Cell. The lead author of that study was postdoctoral scholar Deniz Simsek, PhD. It showed that ribosomes also differ in the types of proteins they accumulate on their outer shells. It also identified more than 400 ribosome-associated proteins, called RAPs, and showed that they can affect ribosomal function.

Every biology student learns the basics of how the genetic code is used to govern cellular life. In broad strokes, the DNA in the nucleus carries the building instructions for about 20,000 genes. Genes are chosen for expression by proteins that land on the DNA and "transcribe" the DNA sequence into short pieces of mobile, or messenger, RNA that can leave the nucleus. Once in the cell's cytoplasm, the RNA binds to ribosomes to be translated into strings of amino acids known as proteins.

Every living cell has up to 10 million ribosomes floating in its cellular soup. These tiny engines are themselves complex structures that contain up to 80 individual core proteins and four RNA molecules. Each ribosome has two main subunits: one that binds to and "reads" the RNA molecule to be translated, and another that assembles the protein based on the RNA blueprint. As shown for the first time in the Cell study, ribosomes also collect associated proteins called RAPs that decorate their outer shell like Christmas tree ornaments.

'Hints of a more complex scenario'

"Until recently, ribosomes have been thought to take an important but backstage role in the cell, just taking in and blindly translating the genetic code," said Barna. "But in the past couple of years there have been some intriguing hints of a more complex scenario. Some human genetic diseases caused by mutations in ribosomal proteins affect only specific organs or tissues, for example. This has been very perplexing. We wanted to revisit the textbook notion that all ribosomes are the same."

In 2011, members of Barna's lab showed that one core ribosomal protein called RPL38/eL38 is necessary for the appropriate patterning of the mammalian body plan during development; mice with a mutation in this protein developed skeletal defects such as extra ribs, facial clefts and abnormally short, malformed tails.

Shi and Fujii used a quantitative proteomics technology called selected reaction monitoring to precisely calculate the quantities, or stoichiometry, of each of several ribosomal proteins isolated from ribosomes within mouse embryonic stem cells. Their calculations showed that not all the ribosomal proteins were always present in the same amount. In other words, the ribosomes differed from one another in their compositions.

"We realized for the first time that, in terms of the exact stoichiometry of these proteins, there are significant differences among individual ribosomes," said Barna. "But what does this mean when it comes to thinking about fundamental aspects of a cell, how it functions?"

To find out, the researchers tagged the different ribosomal proteins and used them to isolate RNA molecules in the act of being translated by the ribosome. The results were unlike what they could have ever imagined.

"We found that, if you compare two populations of ribosomes, they exhibit a preference for translating certain types of genes," said Shi. "One prefers to translate genes associated with cell metabolism; another is more likely to be translating genes that make proteins necessary for embryonic development. We found entire biological pathways represented by the translational preferences of specific ribosomes. It's like the ribosomes have some kind of ingrained knowledge as to what genes they prefer to translate into proteins."

The findings dovetail with those of the Cell paper. That paper "showed that there is more to ribosomes than the 80 core proteins," said Simsek. "We identified hundreds of RAPs as components of the cell cycle, energy metabolism, and cell signaling. We believe these RAPs may allow the ribosomes to participate more dynamically in these intricate cellular functions."

"Barna and her team have taken a big step toward understanding how ribosomes control protein synthesis by looking at unperturbed stem cells form mammals," said Jamie Cate, PhD, professor of molecular and cell biology and of chemistry at the University of California-Berkeley. "They found 'built-in' regulators of translation for a subset of important mRNAs and are sure to find more in other cells. It is an important advance in the field." Cate was not involved in the research.

Freeing cells from micromanaging gene expression

The fact that ribosomes can differ among their core protein components as well as among their associated proteins, the RAPs, and that these differences can significantly affect ribosomal function, highlights a way that a cell could transform its protein landscape by simply modifying ribosomes so that they prefer to translate one type of genesay, those involved in metabolismover others. This possibility would free the cell from having to micromanage the expression levels of hundreds or thousands of genes involved in individual pathways. In this scenario, many more messenger RNAs could be available than get translated into proteins, simply based on what the majority of ribosomes prefer, and this preference could be tuned by a change in expression of just a few ribosomal proteins.

Barna and her colleagues are now planning to test whether the prevalence of certain types of ribosomes shift during major cellular changes, such as when a cell enters the cell cycle after resting, or when a stem cell begins to differentiate into a more specialized type of cell. They'd also like to learn more about how the ribosomes are able to discriminate between classes of genes.

Although the findings of the two papers introduce a new concept of genetic regulation within the cell, they make a kind of sense, the researchers said.

"About 60 percent of a cell's energy is spent making and maintaining ribosomes," said Barna. "The idea that they play no role in the regulation of genetic expression is, in retrospect, a bit silly."

Explore further: In creation of cellular protein factories, less is sometimes more

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Again we're shocked to discover that the higher energy environment our solar system experiences, the greater the tightening and finite organizing we see at the cellular level. What will we find only to lose it as our system passes out of higher energy is astonishing. Looking thru this lens of higher energy in past cycles reforms myths into potential truths.

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Newly identified method of gene regulation challenges accepted ... - Phys.Org

Population health and precision medicine seem like such polar opposites standing 180 degrees apart. But the path to fully realizing the benefits of precision medicine stands to reap rewards for population health along the way. That was the takeaway from an interview with India Hook-Barnard, the director of research strategy and associate director of Precision Medicine at the University of California San Francisco. She talked about the balance between the two areas of healthcare in an interview in Boston after she spoke at HIMSS Precision Medicine Summit this week.

Hook-Barnard called attention to a list of projects related to precision medicine. They included the Cell Cancer Map Initiative to discover molecular networks of cancer, the University of California Data Warehouse to connect 15 million electronic health records across the University of California health system, a Biobank that seeks to simplify the informed consent process and the Scalable Precision Open Knowledge Engine.

All of these projects are helping to advance precision medicine in different ways. They will enable us to more quickly make discoveries, provide better care, but also make better decisions in public health.

She called attention to some of the work of her colleagues. Atul Butte is the first director for the Institute of Computational Health Sciences. Among his many roles, he is one of the leaders of the University of California Data Warehouse. Among their tasks are to address privacy and security issues for making data from those records accessible across health systems plugged into the University of California network.

Theyre looking at being able to repurpose drugs, what will really provide better outcomes. It will be really huge being able to connect that kind of data and use it in a healthcare space and research space.

The San Francisco Cancer Initiative, is about sharing information for what works and what doesnt work for five types of cancer with the highest cost burden: prostate, breast, liver, colorectal and tobacco-related cancers. Each will be assigned a taskforce, Hook-Barnard said. The public-private partnership launched last year with a $3 million investment from a donor to the UCSF Helen Diller Family Comprehensive Cancer Center. The initiative is led by Dr. Robert Hiatt, the chair of the Department of Epidemiology and Biostatistics at UCSF. He authored a report on health disparities for cancer treatment outcomes.

Hook-Barnard described what the program seeks to accomplish using tobacco-related cancer as an example, and highlighted some of the questions the initiative seeks to address in this area. Social determinants of health will also come into play.

We know the dangers of smoking and the impact of it, yet there are certain communitiesthat are still developing lung cancer at much higher rate than others. Why is that? Is the messaging on prevention not resonating? Are cessation efforts not tailored enough to be effective? Is access to early screening for detection in certain neighborhoods [the problem]? Being able to tailor those kinds of preventive messaging, early screenings, diagnostics and access, could improve earlier access to treatment.

The Molecular Oncology initiative led by Michael Korn of UCSF is yet another initiative. The website offers this description of the UCSF500 gene panel assay the laboratory conducts.

a cutting-edge sequencing test that, in contrast with commercial cancer gene panel tests, sequences tumor DNA and the patients germline (inherited) DNA. This unique component of the UCSF500 molecular diagnostic test enables identification of genetic changes (mutations) in the DNA of a patients cancer, which helps oncologists improve treatment by identifying targeted therapies, or appropriate clinical trials, or in some cases clarify the exact type of cancer a patient has.

Although it is about using genomics in the clinic to get a more precise diagnosis, the goal of the initiative is to solve some of the wider questions that often go unanswered and to make sure that data isnt locked in a silo somewhere. What treatment(s) worked and why?

How do we capture that information to make sure that is shared and duplicated? We want to make sure those lessons, those findingsonce you have that piece of knowledge, how do you make sure it is shared with other medical centers? For precision medicine to work, it is about these different kinds of data and acquiring knowledge we need to enable data sharing.

Photo: Getty Images

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How population health will benefit from the journey to precision medicine - MedCity News

Liver cancer has the second-highest worldwide cancer mortality, and yet there are limited therapeutic options to manage the disease. To learn more about the genetic causes of this cancer, and to identify potential new therapeutic targets for HCC, a nation-wide team of genomics researchers co-led by David Wheeler, Director of Cancer Genomics and Professor in the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine, and Lewis Roberts, Professor of Medicine at the Mayo Clinic, analyzed 363 liver cancer cases from all over the world gathering genome mutations, epigenetic alteration through DNA methylation, RNA expression and protein expression. The research appears in Cell.

Part of the larger Cancer Genome Atlas project (TCGA), this work represents the first large scale, multi-platform analysis of HCC looking at numerous dimensions of the tumor. There have been large-cohort studies in liver cancer in the past, but they have been limited mainly to one aspect of the tumor, genome mutation. By looking at a wide variety of the tumors molecular characteristics we get substantially deeper insights into the operation of the cancer cell at the molecular level, Wheeler said.

The research team made a number of interesting associations, including uncovering a major role of the sonic hedgehog pathway. Through a combination of p53 mutation, DNA methylation and viral integrations, this pathway becomes aberrantly activated. The sonic hedgehog pathway, the role of which had not been full appreciated in liver cancer previously, is activated in nearly half of the samples analyzed in this study.

We have a very active liver cancer community here at Baylor, so we had a great opportunity to work with them and benefit from their insights into liver cancer, Wheeler said. Among the many critical functions of the liver, hepatocytes expend a lot of energy in the production of albumin and urea. It was fascinating to realize how the liver cancer cell shuts these functions off, to its own purpose of tumor growth and cell division.

Intriguingly, we found that the urea cycle enzyme carbamyl phosphate synthase is downregulated by hypermethylation, while cytoplasmic carbamyl phosphate synthase II is upregulated, said Karl-Dimiter Bissig, Assistant Professor of Molecular and Cellular Biology at Baylor and co-author of the study. This might be explained by the anabolic needs of liver cancer, reprogramming glutamine pathways to favor pyrimidine production potentially facilitating DNA replication, which is beneficial to the cancer cell.

Albumin and apolipoprotein B are unexpected members on the list of genes mutated in liver cancer. Although neither has any obvious connection to cancer, both are at the top of the list of products that the liver secretes into the blood as part of its ordinary functions, explained Dr. David Moore, professor of molecular and cellular biology at Baylor. For the cancer cell, this secretion is a significant loss of raw materials, amino acids and lipids that could be used for growth. We proposed that mutation of these genes would give the cancer cells a growth advantage by preventing this expensive loss.

Multiple data platforms coupled with clinical data allowed the researchers to correlate the molecular findings with clinical attributes of the tumor, leading to insights into the roles of its molecules and genes to help design new therapies and identify prognostic implications that have the potential to influence HCC clinical management and survivorship.

This is outstanding research analyzing a cancer thats increasing in frequency, especially in Texas. Notably, the observation of gene expression signatures that forecast patient outcome, which we validate in external cohorts, is a remarkable achievement of the study. The results have the potential to mark a turning point in the treatment of this cancer, said Dr. Richard Gibbs, director of the HGSC at Baylor. The HGSC was also the DNA sequence production Center for the project.

Wheeler says they expect the data produced by this TCGA study to lead to new avenues for therapy in this difficult cancer for years to come. There are inhibitors currently under development for the sonic hedgehog pathway, and our results suggest that those inhibitors, if they pass into phase one clinical trials, could be applied in liver cancer patients, since the pathway is frequently activated in these patients, added Wheeler.

This work was supported by the National Institutes of Health and represents the last major cancer to be analyzed in the TCGA program. See a full list of contributors.

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Analyses of liver cancer reveals unexpected genetic players - Baylor College of Medicine News (press release)