Category Archives: Gene Medicine

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 School of Medicine. She talked about the balance between the two areas of healthcare in an interview in Boston after she spoke at the 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

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

In 1999, a group of scientists scoured the genomes of around 150 pairs of siblings in an attempt to find genes that are involved in autism. They came up empty. They reasoned that this was because the risk of autism is not governed by a small number of powerful genes, which their study would have uncovered. Instead, its likely affected by a large number of genes that each have a small effect. Perhaps, they wrote, there might be 15 such genes or more.

Two decades later, that figure seems absurdly and naively low. If you told a modern geneticist that a complex traitwhether a physical characteristic like height or weight, or the risk of a disease like cancer or schizophreniawas the work of just 15 genes, theyd probably laugh. Its now thought that such traits are the work of thousands of genetic variants, working in concert. The vast majority of them have only tiny effects, but together, they can dramatically shape our bodies and our health. Theyre weak individually, but powerful en masse.

But Evan Boyle, Yang Li, and Jonathan Pritchard from Stanford University think that this framework doesnt go far enough.

They note that researchers often assume that those thousands of weakly-acting genetic variants will all cluster together in relevant genes. For example, you might expect that height-associated variants will affect genes that control the growth of bones. Similarly, schizophrenia-associated variants might affect genes that are involved in the nervous system. Theres been this notion that for every gene thats involved in a trait, thered be a story connecting that gene to the trait, says Pritchard. And he thinks thats only partly true.

Yes, he says, there will be core genes that follow this pattern. They will affect traits in ways that make biological sense. But genes dont work in isolation. They influence each other in large networks, so that if a variant changes any one gene, it could change an entire gene network, says Boyle. He believes that these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.

The Stanford trio call this the omnigenic model. In the simplest terms, theyre saying that most genes matter for most things.

More specifically, it means that all the genes that are switched on in a particular type of cellsay, a neuron or a heart muscle cellare probably involved in almost every complex trait that involves those cells. So, for example, nearly every gene thats switched on in neurons would play some role in defining a persons intelligence, or risk of dementia, or propensity to learn. Some of these roles may be starring parts. Others might be mere cameos. But few genes would be left out of the production altogether.

This might explain why the search for genetic variants behind complex traits has been so arduous. For example, a giant study called er GIANT looked at the genomes of 250,000 people and identified 700 variants that affect our height. As predicted, each has a tiny effect, raising a persons stature by just a millimeter. And collectively, they explain just 16 percent of the variation in heights that you see in people of European ancestry. Thats not very much, especially when scientists estimate that some 80 percent of all human height variation can be explained by genetic factors. Wheres that missing fraction?

Pritchards team re-analyzed the GIANT data and calculated that there are probably more than 100,000 variants that affect our height, and most of these shift it by just a seventh of a millimeter. Theyre so minuscule in their effects that its hard to tell them apart from statistical noise, which is why geneticists typically ignore them. And yet, Pritchards team noted that many of these weak signals cropped up consistently across different studies, which suggests that they are real results. And since these variants are spread evenly across the entire genome, they implicate a substantial fraction of all genes, Pritchard says.

The team found more evidence for their omnigenic model by analyzing other large genetic studies of rheumatoid arthritis, schizophrenia, and Crohns disease. Many of the variants identified by these studies seem relevant to the disease in question. For example, some of the schizophrenia variants affect genes involved in the nervous system. But mostly, the variants affect genes that dont make for compelling stories, and that do pretty generic things. According to the omnigenic model, theyre only contributing to the risk of disease in incidental ways, by rippling across to the more relevant core genes. Its the only model I can come up with that make all the data fit, Pritchard says.

Pritchards a very perceptive investigator, who looks beyond what most people do, says Aravinda Chakravarti, a geneticist at John Hopkins Medicine. Do I believe this all correct? No, but its very compelling. Its a serious hypothesis that weve got to prove or disprove.

If Pritchard is right, it has big implications for genetics as a field. Geneticists are running ever-bigger and more expensive searches to identify the variants behind all kinds of traits and diseases, in the specific hope that their results will tell them something biologically interesting. They could show us more about how our bodies develop, for example, or point to new approaches for treating disease. But if Pritchard is right, then most variants will not provide such leads because they exert their influence in incidental ways.

Put it this way: The Atlantic is produced by all of us who work here, but our lives are also affected by all the people we encounterfriends, roommates, partners, taxi drivers, passers-by etc. If you listed everyone who influences what happens at The Atlantic, even in small ways, all of those peripheral people would show up on the list. But almost none of them would tell you much about how we do journalism. They're important, but also not actually that relevant. Pritchard thinks the same is true for our genes. And if thats the case, he says, its not clear to me that increasing your study size is going to help very much.

The alternative, he says, is to map the networks of genes that operate within different cells. Once we know those, well be better placed to understand the results from the forthcoming mega-studies. It is a really hard problem, says Boyle. Historically, even understanding the role of one gene in one disease has been considered a major success. Now we have to somehow understand how combinations of seemingly hundreds or thousands of genes work together in very complicated ways. Its beyond our current ability.

There are, however, projects that are trying to do exactly that. Im very excited about trying to understand whether these network ideas are correct, says Pritchard. I think its telling us something profound about how our cells work.

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What If (Almost) Every Gene Affects (Almost) Everything? - The Atlantic

Additionally Intrexon's RheoSwitch Therapeutic Systemplatform combined with GenVec's AdV-based technology is projected to accelerate its ability to develop cutting-edge gene therapies that regulatein vivoexpression of one or several therapeutic effectors. GenVec's selection of vector origins and serotypes as well as know-how in specifying cellular and tissue targets is expected to expedite the design and production of vectors that complement Intrexon's multigene programming and keen focus on safety with limited off-target effect.

"GenVec's AdenoVerse platform is highly adaptable and can be customized to develop applications for regenerative and cell therapeutics as well as gene and antigen delivery strategies," commented Thomas D. Reed, Ph.D., Intrexon's Chief Science Officer. "The breadth of GenVec's natural and engineered adenovector serotypes displaying valuable targeted tissue specificity, when combined with our RheoSwitch Therapeutic System gene switch offer significant potential for cutting-edge in vivo multi-gene therapies."

Douglas E. Brough, Ph.D., GenVec's Chief Scientific Officer stated, "We look forward to combining our research and drug development team with Intrexon to advance groundbreaking in vivo therapeutics. Together we expect to develop a next-generation delivery platform capable of increasing payload capacity far beyond that of other viral methods for application to Intrexon's current and future health programs."

About Intrexon Corporation Intrexon Corporation (NYSE: XON) is Powering the Bioindustrial Revolution with Better DNA to create biologically-based products that improve the quality of life and the health of the planet. The Company's integrated technology suite provides its partners across diverse markets with industrial-scale design and development of complex biological systems delivering unprecedented control, quality, function, and performance of living cells. We call our synthetic biology approach Better DNA, and we invite you to discover more at http://www.dna.com or follow us on Twitter at @Intrexon, on Facebook, and LinkedIn.

Trademarks Intrexon, RheoSwitch Therapeutic System, Powering the Bioindustrial Revolution with Better DNA, and Better DNA are trademarks of Intrexon and/or its affiliates. Other names may be trademarks of their respective owners.

Safe Harbor Statement Some of the statements made in this press release are forward-looking statements. These forward-looking statements are based upon our current expectations and projections about future events and generally relate to our plans, objectives and expectations for the development of our business. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties and actual future results may be materially different from the plans, objectives and expectations expressed in this press release.

For more information regarding Intrexon Corporation, contact: Investor Contact:Christopher Basta Vice President, Investor Relations Tel: +1 (561) 410-7052 investors@intrexon.com

Corporate Contact:Marie Rossi, Ph.D. Director, Technical Communications Tel: +1 (301) 556-9850 publicrelations@intrexon.com

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/intrexon-integrates-leading-adenoviral-gene-delivery-technology-with-completion-of-genvec-acquisition-300475225.html

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Intrexon Integrates Leading Adenoviral Gene Delivery Technology with Completion of GenVec Acquisition - PR Newswire (press release)

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.

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

Genomics is being hailed as the wave of the future in medicine. The growing fieldjust two decades oldis focusing attention on how the genetic code and sequencing unique to each persons DNA becomes distorted during the development of cancer and other major diseases. By personalizing the genetic code sequencing, oncologists believe they can use genomics to design and implement far more precise and effective medical treatment plans, saving lives and also money.

In fact, therapeutic development has already been transformed by genomics. According to bio-geneticist Eric S. Lander, a pioneer in the field, there are 800 different anticancer drugs in clinical development today. Cancer drugs used to be just cellular poisons, but almost all of these new ones are targeted at particular gene products that have been discovered, he said recently.

The contribution of private philanthropies to genomics is fairly newbut mushrooming rapidly. Back in 2001, the federal government set up the Human Genome Project to create the first fully documented genetic code modeled on the DNA of a handful of individuals. It took 15 years and a $3 billion investment to achieve that result. Since then, other genomic projects like the Cancer Genome Atlas, the Human Microbiome Project, and the 1,000 Genomes Project have emerged, based largely on major grants from the National Institutes of Health and the National Cancer Institute.

But with growing cutbacks in federal funding for biomedical researchwhich are expected to increase under the new Trump administrationa number of private medical charities, often operating with a venture philanthropy model,have moved to fill the void.

Some of them, like the American Cystic Fibrosis Foundation, are large entities that used to advise their members on how to prevent or cope with a chronic disease. Now, they are integral parts of the search for a cure. Medical and disease charities once focused almost entirely on raising awareness and encouraging prevention, leaving the search for cures to the imperfect and often serendipitous interplay among government agencies, university researchers and drug companies, one source notes.

Numerous foundations are now funding in this space, each seeking a distinctive niche in genomic medicine. A good example is Nationwide Foundation, which last week approved its fourth consecutive $10 million annual grant to the Pediatric Innovation Foundation based at Nationwide Childrens Hospital. This years $10 million Nationwide grant focuses specifically on pediatric genomics, a fast-growing sub-field of its own. Researchers have found that the types of cancer occurring in the pediatric population are markedly different from those seen in adults. For example, the major brain and solid tumors that arise in children are exceedingly rare in adults. Similarly, the specific genetic subtypes of leukemiathe most common malignancy in childrenare vastly different in children. Cancer, while highly curable in children, remains their highest source of mortality. Moreover, the drugs used to treat pediatric cancer, while highly effective, have severe side effects that can reduce the quality of life in survivors.

The grant to the Nationwide Childrens Hospital, like an earlier grant from St. Jude Children's Hospital from the Elizabeth H. and James S. McDonnell III Genome Institute at Washington University, is aimed at uncovering the unique spectrum of genetic mutations that lead to malignant cell transformations for a selected group of cancers in children. Once identified in newly diagnosed cancer patients, it becomes possible to analyze the specific genetic sequencing pattern that can determine the etiology of the disease.

A similar effort that began last fall at San Diegos Rady Institute of Genomic Medicinefounded in 2014 with a $120 million grant from insurance billionaire Ernest Radyallowed doctors to develop a three-day sequencing model that led them to radically alter their treatment plans for the affected childrenin some cases, cancelling major surgeries and treatments that were deemed likely to be ineffective. The main problem with these genomic diagnostic efforts is the cost: about $20,000 per child, which is beyond the reach of many patients since it may not be covered by their insurance plans. Seeking approval from insurance carriers on a case-by-case basis is an option, but the process is prolonged and can unduly delay treatment, endangering patients in need.

Given the early impressive results from these privately funded efforts, follow-up funding requests to major foundations are expected to mushroom in the coming year. Rady, for example, has ambitions of transforming its three-day sequencing modeland the follow-up analysis requiredinto the industry gold standard. Weve sent in a proposal to the MacArthur Foundation for $100 million over the next five years to put this capability into every childrens hospital in the United States, Dr. Stephen Kingsmore, the Institutes director, said in an interview. (It didn't make the list of finalists in this competition.)

Dr. Lander likens the genomics field to the early days of HIV therapy. It took a couple of decades before treatments became available that made the disease non-life threatening. Private philanthropies could do the same for cancer and other ailments, he believes.

In an objective sense, this is a unique moment to be investing. This is the first decade when we can actually look across diseases in this systematic way. The idea that were not investing to let a generation of young people try their riskiest, cleverest ideas is a tragedy, because weve got such an opportunity now.

A growing number of philanthropists agree.

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"Wave of the Future." The Field of Genomic Medicine Gains SteamAnd Funders - Inside Philanthropy

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."

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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

Forbes

Cancer's Big Infrastructure Problem Forbes That medicine is targeted against cancers caused by mutations in a particular gene, called TRK, but used in many different types of cancer. "The obvious solution is for patients to have their genes tested routinely, and for clinical trials to be ...

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Cancer's Big Infrastructure Problem - Forbes

June 15, 2017 DNA double helix. Credit: public domain

Researchers have identified properties in DNA's protective structure that could transform the way scientists think about the human genome.

Molecules involved in DNA's supportive scaffoldingonce thought to be fixedgo through dynamic and responsive changes to shield against mutations, the research shows.

Experts say this finding is crucial to understanding DNA damage and genome organisation and could impact current thinking on DNA-linked diseases, including cancers.

In human cells, DNA is wrapped around proteins to form chromatin. Chromatin shields DNA from damage and regulates what genetic information can be reada process known as transcription.

Researchersled by the University of Edinburghshowed that a chemical called scaffold attachment factor A (SAF-A) binds to specific molecules known as caRNAs to form a protective chromatin mesh.

For the first time, this mesh was shown to be dynamic, assembling and disassembling and allowing the structure to be flexible and responsive to cell signals.

In addition, loss of SAF-A was found to lead to abnormal folding of DNA and to promote damage to the genome.

SAF-A has previously been shown in mouse studies to be essential to embryo development and mutations of the SAF-A gene have repeatedly been found in cancer gene screening studies.

Scientists say the findings shed light on how chromatin protects DNA from high numbers of harmful mutations, a condition known as genetic instability.

The studypublished in Cellwas carried out in collaboration with Heriot Watt University. It was funded by the Medical Research Council (MRC).

Nick Gilbert, Professor of Genetics at the University of Edinburgh's MRC Institute of Genetics and Molecular Medicine, said: "These findings are very exciting and have fundamental implications for how we understand our own DNA, showing that chromatin is the true guardian of the genome. The results open new possibilities for investigating how we might protect against DNA mutations that we see in diseases like cancer."

Cutting-edge techniques used in the study were developed by the Edinburgh Super-Resolution Imaging Consortium, which is supported by the MRC, the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.

Professor Rory Duncan, Head of the Institute for Biological Chemistry, Biophysics and Bioengineering at Heriot-Watt University said: "The molecules involved in this study are as small to humans as Jupiter is large. The bespoke microscope techniques that we developed to understand these very tiny structures are important not only for this project but for all of biology."

Explore further: In fruit fly and human genetics, timing is everything

Journal reference: Cell

Provided by: University of Edinburgh

Every animal starts as a clump of cells, which over time multiply and mature into many different types of cells, tissues, and organs. This is fundamental biology. Yet, the details of this process remain largely mysterious. ...

A research group led by Hitoshi Kurumizaka, a professor of structural biology at Waseda University, unveiled the crystal structure of an overlapping dinucleosome, a newly discovered chromatin structural unit. This may explain ...

The three-dimensional arrangement of the chromosome within which genes reside can profoundly affect gene activity. These structural effects remain poorly understood, but Assistant Professor of Plant Science Moussa Benhamed ...

The DNA molecules in each one of the cells in a person's body, if laid end to end, would measure approximately two metres in length. Remarkably, however, cells are able to fold and compact their genetic material in the confined ...

Chromatin remodeling proteins (chromatin remodelers) are essential and powerful regulators for critical DNA-templated cellular processes, such as DNA replication, recombination, gene transcription/repression, and DNA damage ...

When scientists finished decoding the human genome in 2003, they thought the findings would help us better understand diseases, discover genetic mutations linked to cancer, and lead to the design of smarter medicine. Now ...

Scientists have developed a new technique for investigating the effects of gene deletion at later stages in the life cycle of a parasite that causes malaria in rodents, according to a new study in PLOS Pathogens. The novel ...

The drill holes left in fossil shells by hunters such as snails and slugs show marine predators have grown steadily bigger and more powerful over time but stuck to picking off small prey, rather than using their added heft ...

Scientists from Rutgers University-New Brunswick, the biotechnology company NAICONS Srl., and elsewhere have discovered a new antibiotic effective against drug-resistant bacteria: pseudouridimycin. The new antibiotic is produced ...

Almost all life on Earth is based on DNA being copied, or replicated. Now for the first time scientists have been able to watch the replication of a single DNA molecule, with some surprising findings. For one thing, there's ...

Researchers have identified properties in DNA's protective structure that could transform the way scientists think about the human genome.

Until now, the fauna of the Himalayas was considered to be an "immigration fauna", with species that have immigrated primarily from neighbouring regions to the west and east since the geological formation of this mountain ...

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Dynamic DNA helps ward off gene damage, study reveals - Phys.Org

A physician who splits his time between family medicine and health tech found himself in the role of a patient when he decided to investigate whether he had inherited genes that increased the likelihood he would develop kidney cancer. Dr Michael Dulin, who also works as Chief Medical Officer with data analytics business Tresata, recounted his patient journey at the HIMSS Precision Medicine Summit in Boston this week.

Family pictures punctuated Dulins story. Following the death of his father from kidney cancer, he looked back at his family tree and realized that several aunts and uncles had succumbed to kidney cancer or some other type of cancer.

I wanted to put a personal face on this because thats the goal today, Dulin. Think about being in my shoes. What would you do if this were your family history?

He recalled that he had a fun career serving as an engineer, a physiologist, primary care physician, data care redesign, He investigated doing genetic testing but with two kids in college, the cost was prohibitive.

I figured if anyone can handle genetic testing it was me. I should know what it means I should be able to handle the information.

He noted that 23andMes test provided some interesting revelations he is predisposed to having a hairy back but he didnt have any of the key disease states.

He eventually found another company doing more thorough genetic analysis one of which referred him to a genetic counselor when he requested it. Two years ago, when he sought the advice of a genetic counselor, the cost of doing a genetic test for the 29 genes known to cause kidney cancer was $14,500. Dulin, who already had two children in college, deemed the cost too high. But only a year later the cost had come down significantly for the same test. So he decided to go for it since the reduced price tag made getting the test a realistic option.

It came back and, shit! It was positive. I really didnt believe itwas going to be positive. Suddenly I wasnt a physician anymore or an executive anymore. I was mortal; I was someone who could die from kidney cancer and probably I would die from kidney cancer. I had never really thought how I would feel about it being positive. Right away I felt pretty guilty because I had this gene I had passed onto my two kids.

Dulin noted that his concern then turned to his electronic medical record which resided with his employer. Could this influence his employment? Would it be considered a pre-existing condition under the Affordable Care Act? What would be the negative impact on Dulin and his family for doing this genetic testing?

I left that day feeling pretty confused, sad, anxious and depressed. Its a pretty scary thing to have happen, he said.

In the days that followed he relied on PubMed and other resources at the University of North Carolina at Chapel Hill and read up on research for papillary renal cell cancer and what steps he could take to improve his health. He learned that people with a high body mass index had a greater chance of developing kidney cancer as did smokers but that [moderate] alcohol consumption could be beneficial, for instance.

Dulin said that one benefit of the experience was finding out that both of his children had tested negative for inheriting the gene. It was a moment that clearly brought great relief to him but was an unexpectedly emotional moment as he talked about it.

He also sought to reconnect with old friends and tick off a few items on his bucket list. But the experience gave him a better understanding of the anxiety and decisions patients in this situation face without the benefit of a medical background.

Photo: Andrzej Wojcicki, Getty Images

See the article here:
Physician shares genetic testing journey and gains a patient's perspective along the way - MedCity News