July 17, 2017 Credit: The District

Gene editing using 'molecular scissors' that snip out and replace faulty DNA could provide an almost unimaginable future for some patients: a complete cure. Cambridge researchers are working towards making the technology cheap and safe, as well as examining the ethical and legal issues surrounding one of the most exciting medical advances of recent times.

Dr James Thaventhiran points to a diagram of a 14-year-old boy's family tree. Some of the symbols are shaded black.

"These family members have a very severe form of immunodeficiency. The children get infections and chest problems, the adults have bowel problems, and the father died from cancer during the study. The boy himself had a donor bone marrow transplant when he was a teenager, but he remains very unwell, with limited treatment options."

To understand the cause of the immunodeficiency, Thaventhiran, a clinical immunologist in Cambridge's Department of Medicine, has been working with colleagues at the Great Northern Children's Hospital in Newcastle, where the family is being treated.

Theirs is a rare disease, which means the condition affects fewer than 1 in 2,000 people. Most rare diseases are caused by a defect in the genetic blueprint that carries the instruction manual for life. Sometimes the mistake can be as small as a single letter in the three billion letters that make up the genome, yet it can have devastating consequences.

When Thaventhiran and colleagues carried out whole genome sequencing on the boy's DNA, they discovered a defect that could explain the immunodeficiency. "We believe that just one wrong letter causes a malfunction in an immune cell called a dendritic cell, which is needed to detect infections and cancerous cells."

Now, hope for an eventual cure for family members affected by the faulty gene is taking shape in the form of 'molecular scissors' called CRISPR-Cas9. Discovered in bacteria, the CRISPR-Cas9 system is part of the armoury that bacteria use to protect themselves from the harmful effects of viruses. Today it is being co-opted by scientists worldwide as a way of removing and replacing gene defects.

One part of the CRISPR-Cas9 system acts like a GPS locator that can be programmed to go to an exact place in the genome. The other part the 'molecular scissors' cuts both strands of the faulty DNA and replaces it with DNA that doesn't have the defect.

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"It's like rewriting DNA with precision," explains Dr Alasdair Russell. "Unlike other forms of gene therapy, in which cells are given a new working gene but without being able to direct where it ends up in the genome, this technology changes just the faulty gene. It's precise and it's 'scarless' in that no evidence of the therapy is left within the repaired genome."

Russell heads up a specialised team in the Cancer Research UK Cambridge Institute to provide a centralised hub for state-of-the-art genome-editing technologies.

"By concentrating skills in one area, it means scientists in different labs don't reinvent the wheel each time and can keep pace with the field," he explains. "At full capacity, we aim to be capable of running up to 30 gene-editing projects in parallel.

"What I find amazing about the technology is that it's tearing down traditional barriers between different disciplines, allowing us to collaborate with clinicians, synthetic biologists, physicists, engineers, computational analysts and industry, on a global scale. The technology gives you the opportunity to innovate, rather than imitate. I tell my wife I sometimes feel like Q in James Bond and she laughs."

Russell's team is using the technology both to understand disease and to treat it. Together with Cambridge spin-out DefiniGEN, they are rewriting the DNA of a very special type of cell called an induced pluripotent stem cell (iPSC). These are cells that are taken from the skin of a patient and 'reprogrammed' to act like one of the body's stem cells, which have the capacity to develop into almost any other cell of the body.

In this case, they are turning the boy's skin cells into iPSCs, using CRISPR-Cas9 to correct the defect, and then allowing these corrected cells to develop into the cell type that is affected by the disease the dendritic cell. "It's a patient-specific model of the cure in a Petri dish," says Russell.

The boy's family members are among a handful of patients worldwide who are reported to have the same condition and among around 3,500 in the UK who have similar types of immunodeficiency caused by other gene defects. With such a rare group of diseases, explains Thaventhiran, it's important to locate other patients to increase the chance of understanding what happens and how to treat it.

He and Professor Ken Smith in the Department of Medicine lead a programme to find, sequence, research and provide diagnostic services to these patients. So far, 2,000 patients (around 60% of the total affected in the UK) have been recruited, making it the largest worldwide cohort of patients with primary immunodeficiency.

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"We've now made 12 iPSC lines from different patients with immunodeficiency," adds Thaventhiran, who has started a programme for gene editing all of the lines. "This means that for the first time we'll be able to investigate whether correcting the mutation corrects the defect it'll open up new avenues of research into the mechanisms underlying these diseases."

But it's the possibility of using the gene-edited cells to cure patients that excites Thaventhiran and Russell. They explain that one option might be to give a patient repeated treatments of their own gene-edited iPSCs. Another would be to take the patient's blood stem cells, edit them and then return them to the patient.

The researchers are quick to point out that although the technologies are converging on this possibility of truly personalised medicine, there are still many issues to consider in the fields of ethics, regulation and law.

Dr Kathy Liddell, who leads the Cambridge Centre for Law, Medicine and Life Sciences, agrees: "It's easy to see the appeal of using gene editing to help patients with serious illnesses. However, new techniques could be used for many purposes, some of which are contentious. For example, the same technique that edits a disease in a child could be applied to an embryo to stop a disease being inherited, or to 'design' babies. This raises concerns about eugenics.

"The challenge is to find systems of governance that facilitate important purposes, while limiting, and preferably preventing, unethical purposes. It's actually very difficult. Rules not only have to be designed, but implemented and enforced. Meanwhile, powerful social drivers push hard against ethical boundaries, and scientific information and ideas travel easily often too easily across national borders to unregulated states."

A further challenge is the business case for carrying out these types of treatments, which are potentially curative but are costly and benefit few patients. One reason why rare diseases are also known as orphan diseases is because in the past they have rarely been adopted by drug companies.

Liddell adds: "CRISPR-Cas9 patent wars are just warming up, demonstrating some of the economic issues at stake. Two US institutions are vigorously prosecuting their own patents, and trying to overturn the others. There will also be cross-licensing battles to follow."

"The obvious place to start is by correcting diseases caused by just one gene; however, the technology allows us to scale up to several genes, making it something that could benefit many, many different diseases," adds Russell. "At the moment, the field as a whole is focused on ensuring the technology is safe before it moves into the clinic. But the advantage of it being cheap, precise and scalable should make CRISPR attractive to industry."

In ten years or so, speculates Russell, we might see bedside 'CRISPR on a chip' devices that screen for mutations and 'edit on the fly'. "I'm really excited by the frontierness of it all," says Russell. "We feel that we're right on the precipice of a new personalised medical future."

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Snip, snip, curecorrecting defects in the genetic blueprint - Phys.Org

Marriage within a limited group, or endogamy, has created millions of people who are susceptible to recessive diseases, which develop only when a child inherits a disease-carrying gene from both parents, said Kumarasamy Thangaraj, an author of the study and a senior scientist at the Center for Cellular and Molecular Biology in Hyderabad.

Along with David Reich, a geneticist at Harvard Medical School, Dr. Thangaraj led an effort to analyze data from more than 2,800 individuals belonging to more than 260 distinct South Asian groups organized around caste, geography, family ties, language, religion and other factors. Of these, 81 groups had losses of genetic variation more extreme than those found in Ashkenazi Jews and Finns, groups with high rates of recessive disease because of genetic isolation.

In previous studies, Dr. Reich, Dr. Thangaraj and colleagues found that social groups in South Asia mixed between around 4,000 and 2,000 years ago. After that, the solidification of Indias caste system resulted in a shift toward endogamy. You can see writ in the genome the effects of this intense endogamy, Dr. Reich said.

Today, South Asia consists of around 5,000 anthropologically well-defined groups. Over 15 years, the researchers collected DNA from people belonging to a broad swath of these groups, resulting in a rich set of genetic data that pushes beyond the fields focus on individuals of European ancestry, Dr. Reich said.

The scientists then looked at something called the founder effect. When a population originates from a small group of founders that bred only with each other, certain genetic variants can become amplified, more so than in a larger starting population with more gene exchange.

Most people carry some disease-associated mutations that have no effect because theyre present only in one parents genes. In an endogamous group, however, its more likely that two individuals carry the same mutation from a common founder. If they reproduce, their offspring have a higher risk of inheriting that disease.

Rare conditions are therefore disproportionately common in populations with strong founder events. Among Finns, for instance, congenital nephrotic syndrome, a relatively rare kidney disease, is uniquely prevalent. Similarly, Ashkenazi Jews are often screened for diseases like cystic fibrosiss or Gaucher disease.

To measure the strength of different founder events, Dr. Reich and Dr. Thangarajs team looked for long stretches of DNA shared between individuals from the same subgroups. More shared sequences indicated a stronger founder event.

The strongest of these founder groups most likely started with major genetic contributions from just 100 people or fewer. Today, 14 groups with these genetic profiles in South Asia have estimated census sizes of over one million. These include the Gujjar, from Jammu and Kashmir; the Baniyas, from Uttar Pradesh; and the Pattapu Kapu, from Andhra Pradesh. All of these groups have estimated founder effects about 10 times as strong as those of Finns and Ashkenazi Jews, which suggests the South Asian groups have just as many, or more, recessive diseases, said Dr. Reich, who is of Ashkenazi Jewish heritage himself.

The next step, the authors say, is to map out and study the genetic origins of diseases prevalent in different groups. As proof of concept, they screened 12 patients from southern India for a gene mutation known to cause a joint disease called progressive pseudorheumatoid dysplasia. Of the six people that had the mutation, five instances could be traced to founder effects, and one case could be traced to a marriage between close relatives.

This distinction is important because its well documented that marriage between close relatives can increase the possibilities of recessive disease. But many South Asians are not yet aware that they should also look out for genetic risks among broader populations, said Svati Shah, an associate professor of medicine at Duke University who was not involved in the research.

Theres a tendency to think, This will never happen to me because I will never marry my first cousin, Dr. Shah said. But thats not whats happening here, according to the data.

There are many other suspected examples of disease associations that have yet to be systematically studied in South Asia. Some medical caregivers speculate that people with the surname Reddy may be more likely to develop a form of arthritis affecting the spine, Dr. Thangaraj said. Others think people from the Raju community, in southern India, may have higher incidents of cardiomyopathy, which affects the heart muscle.

If recessive disease mutations are cataloged, they could potentially be used for prenatal or premarital screening programs, which can be immensely powerful, said Priya Moorjani, an author of the paper and a postdoctoral researcher at Columbia University.

An example of successful genetic cataloging can be found in Dor Yeshorim, a Brooklyn-based organization that screens Ashkenazi and Sephardi Jews for common disease-causing mutations to inform marriage matchmaking. The program is credited with virtually eliminating new cases of Tay-Sachs disease, a neurodegenerative disorder, from these communities.

Beyond rare diseases, groups with founder effects hold lessons about common diseases and basic biology, said Alan Shuldiner, a professor of medicine at the University of Maryland and a genetics researcher for Regeneron Pharmaceuticals, who was not involved in the study. He and his collaborators have gained new insights into heart disease and Type 2 diabetes, for instance, from studying Old Order Amish.

Scientists often try to manipulate, or knock out, genes in mice or flies to better understand human disease. But populations like those found across South Asia provide a powerful opportunity to study how gene changes manifest naturally in humans. These are genetic experiments of nature that have occurred across the planet, Dr. Shuldiner said.

The sheer number of people and different groups in South Asia means theres a huge, untapped opportunity to do biological and genetic research there, Dr. Reich said.

He suggested that knockouts of almost every single gene in the genome probably exist in India.

I would argue that its unequal to anywhere else, he said.

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In South Asian Social Castes, a Living Lab for Genetic Disease - New York Times

The study provides detailed data on how children look at faces, including which features they focus on and when they move their eyes from one place to another. The information, Dr. Nelson said, could help scientists work out the circuitry that controls these eye movements, and then we ought to be able to work out which genes are being expressed in that circuit.

That would be a big advance in autism, he said.

In the study, scientists tracked the eye movements of 338 toddlers while they watched videos of motherly women as well as of children playing in a day care center. The toddlers, 18 months to 24 months old, included 250 children who were developing normally (41 pairs of identical twins, 42 pairs of nonidentical twins and 84 children unrelated to each other). There were also 88 children with autism.

Scientists study identical twins because 100 percent of their genes are the same, so if they share characteristics that are more individualized in other children, those traits are considered at least partly inherited. Nonidentical or fraternal twins share 50 percent of their DNA, so stark differences between identical and nonidentical twins suggest that those traits are strongly influenced by genes.

In the study, how much one identical twin looked at the eyes of people on screen matched the other identical twin 91 percent of the time. For fraternal twins, the match dropped to 35 percent. For unrelated children, when measured as pairs of the same age and sex, the match was 16 percent. And when the unrelated children were paired at random, their time spent looking at eyes did not match at all, said Warren Jones, the studys senior author and an assistant professor of pediatrics at Emory University School of Medicine.

How much the children looked at mouths followed a similar pattern. And although each toddler watched the videos without other children present, identical twins often moved their eyes at nearly the same moment as close as 16.7 milliseconds apart and in the same direction.

Its a really remarkable set of findings in that it really shows that genetic factors are driving differences in the way that toddlers are looking at faces, said Brad Duchaine, a professor of psychological and brain sciences at Dartmouth, who was not involved in the study. This suggests that genetic differences drive this important aspect of the way that we interact with others.

Dr. Jones, whose co-authors include Dr. John Constantino, director of child and adolescent psychiatry at Washington University School of Medicine in St. Louis, and Ami Klin, director of the Marcus Autism Center at Childrens Healthcare of Atlanta, said: When we started to get the results back, I thought that I had the wrong data because the match between identical twins was so strong. I thought I might have mistakenly matched data from the same twin.

With the children with autism, the researchers found that, compared with typically developing toddlers, they spent significantly less time looking at faces and more time looking at objects. That difference was especially pronounced with the day care videos, scenes presenting many more things to look at than the close-up videos of women talking to the camera, Dr. Jones said. When watching the day care videos, toddlers with autism looked at faces half as often as typical children did, and at objects almost twice as much.

The difference was so consistent that researchers could identify most children with autism just by looking at the eye-tracking results, Dr. Jones said. That result reinforced previous research in which Dr. Jones, Dr. Klin and colleagues showed that babies from 2 months to 6 months old who looked less at peoples eyes in videos were more likely to be given an autisim diagnosis at age 3 and that eye-tracking could provide an early behavioral indicator of autism.

Experts said that because the study shows that a social behavior that is significantly different in children with autism is strongly influenced by genetics, it might help scientists home in on specific genes to better understand autism or at least a key autism characteristic.

Even when identical twins watched completely different videos, their results matched. How much Twin 1 looked at the eyes in a video that Twin 2 didnt get to see predicted how much Twin 2 would look at the eyes in a different video, Dr. Jones said.

That suggests, he said, that the genetically driven behavior involves seeking out social information found in the eyes rather than merely responding to facial features, a finding that could help pinpoint what is disrupted in children with autism as they develop and learn about the world.

Dr. Nelson said one question for further research was how specific are these phenomena to autism, or might you see them in other neurological disorders?

Another question is how does this actually affect longer-term development of the brain, said Matthew Peterson, a postdoctoral researcher at the Massachusetts Institute of Technology, whose studies have found that everybody has a preferred location or position on the face where they will always look when they identify someone higher or lower on the face; toward the eyes, nose or mouth.

In the new study, researchers also tested the typically developing children again at age 3 and found that identical twins still strongly matched in how much they looked at eyes and mouths. That suggests that compared with genes, that experience theyre having in that year thats not having much of an influence, said Dr. Duchaine, whose work has found genetic roots to face recognition.

Still, Dr. Nelson cautioned against overemphasizing the direct role of genes. Twins have identical DNA, but they dont have identical experiences and they dont have the same brains, he said.

Most likely, through evolution, we came to have genes that regulate the formation of the neural circuits that underpin how we visually inspect the social world, he said.

That, he said, helps ensure that we are social beings.

A version of this article appears in print on July 13, 2017, on Page A12 of the New York edition with the headline: Study Sees Autism Clues In How We Look at Faces.

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Study of How We Look at Faces May Offer Insight Into Autism - The ... - New York Times

July 17, 2017 First author Kaity Sliger, PhD, and corresponding author Paul Thomas, PhD, member of the Department of Immunology, examine liquid nitrogen samples. Credit: Peter Barta / St. Jude Children's Research Hospital

Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism that explains the elevated risk and offers clues about the broader anti-viral immune response.

St. Jude Children's Research Hospital led the research, which appears as an advance, online publication today in the scientific journal Nature Medicine.

Researchers screened 393 flu patients ranging from infants to 70 years old. Patients with a particular inherited variation in the gene IFITM3 were more than twice as likely to develop severe, life-threatening flu symptoms as those who carried the protective version of the gene.

Working at the molecular level, the investigators showed how expression of the IFITM3 protein was reduced in killer T cells of patients with the high-risk variant compared to other patients. Researchers also found more killer T cellswhich help patients fight the infectionin the upper airways of flu patients with the protective variant compared to other patients.

"A genetic marker of flu risk could make a life-saving difference, particularly during severe flu outbreaks, by helping prioritize high-risk patients for vaccination, drug therapy and other interventions," said corresponding author Paul Thomas, Ph.D., an associate member of the St. Jude Department of Immunology. "These results raise hopes that this newly identified IFITM3 variant might provide such a marker."

Estimated U.S. flu-related deaths in recent years have ranged from 12,000 to 56,000, according to the U.S. Centers for Disease Control and Prevention. Factors like age, obesity, pregnancy and such chronic health conditions as asthma, chronic lung disease and heart disease are associated with an elevated risk of flu complications and death. However, there are no proven genetic markers of flu risk with an established mechanism of action.

IFITM3 is an anti-viral protein that helps to block flu infection of lung cells and to promote survival of the killer T cells that help clear flu infection in the airways. Previous research from other scientists had reported an association between another IFITM3 variant (rs12252) and flu severity in Han Chinese patients. The underlying mechanism has remained unclear, and the rs12252 variant is rare in individuals of European ancestry.

Thomas and his colleagues began this study by searching for other possible IFITM3 variants that correlated with gene expression, levels of the IFITM3 proteins and were common in flu patients in the U.S. The search led to an IFITM3 variant known as rs34481144.

Researchers screened three different groups of U.S. flu patients and found those with the high-risk version of IFITM3 rs34481144 were likely to become infected with flu more rapidly and to develop more severe symptoms than those with another variant. For example, researchers checked 86 children and adults in Memphis with confirmed flu infections and found two-thirds of patients with the most severe symptoms carried at least one copy of the newly identified high-risk IFITM3 variant. The high-risk variant was found in just 32 percent of patients with milder symptoms.

Researchers also found an association between the newly identified high-risk variant and severe and fatal flu infections in 265 critically ill pediatric flu patients hospitalized in one of 31 intensive care units nationwide. The patients did not have health problems that put them at high risk for severe flu. Of the 17 patients in this group who died from the infection, 14 carried at least one copy of the newly identified high-risk variant. "When we looked at patients of European descent who died, they all carried at least one copy of the high-risk variant," Thomas said.

The predictive value of the newly identified IFITM3 variant is now being studied in flu patients in other countries.

The newly identified variation is found in the region of IFITM3 involved in regulation of gene expression through the binding of proteins and other chemicals that promote or suppress gene activity. Working in the laboratory, researchers showed how binding of proteins like CTCF, which can suppress gene activity, differed between the high-risk and protective variants.

Further study revealed how binding differed between the high-risk and protective variants. Those differences led to lower levels of the IFITM3 protein in ndividuals with two copies of the high-risk gene variant compared to other patients, researchers said. The Memphis flu patients also had fewer of the killer T cells in their upper airways.

"While this research focused on flu infections, the mechanism we identified has implications for regulating many genes involved in anti-viral activity," Thomas said. "CTCF has gained prominence in recent years as a master regulator of genomic organization. Evidence in this study suggests the high-risk variant we identified may be part of a larger network of CTCF binding sites involved in regulation in other genes with anti-viral activity."

Explore further: Genetic variant linked to overactive inflammatory response

More information: E Kaitlynn Allen et al, SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans, Nature Medicine (2017). DOI: 10.1038/nm.4370

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Newly identified genetic marker may help detect high-risk flu patients - Medical Xpress

The U.S. Food and Drug Administration is promoting a targeted treatment approach known as precision medicine to help people with diseases stemming from specific, and often rare, genetic features.

Its efforts include expanding the use of approved therapies to other genetic-based conditions, and pushing for the development of more biomarkers of diseases.

Two recent agency approvals exemplify that the approach is working, Dr. Janet Woodcock, director of the FDAsCenter for Drug Evaluation and Research, wrote in ablog on theFDA Voicewebsite.

The article dealt with theexpanded approval of Vertexs Kalydeco (ivacaftor) for patients with a range of rare mutations in the CFTR gene that causes cystic fibrosis. The title of the blog isTwo Recent Scientific Advances Underscore an Encouraging Future for Precision Medicine at FDA.

The agencys decision to increase the number of mutations that Kalydeco can treat from 10 to 33 was based on results of non-human studies rather than clinical trials.

Regulators are increasingly using this approach because it can benefit patients with genetic features so rare that clinical trials of new therapies are difficult to carry out.

Mercks Keytruda (pembrolizumab) is another precision medicine example, Woodcock said. The FDA approved it for people with certain cancer-related genetic featuresrather than a specific type of cancer.

These are only two of more than 25 precision-medicine-type treatments the FDA has approved in the past three years, she said. In addition, it has expanded the conditions that many other drugs that are already on the market can treat.

To continue expanding the use of precision medicine, scientists need to keep making biomarker advances, she said.

Biomarkers measure biological features that tell researchers something about a disease such as the presence of bacteria in airways or levels of an inflammatory molecule.

Among other things, biomarkers can help assess the severity of a condition, determine which patients are likely to respond to a treatment, and predict a disease outcome. They can also play a key role in drug development, Woodcock argued. A suitable marker can make it easier and faster for scientists to recruit the right type of patients for a clinical trial.

Biomarkers can also offer scientists a more sensitive measure of a treatments effectiveness. They do this by identifying measures of patient improvement before their symptoms get better.

To develop biomarkers, researchers need a detailed understanding of both a disease and its response to treatment. But identifying a biomarker is not enough. Scientists must confirm that it measures what they think it measures.

To help assure this, the FDA is working with scientists and others in aBiomarker Qualification Program. It allows any drug developer to use a validated biomarker, further advancing the development process.

We believe it is important to make drugs such as Kalydeco and Keytruda available to as many patients as can benefit from them, Woodcock said, adding that the FDA is actively pursuing more advances in targeted therapies.

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FDA Uses Kalydeco and Keytruda as Examples of How It Is Promoting Precision Medicine - Cystic Fibrosis News Today

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What if Sex Is Just a Garbage Dump for Genetic Mutations? - WIRED

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Twin study reveals strong genetic influences on how infants visually explore social world

Using eye-tracking technology, researchers at Washington University School of Medicine in St. Louis and Emory University School of Medicine in Atlanta have found compelling evidence that genetics plays a major role in how children look at the world and whether they have a preference for gazing at peoples eyes and faces or at objects. The discovery adds new detail to understanding the causes of autism spectrum disorder. Studying twins, the researchers found that where babies focus their eyes is under stringent genetic control.

New research has uncovered compelling evidence that genetics plays a major role in how children look at the world and whether they have a preference for gazing at peoples eyes and faces or at objects.

The discovery by researchers at Washington University School of Medicine in St. Louis and Emory University School of Medicine in Atlanta adds new detail to understanding the causes of autism spectrum disorder. The results show that the moment-to-moment movements of childrens eyes as they seek visual information about their environment are abnormal in autism and under stringent genetic control in all children.

The study is published online July 12 in the journal Nature.

Now that we know that social visual orientation is heavily influenced by genetic factors, we have a new way to trace the direct effects of genetic factors on early social development, and to design interventions to ensure that children at risk for autism acquire the social environmental inputs they need to grow and develop normally, said lead author John N. Constantino, MD, the Blanche F. Ittleson Professor of Psychiatry and Pediatrics at Washington University. These new findings demonstrate a specific mechanism by which genes can modify a childs life experience. Two children in the same room, for example, can have completely different social experiences if one carries an inherited tendency to focus on objects while the other looks at faces, and these differences can play out repeatedly as the brain develops early in childhood.

The researchers studied 338 toddlers ages 18 to 24 months using eye-tracking technology, developed at Emory, allowing them to trace young childrens visual orientation to faces, eyes or objects as the children watched videos featuring people talking and interacting.

The children, who were part of the Missouri Family Registry, a database of twins that is maintained at Washington University School of Medicine, included 41 pairs of identical twins such twins share 100 percent of their DNA and 42 sets of fraternal twins who share only about 50 percent of their DNA. In addition, the researchers studied 84 unrelated children and 88 children diagnosed with autism spectrum disorder.

Constantino, with fellow investigators Warren R. Jones, PhD, and Ami Klin, PhD, of Emory University School of Medicine, evaluated the eye-tracking data. Each twin was tested independently, at different times, without the other twin present.

How much one identical twin looked at another persons eyes or face was almost perfectly matched by his or her co-twin. But in fraternal twins, eye movements in one twin accounted for less than 10 percent of the variation in the eye movements of his or her co-twin. Identical twins also were more likely to move their eyes at the same moments in time, in the same directions, toward the same locations and the same content, mirroring one anothers behavior to within as little as 17 milliseconds. Taken together, the data indicate a strong influence of genetics on visual behavior.

The moment-to-moment match in the timing and direction of gaze shifts for identical twins was stunning and inferred a very precise level of genetic control, said Constantino, who directs the William Greenleaf Eliot Division of Child and Adolescent Psychiatry at Washington University. We have spent years studying the transmission of inherited susceptibility to autism in families, and it now appears that by tracking eye movements in infancy, we can identify a key factor linked to genetic risk for the disorder that is present long before we can make a clinical diagnosis of autism.

The effects persisted as the children grew. When the twins were tested again about a year later, the same effects were found: Identical twins remained almost perfectly matched in where they looked, but fraternal twins became even more different than they were when initially evaluated.

Autism spectrum disorder is a lifelong condition that affects about 1 in 68 children in the United States. It is known to be caused by genetic factors, and earlier work by the Emory University team had shown that babies who look progressively less at peoples eyes, beginning as early as 2-6 months of age, have an elevated risk for autism. Meanwhile, Constantino and others in the group have studied how subtle behaviors and symptoms that characterize autism aggregate in the close relatives of individuals with autism, as a way to identity inherited susceptibilities that run in families and contribute to autism risk.

Studies like this one break new ground in our understanding of autism spectrum disorder: Establishing a direct connection between the behavioral symptoms of autism and underlying genetic factors is a critical step on the path to new treatments, said Lisa Gilotty, PhD, chief of the Research Program on Autism Spectrum Disorders at the National Institute of Mental Health, which provided support for the study in tandem with the Eunice Kennedy Shriver Institute of Child Health and Human Development.

Those new treatments could include interventions that motivate very young children to focus their gazes more on faces and less on objects.

Testing infants to see how they are allocating visual attention represents a new opportunity to evaluate the effects of early interventions to specifically target social disengagement, as a way to prevent the most challenging disabilities associated with autism, said senior author Warren R. Jones, PhD, director of autism research at the Marcus Autism Center at Emory. Such interventions might be appropriate for infants showing early signs of risk or those who have been born into families in which autism has affected close relatives. In addition, learning why some infants who tend to not look at eyes and faces develop without social disability is another priority.

The small percentage of healthy children who tended to avoid looking at eyes and faces may provide researchers with insight on how to successfully compensate for those tendencies and therefore inform the development of higher-impact interventions that will produce the best possible outcomes for infants with inherited susceptibility to autism.

In addition to Constantino, the research team at Washington Universityincluded Anne L. Glowinski, MD, a professor of child psychiatry and associate director of child and adolescent psychiatry;Natasha Marrus, MD, PhD, an assistant professor of child psychiatry; and Stefanie F. Kennon-McGill, PhD, a postdoctoral research associate in psychiatry.

As identical twins watched videos, they almost always looked for the same things at the same times and in the same places. Where gazes fell is marked by the plus signs. Fraternal twins didnt match as well as identical twins, indicating that genes control where children look.

Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus N, Haider A, Glowinski AL, Gillespie S, Klaiman C, Klin A, Jones W. Infant viewing of social scenes is under genetic control and is atypical in autism. Nature. Published online July 12, 2017.

This work was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health of the National Institutes of Health (NIH), grant numbers HD068479 and U54 HD087011 (to Constantino and the Intellectual and Developmental Disabilities Research Center at Washington University) and MH100029 (to Jones and Klin at Emory). Other support was provided by the Missouri Family Register, a joint program of Washington University and the Missouri Department of Health and Senior Services.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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In autism, genes drive early eye gaze abnormalities | Washington ... - Washington University School of Medicine in St. Louis

Lexington Herald Leader

Counseling can help you decide whether to get genetic testing Lexington Herald Leader Genetic counselors are specially trained in cancer genetics and help provide information, resources and support that are needed for decision making about testing. A counselor will collect a detailed personal medical and family health history to ...

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Counseling can help you decide whether to get genetic testing - Lexington Herald Leader

A new era in medicine does not come along very often.We had one, perhaps, in 1854 when John Snow effectively invented the practical applications of epidemiology by removing the handle from Londons Broad Street water pump.We had one about 50 years prior when Edward Jenner discovered the prevention of smallpox with vaccination.We had one when the value to public health of basic sanitation was first sorted out; we had one when micronutrients were discovered to cure and prevent various deficiency syndromes; and we had one when Alexander Fleming and a bit of serendipity combined to discover penicillin, and usher in the antibiotic age.

And we had one yesterday- 7/13/17- at least according to the New York Times, which used just that language to report the provisional approval by a FDA panel of a breakthrough therapy for leukemia involving genetic engineering.The approval is provisional because the recommendations of FDA expert panels, unanimously in favor of the new drug called tisagenlecleucel (good luck!) in this case, require formal action by the agency.Such action, however, rarely departs from panel recommendations, and certainly not in the case of a unanimous decision.

The treatments efficacy was not in question; it clearly works, and has saved the lives of mostly children who would almost certainly have died of their leukemia otherwise.It is, however, capable of various and severe toxicities along the way to a potential cure.Of 68 young people treated with tisagenlecleucel for lymphoblastic leukemia in a study run by Novartis, 52 appear to have been cured by the drug; the other 11 died.

The panel was obligated to address concerns about such rather serious dangers of the treatment, but the conclusion was perhaps a foregone conclusion just the same.Just as the dangers of operating on a brain may be justified by the greater dangers of a tumor or hemorrhage inside the skull, so, too the dangers of tisagenlecleucel are justified- in my view as well as that of the FDA panel- by the greater dangers of the inadequately treated disease.Absent this breakthrough, the 52 young people who had failed other treatments- some of whom attended the FDA meeting with their families- would almost certainly all be dead by now.It is a new era for us all as each of them wakes to a new day- with the opportunity to live through it.

The new therapy is perhaps the epitome of personalized medicine.It extracts a variety of white blood cells called T cells from an individual patient, and engineers a genetic adjustment so that these T cells can recognize the patients own malignant B cells as foreign- and attack them.The immune system is in effect reprogrammed to seek out and destroy the leukemia cells.

Along the way, as in any war, there is considerable potential for collateral damage to the innocent cells and tissues in the area- namely, the patients blood and body- and the severe toxicities of the treatment derive from that.But for those who make it through those battles, as over 82% did in the Novartis study, there appears to be an opportunity for that most elusive of words in cancer treatments: a cure.The reprogrammed T cells can seek out and destroy every last rogue cell.The only reason for any reticence about use of the word cure is that one would like to know the outcome of this treatment over a span of years, decades, and then lifetimes- and since its new, we will all have to wait for that.

But we neednt wait for this new era in medicine; it has arrived.And while tisagenlecleucel is its standard-bearer, it wont be alone for long.This same approach can be, and will be, applied to other diseases, perhaps not just cancers, but certainly other varieties of those.

Predictably, the costs involved in extracting one persons cells, reprogramming them with genetic engineering techniques, and infusing them back into that one person- are potentially quite staggering.The amped-up T cells work only for their owner; there is no scalability.How ironic, and opportune, that this stunning but costly advance should arrive even as the basic mechanisms of health care coverage roil our Congress, and our society.

Now is just the time for every parent and grandparent, whatever their political leanings, to ask: would they want access to this product of human ingenuity if ever their beloved child faced all but certain death without it?Would they want access regardless of their ability to pay?Would they want that child forever after subject to potential uninsurability because of that pre-existing condition?

There are all sorts of ways to reduce the costs and improve the outcomes of our so-called health care system quite massively; denying a desperate 6-year-old life-saving access to the progress born of humanitys relentless resourcefulness- should not figure among them.

Those better ways include universal access, and universal coverage for essential, and preventive care.Those better ways include a fundamental shift from just disease care, to a genuine focus on health care, with lifestyle as the preferred medicine.Those better ways include confronting the hypocrisies of a culture that laments diseases in children, but propagates them for profit.

My particular field- lifestyle medicine- is in the vanguard of all such efforts, with attendant benefits for the planet, too, that no other branch of medicine tends even to mention.I am proud and inspired to be involved in so timely and propitious an effort.

I do note, however, the one potential liability to which my camp is prone.The extreme enthusiasm for lifestyle as medicine that prevails among the aware can at times translate into a relative, at least apparent disparagement of other, more conventional varieties of medicine.Such tendencies are perhaps exacerbated at this juncture in our cultural history when everything seems to be supremely dichotomous and polarized: left or right; nature or science; defend or impeach.

The reality is that while lifestyle can often be the very best of medicine, there are times when some other medicine emphatically is.Most of us have experience with that; I certainly do.We are not obligated to choose.

Lets use lifestyle to promote health and prevent disease as only it can; and lets use it as we can to treat and reverse disease, too.But then lets celebrate the stunning scientific advances that empower us to treat those who get sick anyway- as some inevitably will.

We may think of lifestyle and health like a ship at sea; we may benefit greatly from masterful application of ship and sail, but we will never be masters of wind and wave.Bad things, in other words, can happen to people who do everything right, and well- just as gales can cause the best of ships and crews to founder.

When that happens, the rest of us muster the resources for a rescue mission to save all who can be saved.Medicine- more than one kind of medicine- should be used to do the same.

I applaud the insights and toil, inspiration and perspiration that brought us tisagenlecleucel and that will bring us related advances.I call upon us as a society to do whats necessary to honor this endowment of the human mind- and ensure it is never denied to a child in peril.

Its a new era in medicine.But more importantly, its just another day that 52 young people will live to see.

Senior Medical Advisor, Verywell.com

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Medicine For Another Day - HuffPost

Things are about to speed up dramatically in genetic research, with scientists developing a new technique that can clone thousands of genes in a single reaction.

The new technology, called a LASSO probe, could be used to create libraries of proteins from DNA samples, speeding up the search for new drugs by replacing the tedious methods of gene cloning currently used.

When you think of cloning you may think of Dolly the sheep or the company that promises to clone your favourite pet so you don't have to live sad and alone, but that's a different kind of cloning. Here we're talking about molecular cloning, a natural process that occurs when bacteria, insects, or plants reproduce without a partner.

Scientists clone DNA because they want to do one of two things; either they want to gain information about a particular gene or they want to manipulate genetic information in a cell to give the cell a new property. Both reasons require scientists to have millions of copies of the same DNA molecule in a test tube.

At the moment, to work out what a gene does by cloning its DNA and expressing its protein is done one gene at a time. The standard sequencing method, called molecular inversion probes, involves capturing small fragments of DNA (about 200 base pairs long) and connecting them together to map out the full genome code.

Weaving together these small sections of code to form the full gene sequence isn't easy, but there hasn't been any other way to sequence long fragments of DNA and it's been holding research back.

Not to scale. Credit: Jennifer E. Fairman/Johns Hopkins University

"We think that the rapid, affordable, and high-throughput cloning of proteins and other genetic elements will greatly accelerate biological research to discover functions of molecules encoded by genomes and match the pace at which new genome sequencing data is coming out," says one of the team, Biju Parekkadan, from Rutgers University.

In this new study, the LASSO probe - which stands for "long adaptor single stranded oligonucleotide" - can capture and clone thousands of long DNA fragments and the researchers hope that the new technique will push the limits of what we can currently do.

"Our goal is to make it cheap and easy for any researcher in any field to clone and express the entire set of proteins from any organism," said co-researcher Ben Larman from Johns Hopkins University School of Medicine. "Until now, such a prospect was only realistic for high-powered research consortia studying model organisms like fruit flies or mice."

How does this new technique work?

A collection of LASSO probes were used to grab desired DNA sequences, you can think of it like the way a rope lasso is used to capture cattle. Instead of aiming for the spiky horns of a cow, the LASSO probe targets a DNA sequence up to a few thousand base pairs long - the typical length of a gene's protein code.

The study is a proof of concept, with the LASSO probes used to capture over 3,000 DNA fragments from the E. coli bacterial genome. The results show the probes successfully captured around 75 percent of the gene they targeted.

There were also other benefits to the LASSO probe technique.

The researchers say that the sequences are captured in a way that allows them to also analyse what the genes' proteins do and demonstrated this by giving antibiotic resistance to a cell that would otherwise be killed by the antibiotic.

The researchers were also able to capture and clone a protein library from a human microbiome sample and they hope that it will lead to improved precision medicine and rapid discovery of new medicines for a range of diseases.

"We're very excited about all the potential applications for LASSO cloning," said Larman. "Our hope is that by greatly expanding the number of proteins that can be expressed and screened in parallel, the road to interesting biology and new therapeutic biomolecules will be dramatically shortened for many researchers."

The study has been published in Nature Biomedical Engineering.

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Scientists Can Now Clone Thousands of Genes in a Single Reaction - ScienceAlert

BALTIMORE, Md. - Lara Diamond spit in a tube then put it in the mail. She was expecting to find distant relatives, instead she received a diagnosis.

They told me that I had this BRCA2 mutation, which was a complete shock to me, and I was able to follow-up with my doctor and genetic counselor from that point, said Diamond, a genealogist and author of the blog Laras Jewnealogy.

BRCA genes have been linked to breast and ovarian cancer. Diamond had no knowledge of any family history of either disease.

I was sent for my first ever mammogram, which was clear, and only because I had a BRCA mutation I was sent for an MRI and that wasn't clear. So, they did a biopsy and it turned out I already had cancer, Diamond said.

Diamond was diagnosed with stage I breast cancer.

There were no symptoms. I mean I wouldn't have gotten screened for years. The fact that a mammogram couldn't see it, ultrasound couldn't see it, it would've been a couple more years until there were any symptoms that would've made us question anything, said Diamond.

Thanks to the early notice, doctors were able to remove the 6 mm tumor.

And while the test enabled Diamond to be proactive about her health, it's very rare for someone to have a similar experience. In fact, the FDA put an end to 23andMe BRCA testing back in 2013 because of risks associated with false positive findings.

The majority of people who come in with reports from direct-to-consumer companies are misinterpreting it to either mean they either have some sort of rare condition or they might be at risk for something, and in reality that's not what's going on, said Natalie Beck, a certified genetic counselor at the Johns Hopkins Institute of Genetic Medicine.

Beck said its a good thing that theyve been seeing an increase in appointment requests from people ordering direct-to-consumer tests, however, the National Society of Genetic Counselors suggests that consumers proceed with caution. They recommend consumers consider seeing a genetic counselor to help them determine why they want to get tested and help interpret their results.

It's not as simple as one single variant or one single gene and giving people an absolute increase or decrease risk for their health. And that challenge of patients trying to interpret their own genetic test results I think can lead to a lot of false anxiety or maybe even false reassurance, Beck said.

The tests, however, are inspiring intrigue as well as a desire to learn more about personal health and the people you're connected with.

They want a crystal ball for their health care, and so I think that's adding to people's desire to know more, Beck said.

Diamond credits her genealogy addiction with potentially saving her life.

Yes, I'm very glad that I'm obsessed with genealogy, because my life would be very different in many ways otherwise, said Diamond.

Diamond has tried three different direct-to-consumer tests. 23andMe was the only one with a medical component, however, there are more tests that now offer health screenings. The FDA also recently granted approval to 23andMe to test for gene sequences linked to 10 health risks including Parkinsons disease and late onset Alzheimers.

If you have any family history of disease, it's advised that you meet first with a genetic counselor and not rely on any direct-to-consumer tests.

The cost of direct-to-consumer tests vary from around $100 to nearly $1,000.

Editor's Note: This story has been updated to reflect the National Society of Genetic Counselors' position on direct-to-consumer tests.

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At-home genetic test leads to breast cancer diagnosis - ABC2 News

The ongoing story of Charlie Gard - a baby born in London with a rare genetic disorder known as Mitochondrial Depletion Syndrome - has gained international attention, with such prominent figures as Pope Francis and President Donald Trump commenting on his familys ordeal.

Charlie, born on August 4, 2016, has been on life support for several months at the Great Ormond Street Hospital in London. As his condition continues to deteriorate, his parents are battling with the European courts over how to move forward with his care.

Last week, New York Presbyterian/Columbia Medical University Hospital offered to administer experimental treatment therapy to Gard as long as the British government approves a safe medical transfer to the United States. Thus far, the courts have denied the transfer, but Charlies parents have continued their battle with the legal system.

Meanwhile, Charlies incredibly rare form of mitochondrial disease has generated global attention. Here are some of the common questions about Mitochondrial Depletion syndrome.

MDS is one of a suite of rare disorders that affect the mitochondria - often described as the tiny powerhouses of the cell. Certain genes ensure that these mitochondria are healthy and produce the energy the cells need. Genes come in pairs, one copy comes from the mother and one from the father. When a baby has MDS, it means that both copies received from the parents for this particular gene - the one that keeps mitochondria healthy - are defective. The result is progressive muscle weakness and devastating multi-organ damage.

This disease is very uncommon, with perhaps fewer than 100 cases in the range of related disorders reported worldwide, according to a 2014 study.

Initially, development may appear normal; however, before these children reach 24 months of age, they usually start exhibiting certain signs of muscle weakness -- for example, weakening of eye muscles leading to droopy eyelids and facial weakness. These children may also exhibit signs of organ failure, such as brain and nervous system problems leading to seizure activity, hearing loss, liver damage and difficulty walking, talking, and swallowing.

The prognosis, unfortunately, is very poor. Many children with this condition begin having lung muscle weakness early in life. Normally, this progresses rapidly to respiratory failure and death within a few years of onset. The most common cause of death is infection of the lungs.

Although supportive therapy is available to help treat the conditions that accompany this syndrome - such as the seizures and hearing loss - there is currently no cure for MDS. Experimental therapies tested on mice are intended to target specific defective areas of the mitochondria. Thus far, these treatments have shown only modest success in these animals and some have begun to be tested in a few children. The parents of an American child with a different type of mitochondrial disorder spoke to Gard's parents, according to the Associated Press, about a nucleoside therapy treatment they have been using for their now 6-year-old son who appears to have shown some modest improvement.

Devika Umashanker, M.D., is a recent graduate of the Obesity Medicine fellowship at Weill-Cornell Medical College.

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Baby Charlie Gard's medical condition: What you need to know - ABC News

Precision medicine is, ironically, an imprecise term.

As it is often used today, the phrase suggests that precision is novel to the practice of medicine, and to many, it means incorporating sophisticated genetic testing into its practice.

The term can even suggest that there are now possibilities of miracle cures that were never possible before.

Sometimes healthcare organizations encourage that attitude through their marketing and advertising, but to a degree, that kind of thinking more represents hype than substance.

And while genetic testing and the information it can provide can help better tailor treatment options for individual patients, especially in cancer care, experts say healthcare executives and clinicians must be careful not to encourage false hope among vulnerable patients and their families.

Yet in a time of rapid evolution of more precise and tailored treatment options, executives and clinicians are charged with divining the difficult calculus between the possible and the practical in their precision medicine organizational structure and service offerings.

In reality, precision has always been the goal of physicians as medicine has evolved over the past couple of hundred years, says Robert Mennel, MD, director of the Baylor Precision Medicine Institute in Dallas.

"In some areas we're there. We have well-accepted tests for certain diseases that, if you're not using them, I would consider to be malpractice in many situations," he says.

However, even top-level academic medicine is still quite far away from being able to look at an individual's whole genome and predict a therapy for every disease.

"But the promise of precision medicine is there, and medicine 10 years from now is going to be quite different than it is now," he says.

One area where genetic testing is ready for prime time is in noninvasive prenatal testing, says Scott A. Beck, administrator of the Center for Individualized Medicine at the Mayo Clinic in Rochester, Minn.

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Precision Medicine: Integration May Be Closer Than You Think - HealthLeaders Media

July 12, 2017 by George Lowery Mouse intestinal organoids that scientists genetically engineered to study colon cancer. Using gene editing technology, the investigators fused together the genes Ptprk and Rspo3 to determine their effect on cancer development. Credit: Cornell University

Genetic mutations caused by rearranged chromosomes drive the development and growth of certain colorectal cancers, according to new research conducted by Weill Cornell Medicine investigators.

Many of the genetic mutations present in colorectal cancer have been known for decades. But their exact role in cancer's development and progression has not been clear. "We knew that these mutations existed, but not whether they contribute to the disease," said Lukas Dow, an assistant professor of biochemistry in medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "So we are interested in whether they are actually driving cancer and whether they can potentially be targets for drugs that treat it."

In a paper published July 11 in Nature Communications, Dow and his colleagues describe how large pieces of chromosomes are deleted or inverted, resulting in new, mutated so-called fusion genes created from parts of two other genes that are responsible for the formation of some colon cancers.

The researchers used the gene editing technology CRISPR, which allows scientists to easily alter any piece of DNA in an organism, to cut the DNA in normal human intestinal cells and create fusion genes. In this way, they engineered the genetic mutations in two genes Rspo2 and Rspo3 known to be associated with colorectal cancer. They then created mice containing these genes to study the genes' effect on colon cancer development.

Though CRISPR has received a lot of attention in the last several years, this is the first time the tool has been used this way. "We created the first CRISPR-based transgenic animal model for inducing large-scale chromosomal rearrangements," Dow said.

These chromosomal rearrangements in the Rspo genes did in fact initiate growth of colon cancer in the mice. The mice containing the engineered genes developed multiple precancerous tumors that are the precursors to colorectal cancer. "This is the first evidence that these specific fusions can drive tumor development," Dow said.

Dow's team went on to treat the mice that developed cancer with an experimental drug, LGK974, which blocks a protein necessary for Rspo fusion genes to cause disease. "The tumors shrank and the mice were fine as long as they continued to take LGK974," Dow said. In addition, the drug only suppressed growth of the cancer cells; it had no obvious negative effect on healthy cells in the mouse intestine.

The study's results hold particular promise for the treatment of colorectal cancer in humans, Dow said. This form of cancer has historically been a difficult disease to treat. Chemotherapy drugs have limited impact against colorectal cancer and developing targeted therapies drugs that target aspects of cancer cells that make them different from healthy cells has proven difficult. "Our results give us confidence that if we can deliver LGK974 effectively to patients with these fusion genes," Dow said, "then we should be able to see some tumor response with these targeted agents."

Explore further: Novel gene editing approach to cancer treatment shows promise in mice

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'Fusion genes' drive formation and growth of colorectal cancer - Medical Xpress

July 12, 2017

Scott Hebbring will discuss the impact of genetics on medicine at 6:30 p.m. Monday, July 17, at the Waupaca Area Public Library.

Sponsored by Winchester Academy, the program is the second in a two-part series.

A research scientist at the Marshfield Clinic, Hebbring will focus on how genetic information and electronic medical record data are revolutionizing health care.

He will discuss his research that shows how family and genetic data may be used to predict, prevent and treat human disease.

Hebbring completed his bachelors degree at the University of Wisconsin-Eau Claire and his doctoral degree in biochemistry and molecular biology at the Mayo Clinic Graduate School in Rochester, Minnesota.

At the Mayo Clinic, his research included the study of genes and enzymes involved in folate metabolism, pharmacogenomics and prostate cancer.

This program is free and open to the public.

Winchester Academy is funded through sponsors and tax-deductible donations. Karen and John Hebbring are the sponsors of Dr. Hebbrings program.

For more information about Winchester Academy, check winchesteracademywaupaca.org, follow on Facebook or contact Executive Director Ann Buerger Linden at 715-258-2927 or buergerlinden@gmail.com.

Original post:

Program examines genes, disease - Waupaca County News

Teng Han

Mouse intestinal organoids that scientists genetically engineered to study colon cancer. Using gene editing technology, the investigators fused together the genes Ptprk and Rspo3 to determine their effect on cancer development.

Genetic mutations caused by rearranged chromosomes drive the development and growth of certain colorectal cancers, according to new research conducted by Weill Cornell Medicine investigators.

Many of the genetic mutations present in colorectal cancer have been known for decades. But their exact role in cancers development and progression has not been clear. We knew that these mutations existed, but not whether they contribute to the disease, said Lukas Dow, an assistant professor of biochemistry in medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. So we are interested in whether they are actually driving cancer and whether they can potentially be targets for drugs that treat it.

In a paper published July 11 in Nature Communications, Dow and his colleagues describe how large pieces of chromosomes are deleted or inverted, resulting in new, mutated so-called fusion genes created from parts of two other genes that are responsible for the formation of some colon cancers.

The researchers used the gene editing technology CRISPR, which allows scientists to easily alter any piece of DNA in an organism, to cut the DNA in normal human intestinal cells and create fusion genes. In this way, they engineered the genetic mutations in two genes Rspo2 and Rspo3 known to be associated with colorectal cancer. They then created mice containing these genes to study the genes effect on colon cancer development.

Though CRISPR has received a lot of attention in the last several years, this is the first time the tool has been used this way. We created the first CRISPR-based transgenic animal model for inducing large-scale chromosomal rearrangements, Dow said.

These chromosomal rearrangements in the Rspo genes did in fact initiate growth of colon cancer in the mice. The mice containing the engineered genes developed multiple precancerous tumors that are the precursors to colorectal cancer. This is the first evidence that these specific fusions can drive tumor development, Dow said.

Dows team went on to treat the mice that developed cancer with an experimental drug, LGK974, which blocks a protein necessary for Rspo fusion genes to cause disease. The tumors shrank and the mice were fine as long as they continued to take LGK974, Dow said. In addition, the drug only suppressed growth of the cancer cells; it had no obvious negative effect on healthy cells in the mouse intestine.

The studys results hold particular promise for the treatment of colorectal cancer in humans, Dow said. This form of cancer has historically been a difficult disease to treat. Chemotherapy drugs have limited impact against colorectal cancer and developing targeted therapies drugs that target aspects of cancer cells that make them different from healthy cells has proven difficult. Our results give us confidence that if we can deliver LGK974 effectively to patients with these fusion genes, Dow said, then we should be able to see some tumor response with these targeted agents.

Geri Clark is a freelance writer for Weill Cornell Medicine.

Link:

'Fusion genes' drive formation and growth of colorectal cancer ... - Cornell Chronicle

July 10, 2017

Scientists have found a single proteinPtbp2controls a network of over 200 genes central to how developing sperm move and communicate. The protein works by regulating how RNA is processed during each stage of sperm development.

The study is published in Cell Reports by Donny Licatalosi, PhD, Assistant Professor in the Center for RNA Science and Therapeutics at Case Western Reserve University School of Medicine.

Developing sperm are constantly chopping and trimming their genetic material. This process"splicing"allows the cells to select genes required for each developmental stage. Splicing produces small, trimmed pieces of RNA that serve as protein blueprints. By using different trimming patterns"alternative splicing"the cells can create multiple protein blueprints from a single gene.

Developing sperm use alternative splicing techniques more than other cell types. This produces high levels of alternatively spliced RNA fragments inside sperm progenitor cells, also called germ cells. Scientists are not sure how or why germ cells use alternative splicing at such a high rate.

"The importance of RNA splicing in sperm development has been a longstanding question," Licatalosi said. "We've known for decades that more alternatively spliced RNAs are made during germ cell development compared to most other developmental systems. But whether this is a tightly regulated process, or even a biologically meaningful one, is unclear."

Licatalosi's team is investigating how alternative splicing is controlled during sperm development. Their work focused on a proteinPtbp2that attaches to RNA near splicing sites. Understanding RNA splicing in germ cells could help researchers better understand mechanisms behind developmental defects in humans.

The researchers deleted the gene encoding Ptbp2 in germ cells, then investigated levels and functions of alternatively spliced RNAs in four different stages of sperm development.

All experiments were conducted at Case Western Reserve University (CWRU) School of Medicine. The CWRU Genomics Core assisted with genetic studies and the CWRU Tissue Resources Core helped prepare mouse cell and tissue samples. Licatalosi also collaborated with the CWRU Virology, Next Generation Sequencing, and Imaging Core to observe how the genetically-modified cells interacted with other cells under high-powered microscopes.

The research team discovered that without the Ptbp2 protein, alternative splicing for over 200 genes inside developing sperm went awry. Many of the affected genes encoded proteins involved in protein trafficking within the cell. As a result of their dysregulation, the germ cells could not properly move, transport materials, or communicate with other cells. The genetically-modified germ cells never properly developed into sperm. The results suggest Ptbp2 is central to RNA splicing processes inside germ cells and, consequently, proper sperm development.

Most strikingly, deleting the major protein also impacted other cellsSertoli cellsthat serve as guides for developing germ cells. Sertoli cells in the experiments had defects in their cellular scaffoldingcytoskeletonthat they use to physically move and interact with germ cells.

Said Licatalosi, "The most exciting part is that splicing defects in germ cells, caused by deletion of a splicing regulator gene only in germ cells, caused defects in the neighboring Sertoli cells. This observation underscores the importance of splicing regulation in cellular crosstalk between germ cells and Sertoli cells. This crosstalk is critical to ensure that the germ cells complete development and are not prematurely released before development is complete."

"The dynamics, regulation, and function of alternative splicing during spermatogenesis have remained largely unexplored. In this report, we provide data to significantly advance our knowledge of each of these aspects," wrote the authors.

Said Licatalosi, "Proper tissue development and function depends on highly orchestrated networks of different cell types talking to one another in an ordered and timely manner. Deficits in this process underlie a range of human diseases. Our data, and that from other labs, indicate that tissue-specific splicing regulators may have critical roles in establishing cell-cell networks necessary for proper tissue development and functionality."

According to Licatalosi, previous studies have suggested high levels of spliced RNAs "may be inconsequential, an artifact of the high levels of gene expression that occur during germ cell development. Our data argue that alternative RNA expression in sperm development is highly regulated, and this regulation is critical for the cells to complete development."

"The new insights provided by our study result from the integration of genetic, cellular, biochemical, bioinformatic, and deep sequencing approaches," Licatalosi noted.

Explore further: Scientists discover BCAS2 involved in alternative mRNA splicing in spermatogonia and the transit to meiosis

More information: Molly M. Hannigan et al, Ptbp2 Controls an Alternative Splicing Network Required for Cell Communication during Spermatogenesis, Cell Reports (2017). DOI: 10.1016/j.celrep.2017.05.089

Alternative splicing significantly expands the form and function of the genome of organisms with limited gene numbers and is especially important for several stages of mouse spermatogenesis.

RNA is both the bridge between DNA and the production of proteins that carry out the functions of life and what guides which and how much protein gets made. As messenger RNA (mRNA) is transcribed from DNA to carry genetic ...

Researchers at the Babraham Institute have investigated the early stages of the development of cells called primordial germ cells and developed strategies to generate 'lookalike' cells in the lab. The generation of human ...

Alternative splicing of mRNA precursors enables cells to generate different protein outputs from the same gene depending on their developmental or homeostatic status. It is a complex process that allows the generation of ...

Researchers from the UNC School of Medicine have discovered that the protein RBM4, a molecule crucial to the process of gene splicing, is drastically decreased in multiple forms of human cancer, including lung and breast ...

Highly expressed in the testis, a gene named Ranbp9 has been found to play a critical role in male fertility by controlling the correct expression of thousands of genes required for successful sperm production. A group of ...

Why do lemurs go "hmm?" It's not because they don't know the words, but the answer may provide important clues about how ancient human ancestors may have socialized with each other. In research published in Ethology, U of ...

Researchers at the Francis Crick and Gurdon Institutes have pinpointed the mechanism that activates a key point in embryonic development. This could help scientists develop new treatments for diseases where the cell cycle ...

Scientists at the John Innes Centre have discovered how plants send internal warning signals in response to attack by aphids.

Researchers have identified a pheromone released by female insects after mating that tells males exactly when they are ready to mate again.

Human presence in closed habitats that may one day be used to explore other planets is associated with changes in the composition of the fungal community - the mycobiome - that grows on surfaces inside the habitat, according ...

Throughout the world ocean, animals congregate at certain depths, forming layers that can be hundreds of meters thick and may extend horizontally for dozens or even hundreds of kilometers. Because these dense layers of animals ...

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Single protein controls genetic network essential for sperm development - Phys.Org

Charlie Gard is a terminally ill British child whose parents are fighting for the right to take him to the United States for an experimental treatment. His case has gained international attention, including from Pope Francis and U.S. President Donald Trump.

The 11-month-old is being treated at London's Great Ormond Street Hospital, which maintained the experimental treatment was "unjustified" and might cause Charlie more suffering without doing anything to help him. The hospital planned to take the boy off life support, but petitioned for a new court hearing based on evidence from researchers at the Vatican's children's hospital and another facility outside of Britain.

Below is some background on the medical and legal issues behind Charlie's case:

WHAT IS MITOCHONDRIAL DISEASE?

Mitochondrial disease is the umbrella term for a number of rare conditions caused by genetic mutations that result in the failure of mitochondria, specialized compartments within most cells that supply the energy needed to sustain life and support organ function. When mitochondria fail, cells can be injured or die, causing organ systems to shut down. The brain, heart, muscles and lungs are most affected because they need the most energy.

Charlie suffers from a form of the disease known as infantile onset encephalomyopathic mitochondrial DNA depletion syndrome (MDDS.) It is specifically known as the RRM2B mutation of MDDS. There is no known cure.

WHAT IS THE TREATMENT HIS PARENTS WANT FOR CHARLIE?

Doctors in the United States have been experimenting with a treatment known as nucleoside therapy, which has shown success in reducing the symptoms of some types of mitochondrial disease in laboratory mice. The treatment has been administered to a small number of children who have also shown improvement.

However, the treatment has never been used on either mice or humans with the type of mitochondrial disease from which Charlie suffers, according to court documents.

HAS THE NUCLEOSIDE THERAPY BEEN USED BEFORE?

A boy named Arturito Estopinan in Baltimore was the first child to be given deoxynucleotide monophosphate, an experimental treatment that significantly extended the life of mice with the same condition as Arturito, known as TK2-related mitochondrial depletion syndrome.

Art Estopinan, the boy's father, met with Charlie's parents in London to share his experience. He stressed that while the therapy was a treatment, not a cure, his 6-year-old son was "getting stronger every day." Arturito still needs around the clock care. Estopinan and his wife, Olga, have given their lives over to caring for him, hoping that a cure will come one day. The sacrifices keep coming because "we love our son," he said.

"A lot of very smart doctors are unaware of these experimental medications," Estopinan said. "As a father, I cannot sit back and know that my son was saved and not be vocal in support of Charlie Gard receiving these meds."

A CRUEL DISEASE

Sian Harding, Director of the British Heart Foundation Cardiovascular Regenerative Medicine Center at Imperial College, described the difficulty of treating the disease that Charlie has.

"Mitochondrial diseases are cruel because they strike babies and young children, who rapidly deteriorate," Harding said. "It is because there is no cure that the scientific and medical community have concentrated on pre-conception mitochondrial therapy, and it has been an enormous advance that this is now licensed by the government. It allows parents with these mutations to have healthy children, though sadly, cannot help babies already born."

WHY IS IT UP TO THE COURTS AND NOT CHARLIE'S PARENTS?

Parents in Britain do not have the absolute right to make decisions for their children. It is normal for courts to intervene when parents and doctors disagree on the treatment of a child. The rights of the child take primacy, with the courts weighing issues such as whether a child is suffering and how much benefit a proposed treatment might produce.

Professor Dominic Wilkinson, director of medical ethics at the Oxford Uehiro Center for Practical Ethics, said decisions about life-sustaining treatment for a child are "fraught."

"Sadly, reluctantly, doctors and judges are justified in concluding that continuing life support is not always helpful for a child and is in fact doing more harm than good," Wilkinson said. "Providing comfort, avoiding painful and unhelpful medical treatments, supporting the child and family for their remaining time: sometimes that is the best that we can do, and the only ethical course."

Link:

A brief look at the medical issues in the Charlie Gard case - ABC News

Outside of evolutionary biology, the human body is often spoken of as a miracle of engineering. But those more familiar with its workings point out evolution is no perfectionist, often favoring clunky ad hoc solutions over thosemore elegant in design. In fact, the comparison of evolution to a gambler might be the most apt, and nowhere is this more evident than in reference to genetic diseases like hemophilia. Now a recent study published in the Annals of Internal Medicine suggests far more people than previously thought are carrying variants of rare genetic diseases and could force us to redefine what is considered a healthy genome.

Genetic disorders are those resulting from mutations in ones DNA, often with horrendous results. Previously, scientists believedgenetic disorders were present in only a small fraction of the human population, 5 percent or less. After all, a population riven with genetic mistakes would quickly die out, or so went the logic. However, the present study puts the fraction of people with mutations linked to genetic diseases at something closer to 20 percent.

But is nature really so clumsy as to allow a veritable swarm of deleterious mutations to slip through her quality control mechanisms? It turns out many genetic disorders hide secret advantages. Take a person with the mutation that causes sickle cell anemia. A single copy of the mutation for sickle cellanemiaactually protects against the disease malaria. Its only if someone receivestwo copies of the defective gene that the problematic form of sickle cellanemia results. With many genetic disorders, nature seems to be hedging her bets, allowing some defects to slip through if they can provide a survival advantage to the population at large.

Counterintuitively, an individual suffering from a rare genetic disease may represent a successful population-level response to a given environment. This dance between genes and environments is at the heart of what we think of as health. But for most of history, medicine has considered the well being of an individual in isolation from population-level genetics. A more nuanced understanding of rare genetic diseases would take into account the various benefits genetic mistakes confer. This also suggests a cautious approach when editing our own genomes with tools like tools like CRISPR. Even seemingly terrible mutations we would be tempted to eliminate from the genetic pool may confer some secret advantage geneticists have yet to discover.

The study comes at a time when routine genetic testing is the subject of a far-ranging debate. Many doctors fear the release of genetic data to patients would cause undue anxiety. This study didnt support those claims, and goes a distance to undermine the paternalistic style of medicine currently practiced in many developed nations. In the United States, for instance, doctors remain a crucial chokepoint through which patients must pass through to access genetictesting. That said, anumber of direct-to-consumer genetic testing companies like 23andMe are breaking down these barriers, and a host of websites and even smartphone apps exist to help one make sense of their genetic data.

Now read: What is gene therapy?

Excerpt from:

Far More People Than Thought Are Carrying Rare Genetic Diseases - ExtremeTech

The FINANCIAL -- A new study conducted by an international team of lung cancer researchers, including Professor John Field from the Universitys Institute of Translational Medicine, have identified new genetic variants for lung cancer risk.

Lung cancer continues to be the leading cause of cancer mortality worldwide. Although tobacco smoking is the main risk factor, variations in a persons genetic makeup has been estimated to be responsible for approximately 12% of cases. However, the exact details of these variations have been previously unknown.

Genotyping is the process of determining differences in the genetic make-up (genotype) of an individual by examining the individuals DNA sequence.

Largest study of this type

By gathering genotype data from different studies around the world, through the use of a special research platform called OncoArray, researchers were able to increase the sample size for this study making it the largest one of its type in the world. The Liverpool Lung Project, funded by the Roy Castle Foundation, has made a major contribution to this international project.

Researchers examined the data to identify the genetic variants associated with lung cancer risk.

During the study, published in Nature Genetics, more than 29,200 lung cancer cases and more than 56,000 samples taken from people without lung cancer (controls) were examined. Researchers identified 18 genetic variations that could make people more susceptible to lung cancer and also 10 new gene variations.

Better understanding

Professor John Field, Clinical Professor of Molecular Oncology and the Chief Investigator of the UK Lung Cancer Screening Trial, said: This study has identified several new variants for lung cancer risk that will translate into improved understanding of the mechanisms involved in lung cancer risk.

Samples taken from the major Liverpool Lung Project, funded by the Roy Castle Foundation, was conducted by experts at the University of Liverpool, were used in this study.

These results will help us to further improve the way we can screen for lung cancer in high risk individuals in the UK. Further studies will help in the targeting of specific genes to influencing lung cancer risk, smoking behaviour and smoking effects on brain biology.

Exciting

The co-lead of the study was Christopher Amos, Chair and Professor of Biomedical Data Science, Professor of Community and Family Medicine, and Professor of Molecular and Systems Biology at Dartmouths Geisel School of Medicine, and interim Director and Associate Director for Population Sciences at Dartmouths Norris Cotton Cancer Centre. Of the study he said: What is particularly exciting is the magnitude of the study along with the new findings of genes influencing lung cancer which have not previously been reported.

This study definitely leads to new ideas about mechanisms influencing lung cancer risk.

Continued here:

Largest genome-wide study of lung cancer susceptibility conducted - The FINANCIAL