Category Archives: Human Genetics

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doi: 10.1097/01.NT.0000521715.10826.a9

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Isaac Marin-Valencia, MD, recipient of an AAN Clinical Research Training Scholarship, is studying clinical and molecular aspects of pontocerebellar hypoplasia, a brain metabolism disorder so rare it is virtually unseen in the United States. Here, he discusses his research.

BOSTONFrom the Canary Islands to New York by way of Spain and Texas, Isaac Marin-Valencia, MD, has dedicated his career to investigating pediatric neurologic diseases as exotic as his homeland.

The recipient of an AAN Clinical Research Training Scholarship, Dr. Marin-Valencia is studying clinical and molecular aspects of pontocerebellar hypoplasia, a brain metabolism disorder so rare it is virtually unseen in the United States.

All our patients are in the Middle East, because of the high rates of consanguinity, Dr. Marin-Valencia said during a break from the AAN Annual Meeting here in April. I've been to Cairo, to work with collaborators in hospitals there.

Born and raised in the Canary Islands, the Spanish archipelago off the coast of Morocco, Dr. Marin-Valencia grew up with a younger brother, Abimael, who had autism and epilepsy. He decided when he was six to become a doctor to help Abimael.

He was the reason for my career path, Dr. Marin-Valencia said. He's the inspiration for me to continue working on brain disorders that don't have treatments.

After graduating from medical school at the University of Las Palmas de Gran Canaria, he completed his four-year residency in pediatrics at Sant Joan de Deu Hospital of Barcelona. It was there he met Juan Pascual, MD, PhD, a pediatric neurologist who became his mentor.

I was very impressed by his knowledge and expertise is in brain metabolism disorders, Dr. Marin-Valencia said.

It was in Barcelona that he first began seeing young patients with the disorders that Dr. Pascual specialized in treating. I learned a lot about biochemistry and got fascinated, he said.

In 2008, he moved to the University of Texas-Southwestern Medical Center, to pursue postdoctoral research in pediatric neurology. Three years later, a poster of his won a grand prize at the university's postdoctoral research symposium, becoming the basis of a paper, published in the journal Cell Metabolism, that overturned 50 years of scientific dogma.

The so-called Warburg effect, named after Nobel Prize winner Otto Warburg, had been based on his in vitro observation that cancer cells preferentially metabolize glucose to lactate, even in the presence of sufficient oxygen in the mitochondria.

Dr. Marin-Valencia and colleagues disproved the long-held assumption that the same process holds true in vivo, using human glioblastomas implanted into the mouse brain to show that the cells' mitochondria oxidize glucose.

Determined to get back to his primary interest in metabolic disorders of the brain, he moved to Rockefeller University in 2015 to study human genetics and developmental neurobiology.

My background until then was in biochemistry and electrophysiology, Dr. Marin-Valencia said. I was missing two important pieces of the puzzle. Most of these metabolic disorders are genetic, and therefore they affect development of the brain. Learning these two areas have helped me to have a global picture about these disorders. If you're an expert in just one thing, you're going to miss other important facets that could be essential to understand and improve the diseases. Making more connections, meeting other investigators, associating with other laboratories all of that enriches my knowledge and way of thinking.

Under the mentorship of Joseph Gleeson, MD, a pediatric neurologist and neurogeneticist at University of California, San Diego, who has identified some 200 genetic mutations linked to brain disorders, Dr. Marin-Valencia is now looking for genes associated with pontocerebellar hypoplasia.

We use zebrafish and mice, Dr. Marin-Valencia said. We knock out or knock down genes and then see if there is a problem in the development of the brain. From the developmental standpoint, we want to replicate the disease in the animal model, to see what kind of cells are compromised and when the problem is first manifested. Then we go down to the cell and molecular level to localize where the gene is expressed and what the product of the gene is, where the protein is located in the cell and what its role is. Once we know all that, once we sort out the mechanism, we try to development new therapies.

Asked if he has yet identified a particular gene associated with pontocerebellar hypoplasia, he paused and said, I cannot tell you. It's not published yet.

Ultimately, his goal is to identify treatments for diseases that are now untreatable, something Dr. Gleeson's research has already done for a number of pediatric brain diseases.

One of the major problems we have in neurology is that we have few treatments for these devastating diseases that kill children at a very early age, Dr. Marin-Valencia said. There are things we can do to alleviate pain, to alleviate suffering, to provide a better quality of life. But from the biochemical and genetic standpoint, we cannot do much to change the outcome of many of these diseases.

Might his research into pontocerebellar hypoplasia one day lead to a treatment? It's a long way, Dr. Marin-Valencia said, but we are working to get there.

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At the Bench: Inspired by a Brother, AAN Scholarship Awardee Investigates Brain Metabolism Disorders - LWW Journals

This article was originally published on The Conversation. Read the original article.

Artificial intelligence is already being put to use in the U.K.'s National Health Service (NHS), with Googles AI firm DeepMind providing technology to help monitor patients. Now I have discovered that DeepMind has met with Genomic Englanda company set up by the Department of Health to deliver the 100,000 Genomes Projectto discuss getting involved.

If this does indeed happen, it could help bring down costs and speed up genetic sequencingpotentially helping the science to flourish. But what are the risks of letting a private company have access to sensitive genetic data?

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Genomic sequencing has huge potentialit could hold the key to improving our understanding of a range of diseases, including cancer, and eventually help find treatments for them. The 100,000 Genomes Project was set up by the government to sequence genomes of 100,000 people. And it wont stop there. A new report from the U.K.s chief medical officer, Sally Davies, is calling for an expansion of the project.

Vaccines were developed based on the person's individual cancer. Creative Commons

However, a statement by the Department of Health in response to a freedom of information (FoI) request I made in February reveals this decision has already been made. The department said in this response that the project will be integrated into a single national genomic database. The purpose of this will be to support care and research, and the acceleration of industrial usage." Though it will inevitably exceed the original 100,000 genomes, we do not anticipate that there will be a set target for how many genomes it should contain, the statement reads.

The costs of sequencing the genome on a national scale are prohibitive. The first human genome was sequenced at a cost of $3 billion. However, almost two decades later, Illumina, who are responsible for the sequencing side of the 100,000 Genomes Project, produced the first $1,000 genomea staggering reduction in cost. Applying machine learning to genomicsthat is, general artificial intelligencehas the potential to significantly reduce the costs further. By building a neural network, these algorithms can interpret huge amounts of genetic, health, and environmental data to predict a persons health status, such as their level of risk of heart attack.

DeepMind is already working with the NHS. As part of a partnership with several NHS trusts, the company has built various platforms, an app and a machine learning system to monitor patients in various ways, alerting clinical teams when they are at risk.

But its been controversial. The company announced the first of these collaborations in February 2016, saying it was building an app to help hospital staff monitor patients with kidney disease. However, it later emerged that the agreement went far beyond this, giving DeepMind access to vast amounts of patient dataincluding, in one instance, 1.6m patient records. The Information Commissioners Office ruled recently that the way patient data was shared by the Royal Free NHS Foundation Trust violated UK privacy law.

A person poses with a magnifying glass in front of a Google search page in this illustrative photograph taken in Shanghai March 23, 2010. Reuters

Googles ambitions to digitise healthcare continue. I received a response to an FoI request in May which reveals that Google and Genomics England have met to discuss using Googles DeepMind among other subjects to analyze genomic data.

Davies insists that data could be anonymized. The Department of Health always promise that medical data used in such initiatives will be anonymized, yet one of the reasons that Care.data (an initiative to store all patient data on a single database) was abandoned is that this was shown to be untrue. I have also shown that the department has misinformed the public about the level of access granted to commercial actors in the 100,000 Genome Project. In particular it said the data would be pseudonymized rather than anonymized, meaning there would still be information available such as age or geographical location.

What would genomic information add to Googles already far-reaching database of individual information? A hint lies in its self-confessed aspiration to organise our lives for us. The algorithms will get better, and we will get better at personalization,"according to Eric Schmidt, executive chairman of Googles parent company Alphabet. This will enable Google users to ask the question, what shall I do tomorrow?, or what job shall I take?."

With personalization as their ultimate goal, Google intend to use the machine learning algorithms which track our digital footprint and target users with personalized advertising based on their preferences. They also want to analyze health and genomic data to make predictions such as when a person might develop bipolar disorder or tell us what we should do with our lives.

Let us not forget that data, genomic or otherwise, is the oil of the digital era. What is stopping genomic information from being captured, bought and sold? We cannot assume that people will make life choices based upon their genetic profile without undue pressurecommercial or governmental.

As for how genomic data might be used and what decisions will be taken about us, the mass surveillance by government agencies of their own citizens is a chilling reminder of the way information technology can be used. There is something unpalatable about everything being connected and everything being known.

When it comes to genetics, the implications are particularly frightening. For example, there is evidence of a link between genes and criminality. We know that 40 percentof sexual offending risk is down to genetic factors. A single national knowledge base as the one the U.K. government is aiming to create might therefore be used for broad genetic profiling. Although early intervention programs that buy into genetically deterministic notions of crime genes are reductive, serious debate about policies involving genetic information will no doubt happen soon.

We can already see the beginnings of this in the United States. The bill Preserving Employee Wellness Programs Actwhich has received strong backing from Republicans and business groupswould allow companies to require employees to undergo genetic testing. The results would be seen by employers, and should employees refuse to participate they would face significantly higher insurance costs.

Too much personalization is likely to be intrusive. The challenge, then, will be to harness the potential of genomics while introducing measures to keep government and big business in check. The U.K. House of Commons Science and Technology Committees inquiry on genomics and genome editing was cut short (due to the recent snap general election). Its recommendations for further lines of enquiry include creating a quasi-independent body, which could be more attuned to broader, social and ethical concerns. This might introduce more balance at a pivotal time for the future of human genetic technologies.

Edward Hockingsis a PhD candidate in bioethics at theUniversity of the West of Scotland

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Google Could Soon Have Access Sensitive Genetic Patient Data We Should All Be Worried - Newsweek

July 5, 2017 Credit: CC0 Public Domain

Pioneering research using the tropical zebrafish could provide new insights into the genetic basis of myopathy, a type of human muscle disease.

An international research team, led by Professor Philip Ingham FRS, inaugural Director of the University of Exeter's Living Systems Institutehas taken the first steps in determining the central role a specific gene mutation in a poorly characterised human myopathy.

Myopathies are diseases that prevent muscle fibres from functioning properly, causing muscular weakness. At present, there is no single treatment for the disease, as it can develop via a number of different pathways.

One particular type is nemaline myopathy, which primarily affects skeletal muscles and can lead to sufferers experiencing severe feeding and swallowing difficulties as well as limited locomotor activity.

Mutations in a specific gene, called MY018B, have recently been found to be present in people exhibiting symptoms of this disease, but the role these mutations play in muscle fibre integrity has until now been unclear.

In this new research, the Ingham team, based in Singapore and Exeter, has used high-resolution genetic analysis to create a zebrafish model of MYO18B malfunction; this research takes advantage of the remarkable similarity between the genomes of zebrafish and humans,which have more than 70 per cent of their genes in common.

The Singapore/Exeter team found that the MYO18B gene is active specifically in the 'fast-twitch' skeletal muscles of the zebrafish, typically used for powerful bursts of movement. Crucially, by studying fish in which the MYO18B gene is disrupted, they were able to show that it plays an essential role in the assembly of the bundles of actin and myosin filaments that give muscle fibres their contractile properties.

The team believe this new research offers a vital new step towards understanding the cause of myopathy in humans, which in turn could give rise to new, tailored treatments in the future.

The leading research is published in the scientific journal, Genetics.

Professor Ingham, said: "The identification of a MYO18B mutation in zebrafish provides the first direct evidence for its role in human myopathy and gives us a model in which to study the molecular basis of MYO18B function in muscle fibre integrity."

A pioneer in the genetic analysis of development using fruit flies and zebrafish as model systems, Prof Ingham is internationally renowned for his contributions to several influential discoveries in the field of developmental biology over the last century.

This is the latest research by Professor Ingham that has revealed important links between the processes that underpin normal embryonic development and disease.

His co-discovery of the 'Sonic Hedgehog' gene, recognised as one of 24 centennial milestones in the field of developmental biology by Nature, in 2004, led directly to the establishment of a biotechnology company that helped develop the first drug to target non-melanoma skin cancer.

The research comes at the University of Exeter holds the official opening of the Living Systems Institute with an Opening Symposium event, from July 5-6 2017.

Two Nobel Laureates, Sir Paul Nurse FRS and Christiane Nsslein-Volhard ForMemRS, who separately won the Nobel Prize for Physiology or Medicine, will deliver keynote speeches as part of the opening event.

The high-profile event, held at the University's Streatham Campus marks the official opening of the LSIa 52 million inter-disciplinary research facility designed to bring new, crucial insights into the causes and preventions of some of the most serious diseases facing humanity.

A Zebrafish Model for a Human Myopathy Associated with Mutation of the Unconventional Myosin MYO18B is published in Genetics.

Explore further: Zebrafish help identify mutant gene in rare muscle disease

Journal reference: Genetics

Provided by: University of Exeter

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Research could give insight into genetic basis of of the human muscle disease, myopathy - Medical Xpress

By Felice J. Freyer Globe Staff July 04, 2017

How did the human brain develop skills far beyond those of any other primate? Which genes enabled language, science, and art?

Those are some of the central questions facing the newly created Allen Discovery Center for Human Brain Evolution, a joint initiative of Boston Childrens Hospital and Harvard Medical School.

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The Paul G. Allen Frontiers Group , a Seattle-based funder of scientific research, announced Wednesday that it is awarding $10 million over four years to launch the center.

The Allen Discovery Center will bring together researchers in neuronal molecular biology, human evolution, genetics, and genomics to figure out what exactly makes humans unique which genes were involved, when they came into play, and how they were affected by experience and environment.

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Its just amazing to try to contemplate how humans developed with all the unique capacities that we have, said Dr. Christopher A. Walsh, chief of the Division of Genetics and Genomics at Boston Childrens Hospital and the centers leader.

The grant, he said, forces interactions between people doing very good work in their own separate areas.

For example, Walshs team at Childrens identified the genetic cause of a rare condition that results in babies born with tiny brains. The condition occurs when a certain gene is disabled. Could that gene have been responsible for the development of humans larger brains? Maybe nature boosted its function as a way of making the brains of our human ancestors get bigger, he said.

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The Allen Discovery Center will make it easier for Walsh to answer that question by teaming up with center co-leader David E. Reich, a Harvard Medical School genetics professor, who studies the evolution of populations.

Michael Greenberg, a Harvard neurobiologist and also a center co-leader, said in a statement that the Allen grant would enable three laboratories that have been working independently to come together and study the genetic, molecular, and evolutionary forces that have given rise to the spectacular capacities of the human brain.

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$10 million gift launches joint Harvard, Children's Hospital brain center - The Boston Globe

By: IANS | New York | Published:July 4, 2017 10:51 pm Mutations in the gene called GDF5 resulted in shorter bones that led to a compact body structure while reducing the risk of bone fracture from falling. Thus, it also favoured early humans to better withstand frostbite. (Source: File photo)

A genetic change associated with shorter stature and increased risk of arthritis might have helped our ancestors survive the Ice Age, a study has showed. The findings showed that mutations in the gene called GDF5 resulted in shorter bones that led to a compact body structure while reducing the risk of bone fracture from falling. Thus, it also favoured early humans to better withstand frostbite as well as helped them migrate from Africa to colder northern climates between 50,000 and 100,000 years ago.

These advantages in dealing with chilly temperatures and icy surfaces may have outweighed the threat of osteoarthritis, which usually occurs after a prime reproductive age, the researchers said. The variant that decreases height is lowering the activity of GDF5 in the growth plates of the bone.

Interestingly, the region that harbours this variant is closely linked to other mutations that affect GDF5 activity in the joints, increasing the risk of osteoarthritis in the knee and hip, said Terence Capellini, Associate Professor at the Harvard University. For the study, published in the journal Nature, the team examined gene GDF5 first linked to skeletal growth in the early 1990s to learn more about how the DNA sequences surrounding GDF5 might affect the genes expression.

They identified a single nucleotide change that is highly prevalent in Europeans and Asians but rarely occurs in Africans. Introducing this nucleotide change into laboratory mice revealed that it decreased the activity of GDF5 in the growth plates of the long bones of foetal mice. The potential medical impact of the finding is very interesting because so many people are affected, said David Kingsley, Professor at the Stanford University.

This is an incredibly prevalent, and ancient, variant. Many people think of osteoarthritis as a kind of wear-and-tear disease, but theres clearly a genetic component at work here as well. Now weve shown that positive evolutionary selection has given rise to one of the most common height variants and arthritis risk factors known in human populations, Kingsley said.

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Genetics causing arthritis possibly helped humans survive Ice Age - The Indian Express

Approaches to Unity

Over the millennia, people have found many different ways to solve coordination problems. Broadly speaking, there was a shift from a more cooperative hunter-gatherer toward a more coercive world after the agricultural revolution (which began around 9500 B.C. in the Middle East) followed by a shift back toward more cooperative versions in the last few hundred years. Between about 1000 B.C. and A.D. 1500, most people in the world lived in empires in which a small elite monopolizing military, administrative, religious and sometimes commercial functions used state power to integrate the activities of vast numbers of people in villages and towns. The Roman and Han Chinese empires coordinated tens of millions of subjects; the Song, Ming and Qing dynasties in China ruled over 100 million.

These empires tried to lower the costs of obtaining their subjects' obedience by promoting shared identities, but local, kin-based loyalties typically retained more appeal than the center. This became a fatal flaw when, in the last 200 years, empires had to compete with nation-states, which fused politics and ethnicity by insisting that the citizens of each state all shared a common ethnicity. Nation-states were, on the whole, much better than empires at persuading their citizens to make sacrifices for the common good, and the strains of competing against nation-states brought about the collapse of all the great traditional empires between 1911 (Qing China) and 1922 (Ottoman Turkey).

In reality, of course, the populations of nation-states were anything but homogeneous, and so their leaders always had to struggle to find ways to override genetic imperatives and make different people feel similar. We might range their responses along a spectrum from the illiberal to the liberal. Illiberal responses aimed to create homogeneity by destroying difference, in extreme cases by expelling or killing people who did not conform to the ideal. Communist Russia and China defined the ideal in terms of class and killed tens of millions of non-proletarians; fascist Germany defined it in terms of race and killed six million Jews.

Liberal responses, by contrast, aimed to create homogeneity by arguing that difference just did not matter. Two hundred years ago, even the most liberal societies excluded the bulk of their populations from full membership on the basis of race, sex, class, religion or some other variable. Since then, legislation and changing attitudes have steadily rolled back the exclusions. Thanks particularly to the defeat of fascism in World War II and Soviet communism in the Cold War, the illiberal vision of the nation-state was broadly discredited in the West, and for seventy years its democracies not only leaned toward liberal solutions but even pursued equality of outcome through aggressive programs of affirmative action.

For a good fifty years, anyone such as Barry Goldwater in the United States in 1964 and Enoch Powell in Britain in 1968 who emphasized racial differences between citizens courted political suicide. But that is now changing. Enough of the liberal consensus survives that politicians still have to treat race carefully, but in 2016 almost half of American voters supported a presidential candidate who promised to spend between $4 billion (his own lowest estimate) and $21.6 billion (the Department of Homeland Security's estimate) to build a wall to keep out Mexicans, and slightly more than half of the British electorate said it was ready to accept the major economic costs of leaving the European single market in order to limit immigration to 100,000 people per year. Something important is happening in politics.

Something important is happening in the scientific study of race too. In June 2000, in a speech celebrating the completion of the first survey of the entire human genome, President Bill Clinton announced that "one of the great truths to emerge from this triumphant expedition inside the human genome is that in genetic terms, all human beings, regardless of race, are more than 99.9 percent the same." This remains true; however, it is also true that humans and chimpanzees are genetically more than 98.8 percent the same. The 1.2 percent, however, makes all the difference in the world; and as they map genetic distributions in increasing detail, scientists have increasingly asked whether the 0.1 percent difference separating human genomes might not also matter.

As yet there is no clear answer to this question, as I learned in June at a conference at the Institute for Advanced Study in Toulouse. There, a group of distinguished economists, biologists, evolutionary anthropologists and psychologists debated the causes of institutional change, and several of the speakers discussed cross-country correlations between genetic differences and institutional differences. This is controversial stuff; any scientist who raises the possibility that genetic distance might have institutional and cultural consequences runs the risk of being dismissed as a Goldwater/Powell kind of crank, not fit for civilized company. However, at a time when racial arguments seem to be on the rise in Western politics, there can surely be few questions more important than this, and I was delighted to learn that scholars of this caliber were willing to take the risks.

However, not everyone is ready to do so. From Toulouse, I went directly to a conference at the British Academy in London, where another distinguished gathering, this time of historians, sociologists and experts in cultural studies were debating the concept of the "Anglosphere." This is a new name for the old idea that something vitally important connects Britain, the United States, Canada, Australia and New Zealand. In a famous book, Winston Churchill called this group The English-Speaking Peoples; other scholars since the late 19th century have preferred to speak of the Anglo-Saxon Race.

The newest term, "Anglosphere," leaves the question of whether we are investigating a racial or a linguistic category deliberately ambiguous. Speakers who thought "Anglosphere" was a useful concept tended to emphasize linguistic ties, arguing that these had created cultural and institutional similarities, which, in the wake of Brexit, should be deepened. Some even argued for that the time is ripe for a formal political union of Canzuk (Canada, Australia, New Zealand and the United Kingdom). Other speakers, however, insisted that the "Anglosphere" is a deeply racist idea, designed merely to legitimate White Anglo-Saxon Protestant oppression of minorities within these countries.

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Getting Serious About Race - Stratfor Worldview (press release) (subscription) (blog)

For many women particularly those who are older, pregnant or overweighta sudden sneeze or laugh can trigger a squirt of urine. And forget about jumping jacks.

Thanks to a genome-wide association study (GWAS) that identifies a gene that may contribute to stress urinary incontinence (the sneezing kind) or even the less common urge incontinence(aka overactive bladder), women may be able to add a re-purposed drug or two to the list of gadgets, medications, and procedures that can lower leak frequency.

The best way to minimize stress incontinence, is to do Kegel exercises, which contract the pelvic floor muscles. Also helpful is the bridge pose in Pilates (head and feet down, abdomen up). Wearing absorbent pads may work, as can losing weight and avoiding foods and drinks that promote peeing.

Of course, there are appsfor leaks. iDry, BladderPal, and Kegel Kat chart trips to the bathroom, schedule Kegel reminders,or, in one app that Charmin sponsors, locate the nearest restroom.

Devices to treat urinary incontinence are held in the vagina to keep things in place, and resemble certain sexual aids that somewhat rhyme with mildew. Advertisements for one FDA-approved product that signals the bladder not to spasm proclaims itselfa trip to the gym for your pelvic floor.

Clinicaltrials.gov, my go-to site for upcoming treatments, lists suchinterventionsas a rectal balloon, a hydrogel shot into the urethra, electrical stimulation, and various single-incision devices. I was excited to see one study coaxing human induced pluripotent stem cells to become skeletal muscle progenitor cells, which presumably can be implanted into the muscles failing at supporting the offending organ.

Related approaches to treat urinary incontinence are already available: Electrodesin the vagina or rectum. Various meshes, slings, hammocks, tapes, and ribbons Drugs(the old antidepressant imipramine, estrogen gel, anticholinergics, and antimuscarinics) Designer vagina surgery that in one unfortunate woman triggered a lasting sensation akin to an internal invasion of fire ants

The non-surgical Nu-Vseemed promising until I noticed the spelling errors on the website, at the literary level of a Trump tweet.

At the recent European Society of Human Genetics annual meeting in Copenhagen, Rufus Cartwright,a visiting researcher at Imperial College, London, reported that his team genotyped 8,979 women, consulted six additional studies, and sampled bladder cells in some participants to identify expressed genes.

The idea behind a GWAS is to narrow down parts of the genome that include specific gene variants that are found nearly exclusively among people with a particular condition in this case, urinary incontinence. Complementing that analysis is cataloguing which genes are active in those with incontinence but not others the transcriptome.

Three genes of interest emerged:

CHRM3 encodes a cholinergic receptor. Its already the main drug target for urge incontinence. SULF2 encodes a signaling enzyme and Im not sure how its connected to incontinence. Maybe the published paper will eventually explain it. EDN1 specifies endothelin 1, a protein produced on the interior surfaces of blood vessels that is the most potent smooth muscle vasoconstrictor known. Its expressed differently in bladders of women with stress incontinence. Bingo!

Implicating endothelin 1 is exciting, because drugs that target its pathway are already used to treat pulmonary hypertensionand Raynauds syndrome, both of which arise from constricted blood vessels.

Cartwright described the work:

Previous studies had failed to confirm any genetic causes for incontinence. Although I was always hopeful that we would find something significant, there were major challenges involved in finding enough women to participate, and then collecting the information about incontinence. It has taken more than five years of work, and has only been possible thanks to the existence of high quality cohort studies with participants who were keen to help. Clearly this will need further debate and an analysis, not just of the cost to healthcare systems, but also of the benefit to women who may be spared the distress of urinary incontinence.

Finding a gene variant that could be behind urinary incontinence is more than a possible route to a repurposed new treatment. It is also a shout-out to the value of basic biomedical research something threatened in the proposed federal budget.

The awkwardly-acronymed genome-wide association study GWAS was at first more or less a fishing expedition, directing attention to a vast swath of genomic territory that might harbor a gene that could explain why a bunch of people with the same trait or condition share it significantly more often than do others. The roots of the technique go back to the earliest days of human genome sequencing, as researchers identified single nucleotide polymorphisms (SNPs) single DNA base differences in a population at specific sites among the 3.2 billion A, T, G, and C nitrogenous bases.

A GWAS is especially helpful to understand the causes of more common conditions, the ones that arise from interactions of more than one gene and the environment and that dont exhibit the simple inheritance patterns of rare, single-gene diseases. A GWAS result can often be articulated in just a sentence or two, but it represents an incredible amount of work.

Now, with so many human genome sequences annotated since thefirst GWASwas published a dozen years ago, the technologys time has truly come. Find enough participants, and a GWAS can zero in on important, possibly causative, genes. The evolution of GWAS is a little like that of Google maps, from imaging a town to highlighting a specific house.

The idea for a GWAS was hatched long before genome analysis became fast enough and deep enough to reveal enough information to dissect the molecular underpinnings of common conditions like incontinence. A short-sighted federal budget that slashes funding for the type of basic research that led to this and other biotechnologies is not in anyones best interest.

Ricki Lewis is a long-time science writer with a PhD in genetics. She writes the DNA Science blog at PLOS and contributes regularly to Rare Disease Report and Medscape Medical News. Ricki is the author of the textbook Human Genetics: Concepts and Applications (McGraw-Hill, 12thedition out late summer); The Forever Fix: Gene Therapy and the Boy Who Saved It (St. Martins Press, 2013) and the just-published second edition of Human Genetics: The Basics (Routledge Press, 2017). She teaches Genethics online for the Alden March Bioethics Institute at Albany Medical College and is a genetic counselor at CareNet Medical Group in Schenectady, NY. You can find her at her website or on Twitter at @rickilewis

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Bladder control: Is there a genetic treatment for urinary incontinence? - Genetic Literacy Project

Three courts in Britain agreed with the hospital, as did the European Court of Human Rights, which last week rejected a last-ditch appeal by Charlies parents.

But Pope Francis and Mr. Trump have also weighed in, adding another dimension to an extraordinarily thorny bioethical and legal dispute that pits Britains medical and judicial establishment against the wishes of the childs parents.

Judges in the case have acknowledged that the case highlights differences in law and medicine and an American willingness to try anything, however unlikely the possibility of success but have held that prolonging the infants life would be inhumane and unreasonable. The case echoes the one of Terri Schiavo, a Florida woman who was left in a persistent vegetative state after a cardiac arrest and was also the subject of a court battle.

A Vatican spokesman, Greg Burke, told Vatican Radio on Sunday that the pope had been following the parents case with affection and sadness, praying that their desire to accompany and care for their own child to the end is not ignored.

Italys top pediatric hospital, which is run by the Vatican, told the Italian news agency ANSA on Monday that it would be willing to take Charlie.

We understand that the situation is desperate, said Mariella Enoc, director of the Bambino Ges hospital in Rome, noting that she had been in touch with British officials to signal a willingness to take the patient, the agency reported. We are close to the parents in prayer and, if this is their desire, we are open to receiving their child at our structure for the time it will take for him to live.

Mr. Trump, who was not known to have previously expressed a view on the matter, wrote on Twitter on Monday that if the United States could help, we would be delighted to do so.

Both the pope and the president stopped short of criticizing the court rulings or the hospital. Helen Aguirre Ferr, the director of the White House office of media affairs, said Mr. Trump had decided to speak out after he learned about this heartbreaking situation. Mr. Trump has not spoken with the family, she said, and does not want to pressure them in any way.

The president is just trying to be helpful if at all possible, she added.

Charlie was born on Aug. 4 with encephalomyopathic mitochondrial DNA depletion syndrome. He is thought to be one of only 16 children globally with the condition, the result of a genetic mutation.

Brendan Lee, the chairman of the department of molecular and human genetics at Baylor College of Medicine, who is not involved in the case, said in a phone interview that mitochondrial depletion syndrome has no cure. Treatments involve different types of vitamin supplementation, but none have been shown to definitively work through studies, he said.

Charlies parents, Connie Yates and Chris Gard, both in their 30s, have been waging a long and wrenching legal battle to keep him alive. They have raised more than 1.3 million pounds, or about $1.7 million, to help finance experimental treatment in the United States. There is also an international campaign, with an online petition, and there have been street protests in front of Buckingham Palace.

Charlie has been treated since October at Great Ormond Street Hospital, where doctors eventually decided that withdrawing life support was the only justifiable option. Although Charlies parents have parental responsibility, overriding control is by law vested in the court exercising its independent and objective judgment in the childs best interests, the hospital said in a statement laying out its position.

Siding with the hospital were the High Court, on April 11; the Court of Appeal, on May 25; and the Supreme Court of the United Kingdom, on June 8.

The High Court ruled that Charlie would face significant harm if his suffering were to be prolonged without any realistic prospect of improvement. Moreover, it said the experimental treatment, known as nucleoside therapy, would not be effective.

Money is not at issue; an academic medical center in the United States has offered to provide the experimental treatment. But a neurologist at the hospital, who has offered to oversee the treatment, told the court by telephone: I can understand the opinion that he is so severely affected by encephalopathy that any attempt at therapy would be futile. I agree that it is very unlikely that he will improve with that therapy.

Neither the hospital nor the neurologist was identified in court documents, and the White House has declined to identify either.

The Court of Human Rights ruled last week that the British courts had acted appropriately in concluding that it was most likely Charlie was being exposed to continued pain, suffering and distress, and that undergoing experimental treatment with no prospects of success would offer no benefit, and continue to cause him significant harm.

The case has drawn attention to important differences in legal systems.

Claire Fenton-Glynn, a legal scholar at the University of Cambridge who studies childrens rights, said that under British law, the courts were the final arbiter in medical disputes about the treatment of children.

She noted a 2001 case of conjoined twins, Jodie and Mary, who were born sharing an aorta. Separating the twins would lead to the death of the weaker twin; if they were not separated, both would die. A court ruled that the twins should be separated against the wishes of their parents; as expected, one died.

Courts in the United States are less inclined to get involved when there are disputes between parents and doctors, said Professor Moreno of the University of Pennsylvania, stressing that it was usually left to doctors, in consultation with parents, to decide on a childs treatment.

He noted the case of Baby Jane Doe, who was born in 1983 with spina bifida and whose parents declined to approve surgery to prolong her life. That case led to a law, signed by President Ronald Reagan, that defined instances in which withholding medical treatment from infants could be considered child abuse, but also provided that in certain cases doctors and parents might choose to withhold treatment from seriously handicapped babies when such action would merely prolong dying.

G. Kevin Donovan, the director of the Pellegrino Center for Clinical Bioethics at Georgetown University Medical Center and a professor of pediatrics, said that in the United States, if parents insisted on continuing life-prolonging treatment against a doctors advice, the child would simply be transferred to another institution willing to comply with the parents wishes.

It doesnt seem to be a supportable position morally or ethically, he said of the stance taken by the hospital in London, adding that what is legal and what is ethical are not always the same.

In the Schiavo case, her husband, who was her legal guardian, wanted to have her feeding tube removed, but her parents disagreed, setting off a seven-year fight that ended in 2005, after courts ruled in the husbands favor. Life support was removed from Ms. Schiavo, who died at 41.

In that case, too, the pope, then John Paul II, and the president, George W. Bush, weighed in. Mr. Bush signed an act of Congress allowing federal courts to intercede in the case. But their interventions did not ultimately affect the outcome.

There was no immediate response to Mr. Trumps statement from Charlies parents, who last week appeared to accept the finality of the courts rulings. Photographs of the couple sleeping with their sick child have circulated on social media recently.

We are really grateful for all the support from the public at this extremely difficult time, Ms. Yates said on Friday. Were making precious memories that we can treasure forever with very heavy hearts. Please respect our privacy while we prepare to say the final goodbye to our son Charlie.

There was also no immediate reaction from the hospital.

In Charlies case we have been discussing for many months how the withdrawal of treatment may work, the hospital said. There would be no rush for any action to be taken immediately. It added that it would consult the family and that discussions and planning in these situations usually take some days.

Follow Dan Bilefsky @DanBilefsky and Sewell Chan @sewellchan on Twitter.

Reporting was contributed by Aneri Pattani and Roni Caryn Rabin from New York, Michael D. Shear from Washington, and Elisabetta Povoledo from Rome.

A version of this article appears in print on July 4, 2017, on Page A1 of the New York edition with the headline: Dispute Over British Babys Fate Draws In President and Pope.

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Dispute Over British Baby's Fate Draws In Pope and US President - New York Times

When the first humans left Africa around 100,000 years ago, they got shorter.

The evolutionary shift helped them cope with the colder conditionsa more compact body size helped protect them from frostbite, whileand shorter limbs would be less breakable when they fellbut it also appears to have come with a downside: arthritis.

In a study published in Nature Genetics on Monday, scientists at Stanford University, California, have shown how variants within the GDF5 gene, which are related to reduced growth, was repeatedly favored by our ancestors as they migrated out of Africa and across the continents.

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But GDF5 has also been linked with osteoarthritis,a degenerative joint disease that affects an estimated 27 million Americans. Risk increases with ageit is sometimes referred to as wear and tear arthritisbut it also has a strong genetic component.

Previous research has shown how mutations in part of the GDF5 gene cause malformation in bone structure in mice. In humans, it has been associated with a shortness and joint problems, and two changes in particular are linked with a heightened risk of osteoarthritis.

In the latest research, the scientists find GDF5 provided an evolutionary boost for our ancestors, with arthritis apparently a byproduct of it."The gene we are studying shows strong signatures of positive selection in many human populations," senior author David Kingsley said in a statement

"It's possible that climbing around in cold environments was enough of a risk factor to select for a protective variant even if it brought along an increase likelihood of an age-related disease like arthritis, which typically doesn't develop until late in life."

A display of a series of skeltons showing the evolution of humans at the Peabody Museum, New Haven, Connecticut, circa 1935. Study finds humans became shorter when they first left Africa 100,000 years ago. Hulton Archive/Getty Images

To better understand GDF5, the team studied the DNA sequences that might affect how the gene is expressedspecifically those that are known as promoters and enhancers. From this they found a previously unidentified region they called GROW1.

When they looked for GROW1 in the 1,000 Genomes Project databasea huge database of genetic sequences of human populations around the worldthe team found a single change that is very common in European and Asian populations, but is hardly ever seen in Africans. The team then introduced this change to mice and found it led to reduced activity in the growth of bones.

They then looked at the change to the genetic variant over the course of human evolution, and found it had been repeatedly favored after Homo sapiens left Africa between 50,000 and 100,000 years ago. The team says the benefits of being shorter in colder conditions probably outweighed the risk of developing osteoarthritis in later life.

Because evolutionary fitness requires successful reproduction, alleles that confer benefits at young or reproductive ages may be positively selected in populations, even if they have some deleterious consequences in post-reproductive ages, they wrote.

Researchers believe this change could help explain why osteoarthritis is rarely seen in Africa, but is more common in other populations.Concluding, Kingsley said: "Because it's been positively selected, this gene variant is present in billions of people. So even though it only increases each person's risk by less than twofold, it's likely responsible for millions of cases of arthritis around the globe.

"This study highlights the intersection between evolution and medicine in really interesting ways, and could help researchers learn more about the molecular causes of arthritis."

Read more:
Human Evolution: Africa Exodus Made Homo Sapiens Shorter and Gave Them Arthritis - Newsweek

July 4, 2017 Genoeconomics looks for genetic ties to life outcomes and economic behavior. Credit: Janice Kun

When Daniel Benjamin was just beginning his PhD program in economics in 2001, he attended a conference with his graduate school advisers. They took in a presentation on neuroeconomics, a nascent field dealing with how the human brain goes about making decisions.

Afterward, as they took a stroll outside, they couldn't stop talking about what they had learned, how novel and intriguing it was. What would be next, they wondered. What would come after neuroeconomics?

"The human genome project had just been completed, and we decided that even more fundamental than the brain would be genes, and that someday this was going to matter a lot for social science," said Benjamin, associate professor (research) of economics at the USC Dornsife College of Letters, Arts and Science's Center for Economic and Social Research (CESR). Indeed, his excitement that day was the foundation of a visionary academic path.

Fast forward to today. Genoeconomics is now an emerging area of social science that incorporates genetic data into the work that economists do. It's based on the idea that a person's particular combination of genes is related to economic behavior and life outcomes such as educational attainment, fertility, obesity and subjective well-being.

"There's this rich new source of data that has only become available recently," said Benjamin, also co-director of the Social Science Genetic Association Consortium, which brings about cooperation among medical researchers, geneticists and social scientists.

Collecting genetic data and creating the large data sets used by economists and other social scientists have become increasingly affordable, and new analytical methods are getting more and more powerful as these data sets continue to grow. The big challenge, he said, is figuring out how scientists can leverage this new data to address a host of important policy questions.

"We're ultimately interested in understanding how genes and environments interact to produce the kinds of outcomes people have in their lives, and then what kinds of policies can help people do better. That is really what economics is aboutand we're trying to use genetics to do even better economics."

The mission at hand

Only a handful of economists are working with genetics, but this brand of research is perfectly at home at CESR. The center, founded three years ago, was conceived as a place where visionary social science could thrive and where research could be done differently than in the past.

"Being in a place where that's the shared vision is pretty rare," said econometrician Arie Kapteyn, professor (research) of economics and CESR director. "There's no restriction on which way you want to go or what you want to do. It doesn't mean that there are no restrictions on resources, but it's the opportunity to think about your vision of what's really exciting in social science research. Then being able to actually implement it is absolutely fantastic."

The mission of CESR is discovering how people around the world live, think, interact, age and make important decisions. The center's researchers are dedicated to innovation and combining their analysis to deepen the understanding of human behavior in a variety of economic and social contexts.

"What we try to do is mold a disciplinary science in a very broad sense," Kapteyn said. "Because today's problems in society, they're really all multidisciplinary."

Case in point: Benjamin's work combining genetics and economics.

The flagship research effort for Benjamin's CESR research group deals with genes and education. In a 2016 study, the team identified variants in 74 genes that are associated with educational attainment. In other words, people who carry more of these variants, on average, complete more years of formal schooling.

Benjamin hopes to use this data in a holistic way to create a predictive tool.

"Rather than just identifying specific genes," he said, "we're also creating methods for combining the information in a person's entire genome into a single variable that can be used to partially predict how much education a person's going to get."

The young field of genoeconomics is still somewhat controversial, and Benjamin is careful to point out that individual genes don't determine behavior or outcome.

"The effect of any individual gene on behavior is extremely small," Benjamin explained, "but the effects of all the genes combined on almost any behavior we're interested in is much more substantial. It's the combined information of many genes that has predictive power, and that can be most useful for social scientists."

Learning about behavior

While the cohort of researchers actively using the available genome-wide data in this way is still somewhat limited, Benjamin says it is growing quickly.

"I think across the social sciences, researchers are seeing the potential for the data, and people are starting to use it in their work and getting excited about it, but right now it's still a small band of us trying to lay the foundations.

"We're putting together huge data sets of hundreds of thousands of peopleapproaching a million people in our ongoing work on educational attainmentbecause you need those really big sample sizes to accurately detect the genetic influences."

As CESR works to improve social welfare by informing and influencing decision-making in the public and private sectors, big data such as Benjamin's is a growing part of that process, according to Kapteyn.

"What big data reflects is the fact that nowadays there are so many other ways in which we can learn about behavior," he said. "As a result, I think we'll see many more breakthroughs and gain a much better understanding of what's going on in the world and in social science than in the past.

"I think we're really at the beginning of something pretty spectacular. What we are doing is really only scratching the surfacethere's so much more that can be done."

Explore further: Scientists find genes associated with educational attainment

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Can genetics play a role in education and well-being? - Medical Xpress