Category Archives: Gene Medicine

In a recent monologue, the comedian James Corden addressed his struggles with being overweight. Despite his best efforts, he said, he has never been able to control his weight confessing that he has good days and bad months. The monologue was a response to an on-air editorial by Bill Maher, who argued that fat shaming needs to make a comeback, excoriating the obese for their lack of self-control. Which of them was correct? Are the obese to blame for their condition?

No. Recent research has revealed that obesity is to a very large extent encoded in our genes. Indeed, studies of identical twins reveal that the heritability of obesity ranges between 7080 percent, a level that is exceeded only by height and is greater than for many conditions that people accept as having a genetic basis. While there has also been an overall increase in the prevalence of obesity over the last several decades, it is the particular set of weight-regulating genes that a person inherits that determines who is lean and who is obese in 2019 America.

Could it be then, as Maher implies, that thin people control their urge to eat and the obese do not? For those who believe that being thin is a result of greater self-control, consider the case of a massively obese four-year-old boy in England, who weighed 80 pounds. After consuming a single test meal of 1,125 calories (half the daily intake of an average adult), he asked for more. This boy had a similarly affected eight-year-old cousin who weighed more than 200 pounds. Both children carry a genetic defect causing their obesity that runs in the family. The defective gene encodes the adipocyte hormone leptin, and the children do not produce it.

However, when they receive leptin injections, their appetite is reduced to normal, and they lose enormous amounts of weight. The boy in fact is now quite thin. These findings confirm that biologic factors play the key role in determining ones appetite undercutting the common misconception that food intake is primarily under voluntary control.

In normal people without leptin mutations, the hormone is secreted by fat cells into the bloodstream and then acts on specialized brain cells that regulate appetite. When the amount of fat increases, leptin production increases, and food intake goes down. When weight is lost, leptin decreases, which then stimulates appetite. This physiologic system acts in a manner analogous to a thermostat (or lipostat) that maintains body weight within a relatively narrow range.

This system serves a vital evolutionary function by maintaining optimal levels of adipose tissue, thus providing a source of calories when food is not available, a not uncommon occurrence during human evolution. However, the decreased mobility associated with excess fat can increase the risk posed by predators. The leptin system appears to have evolved to balance the risk of being too thin (starvation) and the risk of being too obese (predation). Indeed, the weight of all mammals is precisely regulatednotwithstanding that only humans have ever expressed a conscious desire to lose weight.

Specific genetic differences that predispose to obesity or leanness are then propagated by natural selection depending on whether starvation or predation was the greater risk. The weight of each individual is then stably maintained by the leptin system with remarkable precision. The average person takes in a million or more calories per year, maintaining weight within a narrow range over the course of decades. The body balances calorie consumption with expenditure, and with accuracy greater than 99.5 percenta precision far greater even than that on labels showing the calorie content of the food we eat.

Mutations in hormones are rare and there are only a few dozen patients who fail to produce leptin. So, while studies of these individuals establish a role for leptin to control appetite in human, defects in the gene itself are a very infrequent cause of obesity. However, mutations in the neural circuit that is regulated by leptin are more common, including mutations in the receptor for leptin. Patients with mutations cannot receive leptins signal and so also become massively obese. But because these patients cannot receive leptins signal, treatment with the hormone is ineffective and these patients are referred to as being leptin resistant.

The leptin receptor is expressed in the hypothalamus, a primitive part of the brain that regulates most basic biologic drives, including the basic drive to eat. In the hypothalamus, there are specialized neurons expressing the leptin receptor that regulate appetite. One type promotes food intake; a second neural population reduces food intake. Leptin acts by inhibiting the one and activating the other. Similar to mutations in the leptin receptor, mutations in other key genes downstream of the hypothalamus also cause human obesity. Recent genetic studies have shown that as many as 10 percent of markedly obese children carry mutations in one or another of these individual genes. Thus, when Maher categorically asserts that obesity isnt a birth defect, he is (mostly) wrong.

Another mistake that Maher and others make is to assume that the drive to eat is the same for all. Leptin regulates the intensity of the feeding drive. In its absence, patients report being unable to control their appetite and eat voraciously. One patient described it as hunger without end, akin to the hungriest youve ever been. That is how leptin deficient people feel all the time. This sensation appears to be similar for obese patients who lose weight (e.g., The Biggest Loser), the majority of whom put the weight back on

In aggregate, the genes that control food intake and metabolism act to keep weight in a stable range by creating a biological force that resists weight change in either direction. Moreover, the greater the amount of weight that is lost, the greater the sense of hunger that develops. So, when the obese lose large amounts of weight by conscious effort, their bodies fight back with a vengeance. If you think it is difficult to lose15 pounds, imagine what it must feel like to lose 50 or 100!

Can willpower restrain this drive over the long term? The evidence says that for the vast majority of people the answer is no. Yes, a relatively small proportion of patients do maintain long term weight loss. But willpower is not metaphysical, it is encoded in our cerebral cortex, where conscious thought resides. How the cortex successfully communicates with the hypothalamus varies among individuals. The precise ways that this communication happens is not yet known but is an area of active investigation.

What we do know tells us that if you are thin, you should thank your "lean" genes and refrain from stigmatizing the obese. A broad acceptance of the biologic basis of obesity would not only be fair but would allow us to collectively focus on health. Even modest amounts of weight loss, far less than would satisfy Maher, can improve health and this should be the objective for obese people who suffer from its medical complications.

While research is moving toward developing effective therapies for obesity, we are not there yet. In the meantime, we must change our attitudes and turn our focus from appearance and to improved health. The obese are fighting against their biology. But they also are fighting against a society that wrongly believes that being fat is a shameful, personal failing.

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Obesity Is in the Genes - Scientific American

Your genes can effect how you respond to medicine. Genetic testing can help identify the right drug at the right dose for a patient. Courtesy of Mayo Clinic

Predicting whether a patient like KerriePrettitorewill have a fatal reaction to a chemotherapy drug or even whether adrugwill work at all is the future of medicine, and its coming soon.

Genetic testing can help predict how patients will respond to a drug,whether its designed to combat cancer or other illnesses. Eventually, that will enable doctors to individualize patient treatment, choosing a medication and dose to best match a patients genetic profile. The goal is to maximize benefit while minimizing harm.

Research inseveral areasalready is having an impact:

KerriePrettitore, a Ridgewood woman,suffered from a genetic abnormality called DPD deficiency, which prevents someone from breaking down the chemotherapy drug 5-FU, or fluorouracil.Agenetic test can help identify patients who may be at risk of developing such a reaction.

Frances national drug-regulating agency began recommending last year that all patientsprescribed5-FU and related drugs be screened for DPD deficiency beforehand. Two hundred people a year die in France because they receive the drug and have DPD deficiency, according to a company that performs such tests. The company recommends that the genetic test be combined with a blood test for maximum accuracy, a practice that has been used in the Netherlands for almost a decade.

In theUnited States, testing for DPD deficiency is not currently recommended by major cancer treatment organizations.But some scientists say change will come soon.

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Genetic testsmust be inexpensive,produce results quickly and provide clinically useful informationto be cost-effective, said RobertDiasio, an authority on DPD deficiency and director of the Mayo Clinic Cancer Center. The tests currently availablefor DPD deficiencydont yet meet that standard, he said.

The testsdont identify everyone atrisk,and they may identify a mutation in a person who turns out to be able to tolerate the drug, he said. Thats because they test for only a handful of mutations. They dont testfor all possible mutations because it is expensive andyieldsinformation that scientists dont yet know how to interpret.

But the cost of a complete genetic analysis is coming downandthe turnaround time is getting quicker, he noted. Moreknowledge is needed, however,about which mutations are important and which are irrelevant to doctorsmakingprescribing decisions,Diasiosaid.

At the Mayo Clinics Center for Individualized Medicine,astudy of 10,000 Minnesota patientsis underway. It will integratepatients genetic informationinto theirelectronic medical recordsto inform physicians about significant linkages when certain medications are prescribed.

As research advances, more linkages will be discovered and included in the individual records. The goal isto help patients get the right drug at the right dose for their disease personalized medicine at its best.

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Does drinking more alcohol shrink the brain, or does a smaller brain volume actually predispose individuals to drink more alcohol?

Excessive alcohol consumption carries many risks, including heart and liver problems, a higher risk of cancer, and even brain damage.

Research has suggested that there is an association between high alcohol intake and reduced white and gray matter in the brain.

So far, most specialists have maintained that alcohol consumption leads to this decrease in brain volume, but could that conclusion be wrong?

Recently, a team of investigators from Washington University in St. Louis, MO, and Duke University in Durham, NC, has conducted a study that suggests that alcohol may not be the culprit behind lower brain volume.

Instead, the findings indicate that both reduced brain volume and a predisposition toward consuming higher quantities of alcohol may have the same underlying cause: genetic makeup.

"Our results suggest that associations between alcohol consumption and reduced brain volume are attributable to shared genetic factors," says senior author Ryan Bogdan.

"Lower brain volume in specific regions may predispose a person to greater alcohol consumption," he goes on to note.

"The study is impressive because it uses a variety of approaches and data analysis techniques to reach findings that all converge on the same conclusion," Bogdan also adds.

In the study the findings of which appear in the journal Biological Psychiatry the researchers analyzed the data from three separate brain imaging studies. These studies included one that recruited twins and non-twin siblings with different alcohol intake behaviors and one that involved children who had not had exposure to alcohol at baseline.

In the third study, the researchers had conducted analyses to determine gene expression in the brain using tissue samples that they had collected postmortem from donated organs.

In total, the investigators had access to data on 2,423 individuals. The three studies that the researchers accessed the data through were: the Duke Neurogenetics Study, the Human Connectome Project, and the Teen Alcohol Outcomes Study.

"Our study provides convergent evidence that there are genetic factors that lead to both lower gray matter volumes and increased alcohol use," says lead author David Baranger.

More specifically, the team found that individuals who had a higher alcohol intake had lower gray matter volume in the dorsolateral prefrontal cortex and the insula, which are two brain regions that play key roles in emotion, memory retrieval, reward cycles, and decision-making.

The researchers noted that, according to their analysis, lower gray matter in these two brain regions was actually due to a specific genetic makeup, which, in turn, was also associated with an increased risk of higher alcohol consumption, both in adolescence and in young adulthood.

"These findings don't discount the hypothesis that alcohol abuse may further reduce gray matter volumes, but it does suggest that brain volumes started out lower to begin with," Baranger clarifies.

"As a result," he adds, "brain volumes may also serve as useful biological markers for gene variations linked to increased vulnerability for alcohol consumption."

In the conclusion to their study paper, the investigators note that we should, perhaps, pay more attention to genetic risk factors when assessing the risk for higher alcohol consumption.

They write:

"Taken alongside evidence that heavy alcohol consumption induces gray matter volume reductions, our data raise the intriguing possibility that genetically-conferred reductions in regional gray matter volumes may promote alcohol use from adolescence to young adulthood, which may, in turn, lead to accelerated atrophy within these and other regions."

Moreover, the authors note that although the current findings relate specifically to alcohol consumption, they could also apply to the risk of using other substances, which the same genetic risk factors may drive.

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Alcohol intake and reduced brain volume: What explains the link? - Medical News Today

Nathaly Sweeney, a neonatologist at Rady Children's Hospital-San Diego and researcher with Rady Children's Institute for Genomic Medicine, attends to a young patient in the hospital's neonatal intensive care unit. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

Nathaly Sweeney, a neonatologist at Rady Children's Hospital-San Diego and researcher with Rady Children's Institute for Genomic Medicine, attends to a young patient in the hospital's neonatal intensive care unit.

When Nathaly Sweeney launched her career as a pediatric heart specialist a few years ago, she says, it was a struggle to anticipate which babies would need emergency surgery or when.

"We just didn't know whose heart was going to fail first," she says. "There was no rhyme or reason who was coming to the intensive care unit over and over again, versus the ones that were doing well."

Now, just a few years later, Sweeney has at her fingertips the results of the complete genome sequence of her sickest patients in a couple of days.

That's because of remarkable strides in the speed at which genomes can be sequenced and analyzed. Doctors who treat newborns in the intensive care unit are turning to this technology to help them diagnose their difficult cases.

Sweeney sees her tiny patients in the neonatal intensive care unit of Rady Children's Hospital in San Diego. Doctors there can figure out what's wrong with about two-thirds of these newborns without a pricey DNA test. The rest have been medical mysteries.

"We had patients that were lying here in the hospital for six or seven months, not doing very well," she says. "The physicians would refer them for rapid genome sequencing and would diagnose them with something we didn't even think of!"

Rady's Institute for Genomic Medicine, which has been pioneering this technology, has now sequenced the genomes of more than 1,000 newborns.

In a building across the street from the hospital, three $1 million sequencing machines form the core of the operation. Technicians tending to the NovaSeq 6000s can put DNA from babies (and often their parents) into the machine in the late afternoon and have a complete genome sequence back by 11 a.m. or noon the next day, says clinical lab scientist Luca Van der Kraan.

That fact is worth repeating: An entire genome is decoded in about 16 hours.

Kasia Ellsworth is one of the experts waiting in a nearby office to analyze the information. That task has shrunk from months to typically just four hours, thanks to increasingly sophisticated software.

Ellsworth inputs the baby's symptoms into the software, which then spits out a long list of genetic variants that might be related to the illness. She scrolls down the screen.

"I'm looking through a list of those variants and then basically deciding whether something may be truly contributing to the disease or not," she says.

About 40% of the time, a gene stands out, giving doctors a tentative diagnosis. Follow-up tests are often requested, and those can take several days. But in the meantime, doctors can sometimes act on the information they have in hand.

When she or a colleague makes a diagnosis, "You always feel very relieved, very happy and excited," she says. "But at the same time you kind of need to put it in perspective. What does it mean for the family, for the patient, for the clinician as well?"

Often it's a sense of relief. And for a minority of cases, it can affect the baby's treatment.

"We now are at the point where I think the evidence is overwhelming that a rapid genome sequence can save a child's life," says Dr. Stephen Kingsmore, the institute's director and the driving force behind this revolution.

By his reckoning, the results change the way doctors manage these cases about 40% of the time.

Treatments are available for only a small share of these rare diseases. In other cases, the information can help parents and doctors understand what's wrong with their baby even if there is no treatment or learn whether death is inevitable. "And there it's a very different conversation," Kingsmore says. "We help guide parents through picking an appropriate point at which to say enough is enough" and to end futile treatments.

Of course, Kingsmore highlights the happier outcomes. One example is a bouncy girl named Sebastiana, now approaching her third birthday.

As a newborn, Sebastiana Manuel was diagnosed with a rare disease after rapid genome sequencing. She is seen here at 11 months of age. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

As a newborn, Sebastiana Manuel was diagnosed with a rare disease after rapid genome sequencing. She is seen here at 11 months of age.

He showed off her case recently in front of the Global Genes conference, a meeting of families with rare genetic conditions.

"She was critically ill in our intensive care unit," he tells the audience, "and in a couple of days we gave the doctors the answer. It's Ohtahara syndrome. It comes with this specific therapy. And she hasn't had a seizure in 2 1/2 years. She doesn't take any medication."

The audience applauds enthusiastically at an outcome that sounds miraculous. But when you meet Sebastiana and her mother, Dolores Sebastian, a more complicated story emerges.

Ohtahara syndrome isn't actually what made Sebastiana ill it's a term doctors use to describe newborn seizures. Those are actually a symptom of deeper brain issues. That was apparent the day she was born.

"She was acting weird and screaming and crying and turning purple and we weren't sure why," her mother says.

The hospital where Sebastiana was born rushed her to the neonatal intensive care unit, across town at Rady. She was having frequent seizures. The following days were a nightmare for Sebastian and her husband.

"I can't even describe it," she says. "I always keep on saying that at that moment I was kind of like dead, but I was walking."

The hospital ran a battery of tests to look for severe brain damage. They couldn't get to the bottom of it.

"They came in and offered us the genomic testing," Sebastian said. "They never told us how quick it would be."

She was surprised when the results were back in four days. The doctor told her they had identified a gene variant that can trigger seizures as well as do other harm to the brain.

"He said this is how we're going to go ahead and change her medications now and treat her," she says. And that made a "huge difference, [an] amazing difference."

Sebastiana was already on a medication that was helping control her seizures, but they sedated her to the extent that she needed a feeding tube. On the new medication, carbamazepine, she was alert and able to eat, and her seizures were still under control. Sebastian says her daughter is still taking that drug.

Controlling her seizures isn't a cure. Children who have this genetic variant, in a gene called KCNQ2, can have a range of symptoms from benign to debilitating. Sebastiana falls somewhere in between. For example, she has only a few words in her vocabulary as she approaches the age of 3.

"She took her first steps when she was 2 years old, so she's delayed in some things," Sebastian says, "but she's catching up very quickly. She has [physical therapy]; she's going to start speech therapy. She gets a lot of help but everything's working."

Sebastiana Manuel (second from left) with members of her family: Domingo Manuel Jr. (from left), Dolores Sebastian and Tony Manuel. Jenny Siegwart/Rady Children's Institute for Genomic Medicine hide caption

Sebastiana Manuel (second from left) with members of her family: Domingo Manuel Jr. (from left), Dolores Sebastian and Tony Manuel.

KCNQ2 variants are the most common genetic factor in epilepsy, causing about a third of all gene-linked cases and about 5% of all epilepsies. Sebastiana's case could have been diagnosed with a less expensive test. For example, Invitae geneticist Dr. Ed Esplin says his company offers a genetic screen for epilepsy that has a $1,500 list price and a two-week turnaround.

Rady's whole-genome test costs $10,000, Kingsmore says. But it casts a wider net, so it might provide useful information if a baby's seizures are caused by something other than epilepsy.

And Kingsmore says his test costs about as much as a single day in the NICU. "In some babies we avoid them being in the intensive care unit literally for months," he says.

Kingsmore and colleagues have published some evidence that their approach is cost-effective, based on an analysis of 42 cases.

Even so, most insurance companies and state Medicaid programs are still balking at the cost. Kingsmore says private donors are helping support this effort at Rady, which sequences about 10% of the babies in the NICU, and at more than a dozen others scattered from Honolulu to Miami. They send their samples to Rady for analysis.

Kingsmore is pushing to expand his network in the next few years, to reach 10,000 babies at several hundred children's hospitals.

Other providers are also starting to offer whole-genome sequencing. But Dr. Isaac Kohane, chair of the department of biomedical informatics at Harvard Medical School, worries that the technology is too unreliable.

Knowledge of genes and disease is evolving rapidly, so these analyses run the risk of either missing a diagnosis or making a mistaken one. Kohane says there's still a lot of dubious information there a typical person has 10 to 40 gene variants that the textbooks incorrectly identify as causing disease.

Kohane is part of a medical network that helps diagnose people with baffling diseases. A study from 2018 found "a third of the patients who actually come to us already had full genome sequences and interpretations," Kohane says. "They were just not correct."

Even so, Kohane sees this use in the NICU as a relatively fruitful use of gene sequencing. "This is one of the few areas where I think the Human Genome Project is really beginning to pay off in health care," he says, "but buyer beware, it's not something ready to be practiced in every hospital." (He supports the work at Rady in fact, he is a science adviser.)

Kingsmore is already looking ahead. "We want to solve the next bottleneck, which is, 'I don't have a great treatment for this baby,' " he says. That's a far greater challenge, and it's especially difficult for a mutation that has altered a baby's development in the womb. Those problems may often not be reversible.

Kingsmore is undeterred. "It's going to be an incredibly exciting time in pediatrics," he says.

You can contact NPR science correspondent Richard Harris at rharris@npr.org.

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Genome Sequencing In NICU Can Speed Diagnosis Of Rare Inherited Diseases : Shots - Health News - NPR

In celebration of our 15 Year Anniversary, Academic Editor Ronald CW Ma highlights advancements published in PLOS Medicine in diabetes research and care, including improved precision medicine.

Happy 15th Birthday to PLOS Medicine! I still remember reading about the PLOS journals and the idea of making science accessible to all back when PLoS was first launched. It is amazing how far the Open Access movement has developed, how far that idea has advanced and how scientific publishing has been revolutionized. Congratulations PLOS Medicine on this important milestone!

Among the many articles that I have enjoyed reading in PLOS Medicine over the years, I would like to highlight two for sharing with other readers on this special occasion.

1) Event Rates, Hospital Utilization, and Costs Associated with Major Complications of Diabetes: A Multicountry Comparative Analysis

This paper by Philip Clarke and colleagues from the ADVANCE Collaborative Group, published back in 2010, highlighted the significant economic burden of diabetes and rates of hospitalization resulting from diabetes co-morbidities, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a landmark multi-centre trial on the treatment of diabetes conducted in 20 countries. Within the ADVANCE trial settings, the study demonstrated important differences in the rates of hospitalization for different diabetes complications in different regions of the world (Asia, Eastern Europe, and established market economies such as Australia, New Zealand and Canada), mirroring epidemiological observations of comparative higher nephropathy rates, higher stroke risk, and lower risks of coronary artery disease among Asians (mostly from Chinese centres in this particular trial) with type 2 diabetes, thereby highlighting the heterogeneity of risk of diabetes complications (and costs) in different populations.

This study also provided important tools to facilitate estimation of healthcare expenditure associated with diabetes in different healthcare settings. At the time of the study, it was estimated that the average annual per capita health expenditure was approximately 216 international dollars in China, and 698 international dollars in Russia, but that the annual hospital costs for people with diabetes experiencing major macrovascular complications such as coronary or cerebrovascular events would be around four and ten times these average per capita expenditures. Perhaps not fully appreciated at the time was the significant burden associated with hospitalization with heart failure, which is a topic of much current interest in relation to recent advances in the treatment of type 2 diabetes.

Although the work was focused on evaluating the economic burden of diabetes in different parts of the world, this work can be considered as an important example of early attempts to deconstruct the heterogeneity of type 2 diabetes. As the diabetes epidemic continues unabated, the healthcare burden of diabetes complications has become a major concern globally.

2) Type 2 diabetes genetic loci informed by multi-trait associations point to disease mechanisms and subtypes: A soft clustering analysis

The second article, by Jose Florez and colleagues, utilized a state-of-the-art multi-omics approach to use available genetic and epigenomic data to probe the issue of heterogeneity of diabetes. The authors showed that identified genetic loci linked to diabetes can be segregated according to underlying biological mechanisms which can be used to classify individuals, to provide a way forward for individualized diagnosis, monitoring and treatment. The study highlighted the potential role of genetic variants related to the beta cell, pro-insulin, obesity, lipodystrophy and liver/lipid traits in accounting for different patient characteristics, as well as long-term diabetes outcomes.

What was particularly interesting is the soft-clustering approach adopted by the authors, which did not require genetic variants to fit into only one pathway, or for individuals to be classified to have diabetes due to only one specific pathophysiological defect, but instead, for individuals to be identified to have scores in each of the above-mentioned categories, and thereby accepting that individuals may have developed diabetes with different contribution from the different underlying pathophysiology. The use of such genetic risk scores may be useful in selecting the most appropriate therapies for individualized care in the future.

Over the last 15 years, the global burden of diabetes has more than doubled, from less than 200 million people affected back in the early 2000s to now more than 422 million people affected globally (with the majority in LMICs). These 2 articles represent important advances in our understanding of type 2 diabetes over the last decade. Whilst the ADVANCE study was a landmark study that generated much interest, the Clarke paper highlighted much of the burden of diabetes complications, and our lack of understanding regarding the heterogeneity in risk of diabetes complications. Together with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Trial (VADT) studies, these landmark studies, published between 2008-2010, have highlighted the potential dangers of hypoglycaemia, and heralded the debate and call for more individualized treatment in type 2 diabetes, and contributed to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) to propose in their joint position statement on management of hyperglycaemia in type 2 diabetes in 2012 to move away from a one-size-fit-all approach to treatment, but instead adopt a treatment strategy that is more tailored to individual patient profile, disease duration, co-morbidities and expectations. This represented a major watershed moment in the evolution of diabetes research and care.

With recent advances in genomic medicine and the genetics of type 2 diabetes, some of which have been reported in PLOS Medicine, the era of precision medicine in diabetes is very much here to stay. We, as diabetes researchers and clinicians caring for people with diabetes, look forward to further advances in our understanding of how best to treat individuals with diabetes based on their underlying genetics, pathophysiology, and needs, and to improving outcomes for people with diabetes.

Congratulations again PLOS Medicine and we look forward to the next 15 years of exciting advances!

Ronald Ma is Professor and Head of Division of Endocrinology and Diabetes at the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, and co-lead of the Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine. He is a member of the Executive Board, Asian Association for the Study of Diabetes (AASD), and member of the editorial board of PLOS Medicine.

Acknowledgement: RCWM acknowledge support from the Hong Kong Research Grants Council Research Impact Fund (R4012-18).

Image Credit: stevepb, Pixabay (CC0)

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Charting the evolution of diabetes research and care | Speaking of Medicine - PLoS Blogs

Massive inflammation and other changes in the striatum, an area of the brain selectively destroyed in Huntingtons disease (HD), are already present before patients develop any symptoms, a study has found.

These findings could help understand how the disease unravels and why this brain region is particularly sensitive to degeneration in individuals with Huntingtons.

The study, The caudate nucleus undergoes dramatic and unique transcriptional changes in human prodromal Huntingtons disease brain, was published in the journal BMC Medical Genomics.

Huntingtons is a neurodegenerative disease caused by mutations in the huntingtin(HTT) gene and marked by trouble in controlling movement, a progressive loss of thinking ability, and psychiatric problems.

Symptoms, which typically begin when people reach their 30s and 40s, stem from a selective degeneration of certain brain regions, particularly two areas: the basal ganglia, a region deep in the brain thats responsible for functions including movement coordination; and the cortex, the outer and highly twisted layer of the brain which controls thought, behavior, and memory.

Within the basal ganglia, HD targets nerve cells (neurons) of the striatum, especially in two areas known as the caudate nuclei and putamen. These regions can shrink and suffer massive damage as a result of disease progression.

Very little is known about the active disease processes leading to such debilitating symptoms. Obtaining post-mortem brain samples from people with disease-causing mutations who have not yet developed symptoms in other words, still have a largely intact striatum is very rare.

Researchers atBoston University School of Medicine (BUSM) had the opportunity to analyze samples from the striatum more precisely, the caudate nucleus of two HD-positive individuals who had no symptoms at the time of their death.

To pinpoint early drivers of disease, the team compared the activity (expression) of genes those turned on and turned off in the caudate nucleus of these asymptomatic individuals to the prefrontal cortex of 26 symptomatic Huntingtons patients and 56 healthy controls.

Researchers used a high throughput sequencing technology called RNA-Seq to determine gene expression profiles, and a preformed bioinformatics analysis to understand which genes and biological processes were altered.

Our data suggest that the striatum experiences massive inflammation in HD even before symptoms appear, and exhibits a similar gene expression pattern to that observed in prefrontal cortex. Patterns unique to the striatum are also observed, Adam Labadorf, PhD, director of BUs Bioinformatics Nexusand the studys senior author,said in a news release.

In addition to extensive inflammatory processes, the data also suggested that over the diseases course, the striatum undergoes some form of neurogenesis, or the generation of new nerve cells.

While these are only trends that warrant further investigation, researchers propose that active production of neurons could be happening in the striatum during the prodromal phase (before symptom onset) to compensate for the nerve cell loss that precedes symptoms.

The idea that active neurogenesis occurs in the adult brain is controversial, but could lead to exciting discoveries into the innate regenerative capabilities of the central nervous system, Labadorf said.

According to researchers, these findings provide clear evidence that the caudate nucleus is strongly affected in people positive for Huntington disease, before the emergence of any symptoms.

This study presents the most detailed analysis to date of the active disease process in the primarily affected brain region of HD, and although these results do not directly suggest any novel therapies, a better understanding of these processes is likely to lead to them, Labadorfadded.

An important observation was that some genes, like HSPA6, were perturbed across all HD patient samples relative to healthy brains. This set of genes may provide an opportunity to develop prognostic tests for disease progression, the researchers noted.

A robust clinical test measuring disease progression will likely take the form of a panel of key inflammatory and possibly developmental genes measured in the blood or cerebrospinal fluid (the liquid surrounding the brain and spinal cord), they wrote.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.

Total Posts: 79

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

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Huntington's Marked by Inflammation and Changes in Brain's Striatum Before Symptoms, Study Finds - Huntington's Disease News

Maricopa County Sheriff OfficeOfficer Gene Lee

Gene Lee was a detention officer in the Maricopa County Sheriffs Department in Arizona for six years before he was killed in the line of duty.

Lee passed away on October 30, 2019, one day after officials say he was attacked by an inmate at the Lower Buckeye Jail. Lee was 64 years old. He leaves behind a wife and two children.

The inmate accused of killing Lee was identified as Daniel Davitt. Maricopa County Sheriff Paul Penzone explained that Davitt has been in custody for more than two years on sex charges involving children.

Heres what you need to know.

Gene Lee was attacked by inmate Daniel Davitt on Tuesday, October 29, Maricopa County Sheriff Paul Penzone explained during a news conference.

Sheriff Penzone said that there was no interaction between Lee and Davitt before the attack. The inmate is accused of grabbing Lee by his throat and sweeping his legs out from under him, seemingly without any provocation or warning.

Sheriff Penzone said that Lee was thrown to the ground. His head was slammed into the concrete floor, knocking Lee unconscious.

Lee was rushed to Banner University Medical Center. Dr. Paul Dabrowski explained that Lee suffered a traumatic brain injury. Doctors performed a procedure to remove the blood and pressure from around the brain.

But Lee never woke up. He passed away the following day. The news conference embedded above took place a few hours before Lee was declared dead.

Gene Lee was a Detention Officer for six years, but he was involved with the department long before he was sworn in as an officer. Sheriff Penzone noted that Lee had served as a volunteer with the Maricopa County Sheriffs Office while he was still working in his previous career.

Lee was a Posse member. According to departments website, the volunteer Posse consists of non-compensated positions made up of people from all walks of life who want to assist law enforcement as a way to give back to their community. They contribute their varied skills and interests to one goal; support the Maricopa County Sheriffs Office. Posse branches train for many support functions to include: Search and Rescue, Crime Scene Security, Patrol Support, Administrative Assistance, Civic Functions, Disaster Relief, and Emergency Details.

Sheriff Penzone did not mince words when describing the threats that detention officers like Gene Lee face every day on the job. Hours before Lee passed away, the sheriff talked about how the community is aware of the risks that officers on the street face, but stressed that the officers in the jails are putting just as much at risk.

Sheriff Penzone said that the detention officers are expected to manage a population of people who have made bad decisions and, quite frankly and directly, bad people who are violent and wish to do harm with anyone whose paths they cross.

He added that officers are trained to use the least amount of force possible even when facing a violent situation and that detention officers should receive more thanks for the work that they do.

Arizona Governor Doug Ducey ordered all state buildings to fly the flags at half-mast on October 31 to honor Gene Lee. The governor said in a statement:

As a six-year veteran of the Maricopa County Sheriffs Office, Lee put his life on the line to ensure the safety of his fellow citizens and officers. Our hearts go out to the entire Maricopa County Sheriffs Office and our prayers are with Officer Lees family and loved ones.

Daniel Davitt was first arrested on April 20, 2017. According to inmate records on the Maricopa County Sheriffs Office website, Davitt had the following charges pending against him:

Davitt was immediately transferred out of Maricopa County following the attack on Gene Lee. Inmate records confirm he was moved to the Pinal County jail system on October 30.

Maricopa Sheriff Penzone explained during a news conference that his office was committed to assisting prosecutors in their case against Davitt to ensure that we not only convict him but that he sees the longest sentence practical. The sheriff described Davitt as a criminal predator with no respect for authority, for human life or for the community.

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Gene Lee: 5 Fast Facts You Need to Know - Heavy.com

NEW YORK, Oct. 14, 2019 /PRNewswire/ -- According to the current analysis of Reports and Data, the Global Gene Expression market is expected to reach USD 11.37 billion by the year 2026, in terms of value at a CAGR of 8.1% from 2019-2026. Gene expression promises to tap into a previously unexplored segment in the vast and burgeoning genetic engineering industry. Gene expression is the process by which the genetic code - the nucleotide sequence - of a gene is used to direct protein synthesis and produce the structures of a cell. It is the process by which instructions in the DNA are converted into a functional product like protein. The commercial applications of gene expression have been studied and researched upon extensively in recent years. Many diverse and wide ranging applications have been found for this novel technique. With the increased availability and lowering costs of DNA technologies, gene expression has become a more readily used tool indispensable in drug discovery and development.

Increase in investments in the market, which are supporting the technological advancements, and rise in healthcare expenditure are estimated to shape the growth of the gene expression market. Drug discovery & development and increase in demand for personalized medicine in chronic diseases such as cancer will be observed as the most lucrative applications for gene expression analysis in the forecast period. Application of gene expression in clinical diagnostics, on the other hand, will reflect a moderate growth throughout the analysis period. Moreover, the falling costs of sequencing have facilitated the integration of genomic sequencing into medicine. With the increased availability and lowering costs of DNA technologies, gene expression has become a more readily used tool indispensable in drug discovery and development. Many companies and educational institutions are collaborating to make gene expression publicly accessible through databases such as the Connectivity Map (CMap), Library of Integrated Network-based Cellular Signatures (LINCS) and the Tox 21 project.

New product development has been the consistent strategy undertaken by majority of the players to expand their product portfolio for serving a larger consumer base. For example, in September 2019, Qiagen N.V., launched the newly enhanced GeneGlobe Design & Analysis Hub, which integrates the company's manually curated knowledge base on over 10,000 biological entities with the industry's most comprehensive portfolio of tools for next-generation sequencing (NGS), polymerase chain reaction (PCR) and functional analysis. Other companies like Thermo Fisher Scientific and Illumina Inc. have launched new products in the last few months which are being used in the gene expression market.

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Further key findings from the report suggest

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Segments covered in the report:

For the purpose of the study, this Reports and Data has segmented the Gene Expression Market on the basis of product type, platform type, prescription mode, end user and the regional outlook

Product and Services (Revenue, USD Million; 20162026)

Capacity (Revenue, USD Million; 20162026)

Application (Revenue, USD Million; 20162026)

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Regional Outlook: (Revenue, USD Million; 20162026)

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Gene Expression Market to Reach USD 11.37 Billion by 2026 | Reports and Data - P&T Community

A gene therapy being developed atPenn Medicineto treat Duchenne muscular dystrophy (DMD) successfully and safely stopped the severe muscle deterioration associated with the rare, genetic disease in both small and large animal models, according to a first-of-its-kind study from Penn Medicine researchers. The findings, published online on Monday, Oct. 7, inNature Medicine,puts the field within closer reach of a safe and effective gene therapy that uses a substitute protein without triggering immune responses known to hinder other therapeutic approaches.

Found mostly in boys, DMD is caused by mutations in a sex-linked gene that stop production of a muscle-building protein known as dystrophin. Without it, muscles progressively deteriorate and weaken starting at a very young age and only worsen from there. Most patients arent able to walk by age 12 and die of heart or respiratory failure by the time they reach their 30s, though respirators have helped some live longer.

With their modified gene therapy approach, a multidisciplinary team from thePerelman School of Medicineengineered adeno-associated virus (AAV) vectors to deliver a substitute protein for dystrophin in small and large animal DMD models to keep the muscles intact. The synthetic substitute, based on a naturally occurring protein called utrophin, proved to be an effective and safe alternative, as it protected muscle in mice and dogs with naturally occurring DMD-like mutations, including a large deletion that closely mirrors the large dystrophin deletions found in humans.

For the first time, weve shown how a carefully constructed version of a dystrophin-related protein can safely prevent the breakdown of muscle and maintain its function over time in the most informative animal models. This discovery has important implications for gene therapy and how we work toward safe and effective treatments for muscular dystrophy, sayssenior authorHansell Stedman, an associate professor of surgery. With these results, we have a strong rationale to move this forward into human clinical trials.

Read more atPenn Medicine News.

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Gene therapy for Duchenne muscular dystrophy safely preserves muscle function - Penn: Office of University Communications

DUBLIN--(BUSINESS WIRE)--The "Growth Opportunities in the Neurodegenerative Disorder Therapeutics Market, Forecast to 2024" report has been added to ResearchAndMarkets.com's offering.

As one lives longer, one needs to increasingly battle age-related disorders. Neurodegenerative disorders are the most worrisome because they impact millions of people around the world and lack any curative therapy. While companies continue their search, they are also battling declining revenues from marketed products used to manage symptoms. Heavy genericization, followed by price erosion, reliance on patient-reported data for diagnosis and measuring outcomes, and elusive R&D success, has put unprecedented pressure on pharma companies and prompted several to shed their assets mid-way.

This research service, in addition to quantifying the market, provides details of future products and the expected revenue generation from them. While the therapy market is marred by high rates of pipeline attrition, there are several parallel areas of growth. For instance, the study covers regenerative medicine, which has grown by leaps and bounds and offers the promise of curative therapies.

The study also dives deep into different technological advancements, geographical trends, and potential partnership opportunities for Alzheimer's and Parkinson's diseases. The study covers opportunities in prevention facilitated by digital solutions integration, in conjunction with an understanding of disease diagnosis and progression, expedited drug development, and, most importantly, delivery of the required outcome to the patient.

The study captures the competitive landscape and the different strategies employed by companies to stay ahead of the curve and identifies the game-changing companies leading innovation from the front. Acknowledging the high cost of failure, the study investigates the need and growing acceptance of open innovation to curate data, ask better questions, extract meaningful insights, and create more accurate and predictable solutions.

In addition to collaboration with peers, companies will seek partnership with digital partners. Given the growing availability of data, technologies and tools, and research expertise there are several companies seeking clinically validated solutions, which have been profiled in the study. The study lays down strategic imperatives for companies to recalibrate their business models based on collaboration and be future-ready.

Information is also provided on some of the leading M&A activities impacting the market, as well as unconventional collaboration agreements laying the foundation for propelling innovations toward licensure and delivery. Furthermore, present and future market trends such as regulatory support, focus on wellness, and value chain convergence, which would shape the market, are discussed.

Key Issues Addressed

Key Topics Covered:

1. Executive Dashboard

2. Market Overview and Dynamics

3. Forecast and Trends - Total Neurodegenerative Disorder Therapeutics Market

4. Alzheimer's Disease Segment Analysis

5. Parkinson's Disease Segment Analysis

6. Competitive Landscape - Total Neurodegenerative Disorder Therapeutics Market

7. Visioning Scenarios

8. Growth Opportunities

9. The Last Word

10. Appendix

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/igkntv

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Global Neurodegenerative Disorder Therapeutics Market 2019-2024: Opportunities in Digital Biomarkers, Microbiome Therapeutics, Cell and Gene Therapy,...