It’s known that genetics, or an inherited genome, is a major determinant of one’s risk for autoimmune diseases, like Type 1 diabetes. In human cells, a person’s genome—about six feet of DNA—is compressed into the micrometer space of the nucleus via a three-dimensional folding process. Specialized proteins decode the genetic information, reading instruction from our genome in a sequence-specific manner. But what happens when a sequence variation leads to the misinterpretation of instruction, causing pathogenic misfolding of DNA inside the nucleus? Can the different folding patterns make us more susceptible to autoimmune diseases?

Now, in a first-of-its-kind study, researchers at Penn Medicine found, in mice, that changes in DNA sequence can trigger the chromosomes to misfold in a way that puts one at a heightened risk for Type 1 diabetes. The study, published today in Immunity, revealed that differences in DNA sequences dramatically changed how the DNA was folded inside the nucleus, ultimately affecting the regulation—the induction or repression—of genes linked to the development Type 1 diabetes.

“While we know that people who inherit certain genes have a heightened risk of developing Type 1 diabetes, there has been little information about the underlying molecular factors that contribute to the link between genetics and autoimmunity,” said the study’s senior author Golnaz Vahedi, Ph.D., an assistant professor of Genetics in the Perelman School of Medicine (PSOM) at the University of Pennsylvania and a member of the Institute for Immunology and the Penn Epigenetics Institute. “Our research, for the first time, demonstrates how DNA misfolding—caused by sequence variation—contributes to the development of Type 1 diabetes. With a deeper understanding, we hope to form a foundation to develop strategies to reverse DNA misfolding and change the course of Type 1 diabetes.”

Autoimmune diseases, which affect as many as 23.5 million Americans, occur when the body’s immune system attacks and destroys healthy organs, tissues and cells. There are more than 80 types of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and Type 1 diabetes. In Type 1 diabetes, the pancreas stops producing insulin, the hormone that controls blood sugar levels. White blood cells called T lymphocytes play a significant role in the destruction of insulin-producing pancreatic beta cells.

Until now, little has been known about the extent to which sequence variation could cause unusual chromatin folding and, ultimately, affect gene expression. In this study, Penn Medicine researchers generated ultra-high resolution genomic maps to measure the three-dimensional DNA folding in T lymphocytes in two strains of mice: a diabetes-susceptible and diabetes-resistant mouse strain. The two strains of mice have six million differences in their genomic DNA, which is similar to the number of differences in the genetic code between any two humans.

The Penn team, led by Vahedi and co-first authors Maria Fasolino, Ph.D., a postdoctoral fellow in Immunology, and Naomi Goldman, a graduate student in the PSOM, found that previously defined insulin-diabetes associated regions were also the most hyperfolded regions in the T cells of diabetic mice. Researchers then used a high-resolution imaging technique to corroborate the genome misfolding in diabetes-susceptible mice. Importantly, they found the change in folding patterns occurred before the mouse was diabetic. Researchers suggest that the observation could serve as a diagnostic tool in the future if investigators are able to identify such hyperfolded regions in the T cells of humans.

After establishing the where the chromatin is misfolded in the T cells in mice, researchers sought to study gene expression in humans. Through a collaboration with the Human Pancreas Analysis Program, they discovered that a type of homologous gene in humans also demonstrated increased expression levels in immune cells infiltrating the pancreas of human.

“While much more work is needed, our findings push us closer to a more mechanistic understanding of the link between genetics and autoimmune diseases—an important step in identifying factors that influence our risk for developing conditions, like Type 1 diabetes,” Vahedi said.

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(Bloomberg) — Chinese researchers safely treated a man with leukemia and HIV using gene-edited stem cells, a step forward in a field that was shaken last year when another Chinese scientist used the same technology to create the world’s first genetically-edited babies.

The man’s medical case, published Wednesday in the New England Journal of Medicine, is the first detailed report in a major academic journal of how doctors are using the experimental tool Crispr to manipulate the DNA of a living patient in an effort to cure disease. But even before the earlier controversy in China, there’s been a heavy note of caution in the field about how far and fast to proceed with the technology.

The patient’s dual diseases — HIV and cancer — gave researchers at the Peking University Stem Cell Research Center in Beijing an opening. The man needed a transplant of stem cells to replace the damaged ones that were causing his blood cancer. That procedure also gave them the opportunity to re-engineer a gene called CCR5 in the donor cells to be resistant to HIV.

“This is a green light for the whole field of gene editing,” Carl June, a pioneer in the use of gene therapy to treat cancer and HIV at the University of Pennsylvania, said in an interview. He published a companion piece in the journal.

The work has some parallels to the highly controversial effort by scientist He Jiankui to alter the DNA in two embryos to make the babies resistant to HIV. That effort sparked an international backlash and calls to put a moratorium on using Crispr to create permanent changes in a subject’s DNA, especially in an embryo. The latest effort is a far more incremental but legitimate effort, especially given the imprimatur of one of the world’s foremost academic journals.

The work by Peking University’s Hongkui Deng and colleagues had several key differences from the earlier effort, including the controlled use of gene-editing on only select cells, the patient’s consent and the subsequent publication of the findings.

The experiment had mixed results. Nineteen months after the treatment, the young man’s cancer, an acute lymphoblastic leukemia, is in remission, and the modified cells integrated into his body and remain. The attempt to cure his HIV was a failure: Only about 5% of his infection-fighting lymphocytes are now resistant to HIV, making continued treatment of the virus necessary.

Even so, the results show a key proof of the concept that Crispr-edited cells can be transplanted into a person and persist long-term, Deng said in an emailed response to questions.

“We should all hope that this is a significant and powerful advance in scientific research, for if it can be tested safely and ethically — and it surely can — it could transform medicine,” said Laurie Zoloth, a professor of religion and ethics at the University of Chicago. “The first published paper is quite an historical moment.”

The researchers didn’t detect any adverse events from the gene-editing or signs that the man’s DNA had been damaged. Larger studies where more altered cells persist are needed to confirm the findings, Deng said. Concerns over unknown potential effects of Crispr has been one of the major hurdles standing in the way of more trials moving forward.

“If they had gone the other way, with a lot of off-target hits, that would have been chilling for the technology,” June said.

Data on three patients treated with Crispr-manipulated cells at the University of Pennsylvania, perhaps the first in the U.S., will be presented at the American Society of Hematology meeting in December.

Crispr has been compared to a word-processing system that allows writers to easily cut out extraneous words and correct typos. With DNA, it acts like molecular scissors, precisely trimming specific flaws in genes. Scientists are still trying to determine if tinkering with the genome can create stray errors elsewhere or lead to unexpected harms, such as cancers caused by uncontrolled cell growth.

There’s a biological rationale for targeting HIV in a leukemia patient, in part because of a handful of people cured of HIV who had bone-marrow transplants. Timothy Ray Brown became the first adult ever to be cured of HIV in 2007 after he received a bone marrow transplant to treat his leukemia. The donor cells had a rare mutation in the CCR5 gene, found in about 1 in 20 people, that makes it difficult for HIV to infect cells. Brown was known as the “Berlin patient,” and other researchers have tried to replicate his experience.

Researchers are now planning to try to increase the number of cells that are transformed and can thrive inside of a patient, Deng said. Other diseases with genetic causes, such as sickle cell anemia, muscular dystrophy, cystic fibrosis and cancer are likely to see a surge in interest based on the new results.

“Crispr technology is so flexible it can be used for all types of conditions,” June said. “You can rewrite the genetic code at will.”

But the China study also showed some of Crispr’s limits because only about 5% of the cells were affected, said Zoloth, the University of Chicago professor.

“This thoughtful honesty and modesty in scientific claims are an important part” of the project, Zoloth said. “It is a first step, if tentative, toward engineering naturally occurring constructs in nature in ways that benefit humanity.”

Leaders in the field agreed the safety findings are a critical first step, though they are hoping further refinement of the process will lead to better results. One key issue is that cells that have been altered using gene-editing or other types of technology are “finicky and tricky to transplant,” said Jennifer Doudna, professor of biochemistry and molecular biology at the University of California, Berkeley, who is credited as an inventor of Crispr.

“This plants the flag to say that at least in this one instance, this type of therapy appears safe,” she said. “The next step is showing that there is some efficacy, a therapeutic benefit to doing this.”

While the NEJM report is the first publication about the use of Crispr in humans, other pioneering researchers have been using it for years in China. The first trials started in 2016, when Lu You, a physician at Sichuan University, put gene-edited cells into a lung-cancer patient. Since then, scientists have launched multiple trials and reportedly treated dozens of patients. But little is known about some of those studies, and medical research is not as stringently regulated in China as it is in the West, prompting concerns about their safety and ethics.

“In the next 18 to 24 months, we’ll start to see published results from a number of these ongoing trials,” Doudna said. “That’s where the rubber hits the road. Does it benefit patients? Time will tell.”

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The cell polarity protein Par3 controls mechanic changes in the skin and plays an important role in cell division. Malfunction can lead to DNA damages. The balance of the system is of great importance: while too much differentiation leads to loss of stem cells and therefore premature aging, too many cell divisions can be a cause of skin cancer. The new study by a team around Sandra Iden about how polarity regulators control cellular mechanics in the skin was now published in Nature Communications.

The skin serves as a crucial barrier to the outside world. Its task is not only to keep pathogens or toxic chemicals out of the body, but also to keep water inside and maintain hydration. In order to function properly, the skin epidermis constantly needs to keep a balance of cells it sheds off and new cells that replenish the lost ones. The skin epidermis is made up of several layers with different functions. Skin stem cells are responsible for the self-renewing capacity of the skin.

In a previous study, the researchers showed that inactivation of the polarity protein Par3 resulted in a decline of stem cells, impaired skin homeostasis and premature skin aging. Back then, however, the underlying mechanisms remained unclear. ‘We were now able to show that Par3 has a direct influence on the homeostasis of the skin by controlling the mechanical properties of keratinocytes, the main skin epithelial cell,’ said leading scientist of the study Dr Sandra Iden. The polarity protein Par3 controls the mechanical properties of the main skin epithelial cells, called keratinocytes. It has functions that are conserved from worms and flies to mammals. Par3 also regulates barrier function and cell division orientation.

The recent work started with two separate approaches. One of the first authors, Martim Dias Gomes, said: ‘We realized that inactivating Par3 leads to failures in cell divisions, resulting in DNA damage responses.’ At the same time, his colleague and co-first author Soriba Letzian was working on another project: ‘We challenged mouse skin with UV light – but observed an unexpected DNA damage response already in absence of the harmful light, when Par3 was missing. That was the moment we realized that the DNA damage response and the aberrant cell divisions might be tightly linked,’ he said. Based on these results, they teamed up and together examined possible causes of these mitotic failures.

As they now show, Par3 is an important regulator of contractility of keratinocytes, which is required to maintain the accuracy of cell division events. The absence of Par3 led to mitotic errors, causing an alert signal and a cascade of DNA damage responses that then fuelled premature differentiation, and potentially the skin stem cell decline. These findings were surprising, as during the development of epithelial tissues Par3 was considered to serve tissue function rather through orienting mitotic spindles.

These new findings thus revealed that core polarity proteins like Par3 steer mechanochemical networks essential to keep a healthy self-renewal capacity. ‘We are glad that we were able to contribute a piece of the puzzle of how the skin epithelium is maintained intact, and hope that this will serve future medical applications,’ Sandra Iden concludes.

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HelixLife, which is in partnership with GeneLink Biosciences, has launched custom DNA anti-aging skincare serum. It helps to offset a person’s disadvantage of genes and reduce wrinkles with skin cream which is combined and shipped fresh for each customer. This skin cream is advanced and customized to fight wrinkles and aging. HelixLife’s brilliant anti-aging skin serum is developed by a world-class scientific advisory board after 16 years of precise genetic research. The board has over 100 years of combined experience in medicine, nutrition and skin solution.

The company has conducted a clinical trial on a few participants. The trial showed that 65% of participants had a noticeable reduction in wrinkles after 14 days and a 70% reduction in wrinkles after eight weeks. This anti-aging product is predicted to remain competitive in the market like Helix STEM which is a food anti-aging supplement and a perfect companion to the HG Gel.

HelixLife CEO, Brad Rex said, “Many people take a ‘shotgun’ approach to skincare, buying different, expensive products off the shelf and experimenting with the effects.  This is a waste of time and money.  We custom blend a skin cream for you that is scientifically proven to reduce wrinkles and firm skin. Our customers are very happy with the results.”

HelixLife’s anti-aging skincare products contain 50 different natural and organic ingredients. The new skincare cream helps the skin to deal with stress, pollutants, collagen breakdown, and photoaging to give you glowing skin. HelixLife has announced to offer DNA assessment and brilliant skin serum with special pricing, a free gift, and shipping.

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Investigators from the AIDS Clinical Trials Group (ACTG), the world’s largest and longest-established HIV research network, today announced that the Journal of Clinical Investigationpublished new findings from the ACTG HIV Reservoirs Cohort Study (A5321). The study found that HIV DNA remained in the cerebrospinal fluid of half of participants with well-managed HIV (virologic suppression in the plasma), confirming that the central nervous system (CNS) is a major reservoir for latent HIV. Individuals who harbored HIV DNA in the cerebrospinal fluid were more likely than other study participants to experience cognitive deficits on neurocognitive testing.

“The persistence of HIV in sanctuary sites in the human body, even in the presence of long-term therapy, is a challenge to HIV remission and cure that the ACTG is actively working to address,” said ACTG Chair Judith Currier, M.D., MSc, University of California Los Angeles. “Because neurocognitive function can be compromised even in individuals whose HIV is well treated, it is very important that we understand HIV persistence in the CNS so that we can develop strategies to treat it. This study provides preliminary insights into these challenges.”

This substudy in the ACTG HIV Reservoirs Cohort Study (A5321) was led by Serena Spudich, M.D., Yale University, the late Kevin Robertson, Ph.D., University of North Carolina at Chapel Hill, and John Mellors, M.D., University of Pittsburgh. The study included 69 participants with well-treated HIV who had their cerebrospinal fluid and blood collected and underwent neurocognitive assessments, which included tests of memory, learning, motor function, and more. Participants were mostly male (97 percent) and had been on HIV treatment for a median of almost nine years, with a good response to medications (HIV viral loads in the plasma were all <100 copies/mL and median CD4 counts were in the normal range). Using highly sensitive methods to detect HIV, researchers found that almost half of these participants harbored viral DNA in cells found in the cerebrospinal fluid. Of those, 30 percent met the criteria for cognitive impairment.

While the study established an association between HIV DNA in cerebrospinal fluid with poorer performance on cognitive tests, researchers stressed that it did not establish a causal relationship, noting that there could be several explanations for the findings. Further studies will help determine strategies to reverse this persistence and improve neurological functioning in individuals with long-standing HIV.

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Researchers say they have removed HIV from the DNA of mice, an achievement the scientists say could be an early step towards an elusive cure for humans.

The breakthrough, detailed earlier this week in a study credited to more than 30 scientists from Temple University and the University of Nebraska Medical Centre, was made possible by an antiviral drug in combination with the tool called CRISPR that can edit genes.

The researchers eliminated HIV in nine of 23 mice that were modified so their immune systems better mimicked those of humans.

Clinical trials for the gene-editing component of the cure could start as early as next year if the Food and Drug Administration approves them, said Kamel Khalili, one of the study’s senior investigators.

But he and other HIV experts emphasised that there is a big scientific leap from promising results in mice to success in humans.

“We knew what we needed to do, but the technology was unavailable,” Dr Khalili told The Washington Post, saying he and his team had been awaiting a tool like CRISPR to combat a virus that “becomes part of the fabric of our chromosomes”.

With gene editing finally a reality, he said, “the outcome was amazing”.

Once deadly, HIV can now be managed with a treatment called anti-retroviral therapy.

The therapy only keeps the virus in check; without constant medication, the virus will quickly decimate a patient’s ability to fight off sickness.

HIV infects 37 million people worldwide, according to the latest data from the World Health Organisation (WHO), and only about 22 million of those people receive antiretroviral therapy. Nearly one million people died of HIV-related issues in 2017, according to WHO.

Earlier this year, revelations that a second person had seemingly been rid of the virus raised hopes that another patient’s cure 12 years earlier was not a one-off victory.

But scientists cautioned that it was too early to declare the anonymous second patient cured – and that, regardless, the case did not herald a widespread cure for the devastating condition.

Both patients were treated with stem cell transplants, which experts say are risky, bring serious side-effects and would not be preferred for most patients.

Previously, Dr Khalili’s team at Temple had found a way to remove significant amounts of HIV DNA from rats and mice.

But the technique could not completely remove the infection.

So Dr Khalili’s lab joined forces with a University of Nebraska Medical Centre (UNMC) lab attacking the problem in a different way. Together, the scientists combined the gene-editing strategy with a drug designed to beat back HIV.

Howard Gendelman from UNMC said that his team’s experimental drug is engineered to act over a longer time than normal therapies, meaning it can be administered every couple of months instead of every day.

It is also better able to target HIV in the body, he said. It is crucial that gene editing remove every last bit of HIV, he said, and the drug makes that task easier.

“If you can reduce the amount of virus that’s left for CRISPR, the likelihood that the CRISPR will be effective will go up enormously,” he said.

But if Dr Khalili’s team is able to move forward with trials with humans, it will use standard drugs rather than the one developed by UNMC’s lab, since it probably would not be approved yet for use, Dr Khalili said.

Steven Deeks, a professor at the University of California at San Francisco who has worked extensively on HIV, said the use of gene editing to remove HIV from a live animal is a notable step forward.

But he cautioned that using the technique on humans will be far more challenging: scientists will have to grapple with more variations in the virus, more difficulties in delivering the gene-editing technology and the possibility of cutting up human genes while trying to target HIV, he said.

Those are formidable problems, Prof Deeks said, especially with success depending on removing the virus completely.

“For this approach to work, they have to really knock out 100 percent of the genomes – you can’t leave anything behind,” Professor Deeks said. “One of them can reignite the whole process.”

The scientists behind the new study recognise those challenges. Dr Khalili said researchers are in the process of publishing another study on the use of gene editing to target HIV in primates and are hopeful about bringing the solution to human subjects.

But the scientists need to make sure their techniques are safe, he said. They also want to increase their methods’ chances of working from the roughly one-third success rate they saw with mice.

Dr Gendelman said that while modern drugs are good at keeping HIV at bay, a permanent cure would bring big benefits to patients.

Constant drug treatment can contribute to other health complications, he said, and just keeping the pills in your medicine cabinet can invite unwanted scrutiny from family or significant others.

“There’s a tremendous stigma,” he said. “Every time you take those pills you’re reminded that you have HIV.”

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