DNA Is Not the Only Mode of Biological Inheritance

A little over a decade ago, a clutch of scientific studies was published that seemed to show that survivors of atrocities or disasters such as the Holocaust and the Dutch famine of 1944-45 had passed on the biological scars of those traumatic experiences to their children.

The studies caused a sensation, earning their own BBC Horizon documentary and the cover of Time – and no wonder. The mind-blowing implications were that DNA wasn’t the only mode of biological inheritance, and that traits acquired by a person in their lifetime could be heritable. Since we receive our full complement of genes at conception and it remains essentially unchanged until our death, this information was thought to be transmitted via chemical tags on genes called “epigenetic marks” that dial those genes’ output up or down. The phenomenon, known as transgenerational epigenetic inheritance, caught the public imagination, in part because it seemed to release us from the tyranny of DNA. Genetic determinism was dead.

A model of DNA methylation – the process that modulates genes. The influence of environment or lifestyle on this process is being studied

A decade on, the case for transgenerational epigenetic inheritance in humans has crumbled. Scientists know that it happens in plants, and – weakly – in some mammals. They can’t rule it out in people, because it’s difficult to rule anything out in science, but there is no convincing evidence for it to date and no known physiological mechanism by which it could work. One well documented finding alone seems to present a towering obstacle to it: except in very rare genetic disorders, all epigenetic marks are erased from the genetic material of a human egg and sperm soon after their nuclei fuse during fertilisation. “The [epigenetic] patterns are established anew in each generation,” says geneticist Bernhard Horsthemke of the University of Duisburg-Essen in Germany.

Different people define epigenetics differently, which is another reason why the field is misunderstood. Some define it as modifications to chromatin, the package that contains DNA inside the nuclei of human cells, while others include modifications to RNA. DNA is modified by the addition of chemical groups. Methylation, when a methyl group is added, is the form of DNA modification that has been studied  most, but DNA can also be tagged with hydroxymethyl groups, and proteins in the chromatin complex can be modified too.

Researchers can generate genome-wide maps of DNA methylation and use these to track biological ageing, which as everyone knows is not the same as chronological ageing. The first such “epigenetic clocks” were established for blood, and showed strong associations with other measures of blood ageing such as blood pressure and lipid levels. But the epigenetic signature of ageing is different in different tissues, so these couldn’t tell you much about, say, brain or liver. The past five years have seen the description of many more tissue-specific epigenetic clocks.

Mill’s group is working on a brain clock, for example, that he hopes will correlate with other indicators of ageing in the cortex. He has already identified what he believes to be an epigenetic signature of neurodegenerative disease. “We’re able to show robust differences in DNA methylation between individuals with and without dementia, that are very strongly related to the amount of pathology they have in their brains,” Mill says. It’s not yet possible to say whether those differences are a cause or consequence of the pathology, but they provide information about the mechanisms and genes that are disrupted in the disease process, that could guide the development of novel diagnostic tests and treatments. If a signal could be found in the blood, say, that correlated with the brain signal they’ve detected, it could form the basis of a predictive blood test for dementia.

Source: https://www.theguardian.com/

A Forest-based Yard Im­proved the Im­mune Sys­tem of Day­care Chil­dren in Only a Month

Playing through the greenery and litter of a mini forest‘s undergrowth for just one month may be enough to change a child’s immune system, according to an experiment in Finland. When daycare workers rolled out a lawn, planted forest undergrowth (such as dwarf heather and blueberries), and allowed children to care for crops in planter boxes, the diversity of microbes in the guts and on the skin of young kids appeared healthier in a very short space of time.

Compared to other city kids who play in standard urban daycares with yards of pavement, tile and gravel, 3-, 4-, and 5-year-olds at these greened-up daycare centers in Finland showed increased T-cells and other important immune markers in their blood within 28 days.

DURING THE STUDY, FOREST UNDERGROWTH, LAWN TURF AND PLANTER BOXES, IN WHICH CHILDREN PLANTED AND TENDED CROPS, WERE ADDED TO PAVED, TILED AND GRAVEL-COATED YARD AREAS AT DAYCARE CENTRES

We also found that the intestinal microbiota of children who received greenery was similar to the intestinal microbiota of children visiting the forest every day,” explained environmental scientist Marja Roslund from the University of Helsinki in 2020, when the research was published.

Prior research has shown early exposure to green space is somehow linked to a well-functioning immune system, but it’s still not clear whether that relationship is causal or not.

The experiment in Finland is the first to explicitly manipulate a child’s urban environment and then test for changes in their microbiome and, in turn, a child’s immune system.

Source: https://www2.helsinki.fi/

Glue Seals Bleeding Organs in Seconds

Inspired by the sticky substance that barnacles use to cling to rocks, MIT engineers have designed a strong, biocompatible glue that can seal injured tissues and stop bleeding. The new paste can adhere to surfaces even when they are covered with blood, and can form a tight seal within about 15 seconds of application. Such a glue could offer a much more effective way to treat traumatic injuries and to help control bleeding during surgery, the researchers say.

We are solving an adhesion problem in a challenging environment, which is this wet, dynamic environment of human tissues. At the same time, we are trying to translate this fundamental knowledge into real products that can save lives,” says Xuanhe Zhao, a professor of mechanical engineering and civil and environmental engineering at MIT and one of the senior authors of the study. Finding ways to stop bleeding is a longstanding problem that has not been adequately solved, Zhao says. Sutures are commonly used to seal wounds, but putting stitches in place is a time-consuming process that usually isn’t possible for first responders to perform during an emergency situation. Among members of the military, blood loss is the leading cause of death following a traumatic injury, and among the general population, it is the second leading cause of death following a traumatic injury.

In recent years, some materials that can halt bleeding, also called hemostatic agents, have become commercially available. Many of these consist of patches that contain clotting factors, which help blood to clot on its own. However, these require several minutes to form a seal and don’t always work on wounds that are bleeding profusely. Zhao’s lab has been working to address this problem for several years

For their new tissue glue, the researchers once again drew inspiration from the natural world. This time, they focused their attention on the barnacle, a small crustacean that attaches itself to rocks, ship hulls, and even other animals such as whales. These surfaces are wet and often dirty — conditions that make adhesion difficult. “This caught our eye,” Yuk says. “It’s very interesting because to seal bleeding tissues, you have to fight with not only wetness but also the contamination from this outcoming blood. We found that this creature living in a marine environment is doing exactly the same thing that we have to do to deal with complicated bleeding issues.” The researchers’ analysis of barnacle glue revealed that it has a unique composition. The sticky protein molecules that help barnacles attach to surfaces are suspended in an oil that repels water and any contaminants found on the surface, allowing the adhesive proteins to attach firmly to the surface.

The MIT team decided to try to mimic this glue by adapting an adhesive they had previously developed. This sticky material consists of a polymer called poly(acrylic acid) embedded with an organic compound called an NHS ester, which provides adhesion, and chitosan, a sugar that strengthens the material. The researchers froze sheets of this material, ground it into microparticles, and then suspended those particles in medical grade silicone oil.

Christoph Nabzdyk, a cardiac anesthesiologist and critical care physician at the Mayo Clinic in Rochester, Minnesota, is also a senior author of the paper, which appears today in Nature Biomedical Engineering. MIT Research Scientist Hyunwoo Yuk and postdoc Jingjing Wu are the lead authors of the study.

Source: https://news.mit.edu/

Our Bodies Age in 3 Distinct Shifts

The carnival worker who tries to guess your age relies on aspects of your appearance, such as your posture and whether any wrinkles emanate from the corners of your eyes and lips. If the carny’s guess is more than a few years off, you win a stuffed koala.

But a team of Stanford University School of Medicine scientists doesn’t need to know how you look to guess your age. Instead, it watches a kind of physiological clock: the levels of 373 proteins circulating in your blood. If the clock is off, you don’t win a plush toy. But you may find out important things about your health.

We’ve known for a long time that measuring certain proteins in the blood can give you information about a person’s health status — lipoproteins for cardiovascular health, for example,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, the D. H. Chen Professor II and co-director of the Stanford Alzheimer’s Disease Research Center. “But it hasn’t been appreciated that so many different proteins’ levels — roughly a third of all the ones we looked at — change markedly with advancing age.

Changes in the levels of numerous proteins that migrate from the body’s  tissues into circulating blood not only characterize, but quite possibly cause, the phenomenon of aging, Wyss-Coray said. A paper describing the research was published Dec. 5 in Nature Medicine. Wyss-Coray is the senior author. The lead author is neurology instructor Benoit Lehallier, PhD.

The researchers analyzed plasma — the cell-free, fluid fraction of blood — from 4,263 people ages 18-95. “Proteins are the workhorses of the body’s constituent cells, and when their relative levels undergo substantial changes, it means you’ve changed, too,” Wyss-Coray said. “Looking at thousands of them in plasma gives you a snapshot of what’s going on throughout the body.”

The study’s results suggest that physiological aging does not simply proceed at a perfectly even pace, but rather seems to chart a more herky-jerky trajectory, with three distinct inflection points in the human life cycle. Those three points, occurring on average at ages 34, 60 and 78, stand out as distinct times when the number of different blood-borne proteins that are exhibiting noticeable changes in abundance rises to a crest. This happens because instead of simply increasing or decreasing steadily or staying the same throughout life, the levels of many proteins remain constant for a while and then at one point or another undergo sudden upward or downward shifts. These shifts tend to bunch up at three separate points in a person’s life: young adulthood, late middle age and old age.

The investigators built their clock by looking at composite levels of proteins within groups of people rather than in individuals. But the resulting formula proved able to predict individuals’ ages within a range of three years most of the time. And when it didn’t, there was an interesting upshot: People whose predicted age was substantially lower than their actual one turned out to be remarkably healthy for their age.

The researchers obtained their samples from two large studies. One of them, known as the LonGenity study, has assembled a registry of exceptionally long-lived Ashkenazi Jews. It was able to provide many blood samples from people as old as 95. On measuring the levels of roughly 3,000 proteins in each individual’s plasma, Wyss-Coray’s team identified 1,379 proteins whose levels varied significantly with participants’ age.

Source: https://med.stanford.edu/
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https://www.sciencealert.com/

A Single Drop of Blood Can Reveal Stress Hormones

A Rutgers-led team of researchers has developed a microchip that can measure stress hormones in real time from a drop of blood.

Cortisol and other stress hormones regulate many aspects of our physical and mental health, including sleep quality. High levels of cortisol can result in poor sleep, which increases stress that can contribute to panic attacks, heart attacks and other ailments.

Currently, measuring cortisol takes costly and cumbersome laboratory setups, so the Rutgers-led team looked for a way to monitor its natural fluctuations in daily life and provide patients with feedback that allows them to receive the right treatment at the right time.

The researchers used the same technologies used to fabricate computer chips to build sensors thinner than a human hair that can detect biomolecules at low levels. They validated the miniaturized device’s performance on 65 blood samples from patients with rheumatoid arthritis.

The use of nanosensors allowed us to detect cortisol molecules directly without the need for any other molecules or particles to act as labels,” said lead author Reza Mahmoodi, a postdoctoral scholar in the Department of Electrical and Computer Engineering at Rutgers University-New Brunswick.

With technologies like the team’s new microchip, patients can monitor their hormone levels and better manage chronic inflammation, stress and other conditions at a lower cost, said senior author Mehdi Javanmard, an associate professor in RutgersDepartment of Electrical and Computer Engineering.

Our new sensor produces an accurate and reliable response that allows a continuous readout of cortisol levels for real-time analysis,” he added. “It has great potential to be adapted to non-invasive cortisol measurement in other fluids such as saliva and urine. The fact that molecular labels are not required eliminates the need for large bulky instruments like optical microscopes and plate readers, making the readout instrumentation something you can measure ultimately in a small pocket-sized box or even fit onto a wristband one day.”

The study included Rutgers co-author Pengfei Xie, a Ph.D. student, and researchers from the University of Minnesota and University of Pennsylvania. The research was funded by the DARPA ElectRX program.

The study appears in the journal Science Advances.

Source: https://www.rutgers.edu/

Early Cancer Detection Test

Mayo Clinic today recognized the debut of a groundbreaking multi-cancer early detection (MCED) test called Galleri™ that can detect more than 50 types of cancers through a simple blood draw. The  Galleri test is intended  to complement U.S. guideline-recommended cancer screenings.

Mayo Clinic Oncologist Minetta Liu, M.D. was involved in the development of the new test. “Today, many cancers are found too late, leading to poor outcomes,” says Dr. Liu. “The ability to detect cancer early is critical to successful treatment.”

Cancer is expected to become the leading cause of death in the U.S. this year. Currently recommended cancer screening tests only cover five cancer types and screen for a single cancer at a time. In fact, there are no recommended early detection screening tests for other cancers, which account for 71% of cancer deaths.

Researchers used the Galleri test in the Circulating Cell-free Genome Atlas (CCGA) Study, a prospective, observational, longitudinal study designed to characterize the landscape of genomic cancer signals in the blood of people with and without cancer. In the study, the Galleri test demonstrated the ability to detect more than 50 types of cancers — over 45 of which have no recommended screening tests today — with a low false-positive rate of less than 1%.

According to Dr. Liu, when a cancer signal is detected, the Galleri test can identify where in the body the cancer is located with high accuracy — a critical component to help enable health care providers to direct diagnostic next steps and care.

We are grateful to Mayo Clinic for its dedication to advancing new technologies for early cancer detection and for playing a pivotal role in the development of Galleri,” says Dr. Josh Ofman, chief medical officer and head of external affairs at GRAIL.“A simple blood test capable of detecting more than 50 cancers is a ground-breaking advancement and could have a tremendous human and economic benefit.

Initial results from the interventional PATHFINDER Study, which involved the return of Galleri test results to providers to communicate to participants, were presented today at the 2021 American Society of Clinical Oncology Annual Meeting. They demonstrate Galleri’s performance in the clinical setting was consistent with findings from previous observational studies, underscoring the potential real-world ability of Galleri to find deadly cancers earlier.

Source: https://individualizedmedicineblog.mayoclinic.org/

Intravenous Immunoglobulins Could Stop Thrombosis after Astrazeneca Vaccination

Some people have developed dangerous blood clots in the brain after receiving the corona vaccination with the AstraZeneca preparation The University Medical Center Greifswald in Germany has now broken down the likely cause of the blood clots. According to Andreas Greinacher, he and his team found special antibodies in the blood of those affected, which are directed against the body’s own blood platelets. These cells play an important role in blood clotting. The antibodies activate the platelets: they clump together, as they normally do to close a wound, and thus form blood clots. The basic problem is therefore an autoimmune reaction.

In Germany, 13 cases of sinus vein thrombosis were reported shortly after an AstraZeneca vaccination, all of which were associated with a lack of blood platelets, i.e. a so-called thrombocytopenia. Around 1.6 million people in Germany were vaccinated. According to Greinacher, the problems that arose shortly after the vaccination are similar to a long-known complication with the administration of another agent, heparin-induced thrombocytopenia, or HIT for short. There, too, antibodies activate platelets so that clots form. In both cases the symptoms appear within 5 to 14 days after administration of the preparation. Greinacher therefore emphasized that the flu-like symptoms that often occur on the day after the vaccination are not a warning signal that a blood clot is developing. But anyone who has a painful leg about five days after the vaccination – as a sign of a deep vein thrombosis – or a severe headache should see a doctor immediately.

The Society for Thrombosis and Hemostasis Research has already published recommendations for doctors based on the Greifswald findings. She assumes that the formation of clots in people with sinus vein thrombosis and thrombocytopenia can be stopped by giving high doses of intravenous immunoglobulins. Greinacher could not answer how reliably this therapy helps those affected. That is not his area of expertise, he said.

Source: https://www.uni-greifswald.de/
AND
https://www.quora.com/

CRISPR Treatment Cuts Cholesterol by Up to 57% in a Single Shot

Scientists have improved upon a form of gene-editing therapy, creating an experimental treatment that looks to hold great promise for treating high cholesterol – a diagnosis affecting tens of millions of Americans, and linked to a number serious health complications. In new research conducted with mice, researchers used an injection of a newly-formulated lipid nanoparticle to deliver CRISPR-Cas9 genome editing components to living animals, with a single shot of the treatment reducing levels of low-density lipoprotein (LDL) cholesterol by up to 56.8 percent. In contrast, an existing FDA-approved lipid nanoparticle (or LNP; a tiny, biodegradable fat capsule) delivery system could only manage to reduce LDLs by 15.7 percent in testing. Of course, these results have so far only been demonstrated in mice, so the new therapy will take a lot of further testing before we know it’s both safe and equally effective in humans. But based on these results so far, signs are promising.

The way the treatment works relates to a gene in humans called Angiopoietin-like 3 (Angptl3), which produces proteins that inhibit the breakdown of certain fats in the bloodstream. People with a mutation in this gene tend to have lower amounts of fatty triglycerides and cholesterol in their blood – without showing other kinds of health complications – and for years scientists have been trying to recreate the process, with treatments that effectively mimic the effects of the mutation.

If we can replicate that condition by knocking out the Angptl3 gene in others, we have a good chance of having a safe and long term solution to high cholesterol,” says biomedical engineer Qiaobing Xu from Tufts University. “We just have to make sure we deliver the gene editing package specifically to the liver so as not to create unwanted side effects.

In the new research, Xu’s team developed a new formulation of LNPs called 306-O12B to target the gene, producing therapeutic effects in wild-type C57BL/6 mice that lasted at stable levels for 100 days after just a single injection of the treatment.

In addition to the cholesterol reduction, the experiment produced a 29.4 percent decrease in triglycerides in the animals’ blood, whereas the FDA-approved delivery method showed only a 16.3 percent reduction.

The findings are reported in PNAS.

New Blood Test Could Replace Biopsies

No one enjoys getting a biopsy, in which a tissue sample is surgically taken and analyzed in a lab for signs of disease, such as cancer. It’s not only unpleasant for the patient, but has clinical drawbacks: A biopsy doesn’t always extract the diseased tissue and isn’t helpful in detecting disease at early stages. These concerns have encouraged researchers to find less invasive and more accurate diagnostic methods. Prof. Nir Friedman and Ronen Sadeh of the Hebrew University of Jerusalem have developed a blood test that enables lab technicians to diagnose cancer and diseases of the heart and liver by identifying and determining the state of the dead cells throughout the body.

Millions of cells die every day and are replaced by new cells. When cells die, their DNA is fragmented. Some of these DNA fragments reach the blood and can be “read” by advanced DNA sequencing methods.

As a result of these scientific advancements, we understood that if this information is maintained within the DNA structure in the blood, we could use that data to determine the tissue source of dead cells and the genes that were active in those very cells. Based on those findings, we can uncover key details about the patient’s health,” Friedman said.

We are able to better understand why the cells died — whether it’s an infection or cancer — and based on that, be better positioned to determine how the disease is developing,” he said. Co-author Israa Sharkia added the simple blood test could “be administered often and quickly, allowing the medical staff involved to follow the presence or development of a disease more closely.”

A startup company, Senseera, has been established to pursue clinical testing of this innovative approach in partnership with major pharmaceutical companies.

The multi-author study published in Nature Biotechnology explains the test can even identify markers that may differentiate between patients with similar tumors, which could help physicians develop personalized treatments.

Source: https://www.zenger.news/

Diabetics die 3 times more of Covid-19

From the outset of the pandemic, data coming out of early coronavirus hot spots like China, Italy, and New York City foretold that certain groups of people would be more vulnerable to Covid-19. The disease hit older people and people with underlying medical conditions the hardest. As early as February, diabetes had emerged as one of the conditions associated with the highest risk. In one large study out of China, people with diabetes were more than three times as likely to die of Covid-19 than the overall population.

But that’s not what brought four diabetes experts from Australia and the United Kingdom onto a Zoom call back in April. They were supposed to just be catching up—a virtual tea among friends. But talk soon turned to something strange that they’d been seeing in their own hospitals and hearing about through the grapevine. The weird thing was that people were showing up in Covid-19 wards, after having tested positive for the virus, with lots of sugar in their blood. These were people with no known history of diabetes. But you wouldn’t know it from their lab results.

After that call, the experts reached out to colleagues in other countries to see if they’d seen or heard of similar cases. They had. Acute viral infections of all sorts can stress the body, causing blood sugar levels to rise. So that in itself wasn’t unusual, says Francesco Rubino, a bariatric surgeon and diabetes researcher at King’s College in London, who was on that first Zoom call. “What we were seeing and hearing was a little bit different.”

Doctors around the world had described to him strange situations in which Covid-19 patients were showing symptoms of diabetes that didn’t fit the typical two-flavor manifestation of the disease. In most people with type 1 diabetes, their immune cells suddenly turn traitorous, destroying the cells in the pancreas that produce insulin—the hormone that allows glucose to exit the bloodstream and enter cells. People with type 2 diabetes have a different problem; their body slowly becomes resistant to the insulin it does produce. Rubino and his colleagues were seeing blended features of both types showing up spontaneously in people who’d recently been diagnosed with Covid-19.

That was the first clinical puzzle,” he says. For clues to an explanation, Rubino and his colleagues looked to ACE2, the protein receptor that SARS-CoV-2 uses to invade human cells. It appears in the airways, yes, but also in other organs involved in controlling blood sugar, including the gut. Doctors in China discovered copies of the coronavirus in the poop of their Covid-19 patients. And a meta-analysis found that gastrointestinal symptoms plague one out of 10 Covid-19 sufferers.

In the last few decades, scientists have discovered that the gut is not the passive digestive organ once thought. It actually is a major endocrine player—responsible for producing hormone signals that talk to the pancreas, telling it to make more insulin, and to the brain, ordering it to make its owner stop eating. If the coronavirus is messing with these signals, that could provide a biological basis for why Covid-19 would be associated with different forms of diabetes, including hybrid and previously unknown manifestations of the disease. Rubino is one of a growing number of researchers who think that the relationship between the coronavirus and diabetes is actually a two-way street. Having diabetes doesn’t just tip the odds toward contracting a worse case of Covid-19. In some people, the virus might actually trigger the onset of diabetes, and the potential for a lifetime of having to manage it.

Source: https://www.wired.com/