Crispr Can Edit Directly Genes Inside Human Bodies

A decade ago, biologists Jennifer Doudna and Emmanuelle Charpentier published a landmark paper describing a natural immune system found in bacteria and its potential as a tool for editing the genes of living organisms. A year later, in 2013, Feng Zhang and his colleagues at the Broad Institute of MIT and Harvard reported that they’d harnessed that systemknown as Crispr, to edit human and animal cells in the lab. The work by both teams led to an explosion of interest in using Crispr to treat genetic diseases, as well as a 2020 Nobel Prize for Doudna and Charpentier.

Many diseases arise from gene mutations, so if Crispr could just snip out or replace an abnormal gene, it could in theory correct the disease. But one of the challenges of turning test tube Crispr discoveries into cures for patients has been figuring ouhow to get the gene-editing components to the place in the body that needs treatment.

One biotech company, Crispr Therapeutics, has gotten around that issue by editing patients’ cells outside the body. Scientists there have used the tool to treat dozens of people with sickle cell anemia and beta thalassemia—two common blood disorders. In those trials, investigators extract patients’ red blood cells, edit them to correct a disease-causing mutation, then infuse them back into the body.

But this “ex vivo” approach has downsides. It’s complex to administer, expensive, and has limited uses. Most diseases occur in cells and tissues that can’t be easily taken out of the body, treated, and put back in. So the next wave of Crispr research is focused on editingin vivo”—that is, directly inside a patient’s body. Last year, Intellia Therapeutics was the first to demonstrate that this was possible for a disease called transthyretin amyloidosis. And last week, the Cambridge, Massachusetts-based biotech company showed in-the-body editing in a second disease.

Source: https://www.intelliatx.com/
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https://www.wired.com/

New Bandage Could Seal Hole in the Heart

A Band-Aid® adhesive bandage is an effective treatment for stopping external bleeding from skin wounds, but an equally viable option for internal bleeding does not yet exist. Surgical glues are often used inside the body instead of traditional wound closure techniques like stitches, staples, and clips because they reduce the patient’s time in the hospital and lower the risk of secondary injury/damage at the wound site. An effective surgical glue needs to be strong, flexible, non-toxic, and able to accommodate movement, yet there are no adhesives currently available that have all of those properties. Researchers at the Wyss Institute (Harvard University) have developed a new super-strong hydrogel adhesive inspired by the glue secreted by a common slug that is biocompatible, flexible, and can stick to dynamically moving tissues even in the presence of blood.

The hydrogel itself is a hybrid of two different types of polymers: a seaweed extract called alginate that is used to thicken food, and polyacrylamide, which is the main material in soft contact lenses. When these relatively weak polymers become entangled with each other, they create a molecular network that demonstrates unprecedented toughness and resilience for hydrogel materials – on par with the body’s natural cartilage. When combined with an adhesive layer containing positively-charged polymer molecules (chitosan), the resulting hybrid material is able to bind to tissues stronger than any other available adhesive, stretch up to 20 times its initial length, and attach to wet tissue surfaces undergoing dynamic movement (e.g., a beating heart).

Studies of the hydrogel adhesive demonstrated that it is capable of withstanding three times the amount of tension that disrupts the best current medical adhesives, maintaining its stability and adhesion when implanted into rats for two weeks, and sealing a hole in a pig heart that was subjected to tens of thousands of cycles of pumping. Additionally, it caused no tissue damage or adhesions to surrounding tissues when applied to a liver hemorrhage in mice.

The hydrogel adhesive has numerous potential applications in the medical field, either as a patch that can be cut to desired sizes and applied to many tissues including bone, cartilage, tendon, or pleura, or as an injectable solution for deeper injuries. It can also be used to attach medical devices to their target structures, such as an actuator to support heart function. While the current iteration is designed to be a permanent structure, it could be made to biodegrade over time as the body heals from injury.

Source: https://wyss.harvard.edu/

How to Detect Diabetes Early Enough To Reverse It

Diabetes is a severe and growing metabolic disorder. It already affects hundreds of thousands of people in Switzerland. A sedentary lifestyle and an excessively rich diet damage the beta cells of the pancreas, promoting the onset of this disease. If detected early enough, its progression could be reversed, but diagnostic tools that allow for early detection are lacking. A team from the University of Geneva (UNIGE) in collaboration with several other scientists, including teams from the HUG, has discovered that a low level of the sugar 1,5-anhydroglucitol in the blood is a sign of a loss in functional beta cells. This molecule, easily identified by a blood test, could be used to identify the development of diabetes in people at risk, before the situation becomes irreversible. These results can be found in the Journal of Clinical Endocrinology & Metabolism.
In Switzerland, almost 500,000 people suffer from diabetes. This serious metabolic disorder is constantly increasing due to the combined effect of a lack of physical activity and an unbalanced diet. If detected early enough at the pre-diabetes stage, progression to an established diabetes can be counteracted by adopting an appropriate lifestyle. Unfortunately, one third of patients already have cardiovascular, renal or neuronal complications at the time of diagnosis, which impacts their life expectancy.

When diabetes starts to develop but no symptoms are yet detectable, part of the beta cells of the pancreas (in green) disappear (right image) compared to a healthy individual (left image). This previously undetectable decrease could be identified by measuring the level of 1,5-anhydroglucitol in the blood

‘‘Identifying the transition from pre-diabetes to diabetes is complex, because the status of the affected cells, which are scattered in very small quantities in the core of an organ located under the liver, the pancreas, is impossible to assess quantitatively by non-invasive investigations. We therefore opted for an alternative strategy: to find a molecule whose levels in the blood would be associated with the functional mass of these beta cells in order to indirectly detect their alteration at the pre-diabetes stage, before the appearance of any symptoms,’’ explains Pierre Maechler, a Professor in the Department of Cell Physiology and Metabolism and in the Diabetes Centre of the UNIGE Faculty of Medicine, who led this work.

Several years ago, scientists embarked on the identification of such a molecule able to detect pre-diabetes. The first step was to analyse thousands of molecules in healthy, pre-diabetic and diabetic mouse models. By combining powerful molecular biology techniques with a machine learning system (artificial intelligence), the research team was able to identify, from among thousands of molecules, the one that best reflects a loss of beta cells at the pre-diabetic stage: namely 1,5-anhydroglucitol, a small sugar, whose decrease in blood would indicate a deficit in beta cells.

Source: https://www.unige.ch/

Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Researchers from the Johns Hopkins University School of Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson’s disease, Lewy body dementia, and other neurocognitive disorders. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim was to find a new type of treatment that could specifically target the misshapen proteins, called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, onePFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” Mao says.

Source: https://hub.jhu.edu/

Stretchy Brain-mimicking AI BioSensor Tracks Continuously Your Health

It’s a brainy Band-Aid, a smart watch without the watch, and a leap forward for wearable health technologies. Researchers at the University of Chicago’s Pritzker School of Molecular Engineering (PME) have developed a flexible, stretchable computing chip that processes information by mimicking the human brain. The device, described in the journal Matter, aims to change the way health data is processed.

With this work we’ve bridged wearable technology with artificial intelligence and machine learning to create a powerful device which can analyze health data right on our own bodies,” said Sihong Wang, a materials scientist and Assistant Professor of Molecular Engineering.

Today, getting an in-depth profile about your health requires a visit to a hospital or clinic. In the future, Wang said, people’s health could be tracked continuously by wearable electronics that can detect disease even before symptoms appear. Unobtrusive, wearable computing devices are one step toward making this vision a reality.

The future of healthcare that Wang—and many others—envision includes wearable biosensors to track complex indicators of health including levels of oxygen, sugar, metabolites and immune molecules in people’s blood. One of the keys to making these sensors feasible is their ability to conform to the skin. As such skin-like wearable biosensors emerge and begin collecting more and more information in real-time, the analysis becomes exponentially more complex. A single piece of data must be put into the broader perspective of a patient’s history and other health parameters.

Source: https://pme.uchicago.edu/

Early Alzheimer’s Detection up to 17 Years in Advance

A sensor identifies misfolded protein biomarkers in the blood. This offers a chance to detect Alzheimer’s disease before any symptoms occur. Researchers intend to bring it to market maturity. The dementia disorder Alzheimer’s disease has a symptom-free course of 15 to 20 years before the first clinical symptoms emerge. Using an immuno-infrared sensor developed in Bochum (Germany), a research team is able to identify signs of Alzheimer’s disease in the blood up to 17 years before the first clinical symptoms appear. The sensor detects the misfolding of the protein biomarker amyloid-beta. As the disease progresses, this misfolding causes characteristic deposits in the brain, so-called plaques.

Our goal is to determine the risk of developing Alzheimer’s dementia at a later stage with a simple blood test even before the toxic plaques can form in the brain, in order to ensure that a therapy can be initiated in time,” says Professor Klaus Gerwert, founding director of the Centre for Protein Diagnostics (PRODI) at Ruhr-Universität Bochum (RUB). His team cooperated for the study with a group at the German Cancer Research Centre in Heidelberg (DKFZ) headed by Professor Hermann Brenner.

The team published the results obtained with the immuno-infrared sensor in the journal “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association” on 19 July 2022. This study is supported by a comparative study published in the same journal on 2 March 2022, in which the researchers used complementary single-molecule array (SIMOA) technology.

The researchers analysed blood plasma from participants in the ESTHER study conducted in Saarland for potential Alzheimer’s biomarkers. The blood samples had been taken between 2000 and 2002 and then frozen. At that time, the test participants were between 50 and 75 years old and hadn’t yet been diagnosed with Alzheimer’s disease. For the current study, 68 participants were selected who had been diagnosed with Alzheimer’s disease during the 17-year follow-up and compared with 240 control subjects without such a diagnosis. The team headed by Klaus Gerwert and Hermann Brenner aimed to find out whether signs of Alzheimer’s disease could already be found in the blood samples at the beginning of the study.

The immuno-infrared sensor was able to identify the 68 test subjects who later developed Alzheimer’s disease with a high degree of test accuracy (0,78 AUC, Area under Curve). For comparison, the researchers examined other biomarkers with the complementary, highly sensitive SIMOA technology – specifically the P-tau181 biomarker, which is currently being proposed as a promising biomarker candidate in various studies.

Blood Test Spots Signs of Alzheimer’s Years Before Symptoms Appear

“Unlike in the clinical phase, however, this marker is not suitable for the early symptom-free phase of Alzheimer’s disease,
” as Klaus Gerwert summarises the results of the comparative study. “Surprisingly, we found that the concentration of glial fibre protein (GFAP) can indicate the disease up to 17 years before the clinical phase, even though it does so much less precisely than the immuno-infrared sensor.” Still, by combining amyloid-beta misfolding and GFAP concentration, the researchers were able to further increase the accuracy of the test in the symptom-free stage to 0,83 AUC.

The Bochum researchers hope that an early diagnosis based on the amyloid-beta misfolding could help to apply Alzheimer’s drugs at such an early stage that they have a significantly better effect – for example, the drug Aduhelm, which was recently approved in the USA. “We plan to use the misfolding test to establish a screening method for older people and determine their risk of developing Alzheimer’s dementia,” says Klaus Gerwert. “The vision of our newly founded start-up betaSENSE is that the disease can be stopped in a symptom-free stage before irreversible damage occurs.” Even though the sensor is still in the development phase, the invention has already been patented worldwide. BetaSENSE aims to bring the immuno-infrared sensor to market and have it approved as a diagnostic device so that it can be used in clinical labs.

Source: https://news.rub.de/

Memory Problems Common in Old Age Can Be Reversed

While immortality might forever be out of reach, a long, healthy retirement is the stuff dreams are made of. To that end, a recent study suggests that the kinds of memory problems common in old age can be reversed, and all it takes is some cerebrospinal fluid (CSF) harvested from the young. In mice, at least.

If this is sounding a little familiar, you might be thinking of a similar series of studies done back in the mid-2010s, which found that older mice could be generally ‘rejuvenated‘ with the blood of younger animals – both from humans and from mice. The FDA even had to warn people to stop doing it. This new study instead examined the links between memory and cerebrospinal fluid  (CSF), and the results show considerable promise, even providing a mechanism for how it works, and highlighting a potential growth factor that could mimic the results.

“We know that CSF composition changes with age, and, in fact, these changes are used routinely in the clinic to assess brain health and disease biomarkers,” Stanford University neurologist Tal Iram said. “However, we don’t know well how these changes affect the function of the cells in the aging brain.

To investigate, the researchers, led by Iram, took older mice (between 18–22 months old) and gave them light shocks on the foot, at the same time as a tone and flashing light were activated. The mice were then split into groups, and either given young mouse CSF (from animals 10 weeks old) or artificial CSF. In experiments like this, if the mice ‘freeze’ when they see the tone and light, it means they’re remembering the foot shock, and are preparing for it to happen again. In this study, three weeks after the foot shocks were conducted (which the team called “memory acquisition“), the researchers tested the mice, finding that the animals that had been given the CSF from young mice showed higher-than-average freezing rates, suggesting they had better memory. This was followed up by a battery of other experiments to test the theory, which revealed that certain genes (that are different in young-versus-old CSF) could be used to get the same response. In other words, without needing to extract someone’s brain fluid.

When we took a deeper look into gene changes that occurred in the hippocampus (a region associated with memory and aging-related cognitive decline), we found, to our surprise, a strong signature of genes that belong to oligodendrocytes,” Iram explained. “Oligodendrocytes are unique because their progenitors are still present in vast numbers in the aged brain, but they are very slow in responding to cues that promote their differentiation. We found that when they are re-exposed to young CSF, they proliferate and produce more myelin in the hippocampus.” Oligodendrocytes are particularly helpful because they produce myelin, a material that covers and insulates neuron fibers.

Blood iron levels could be key to slowing ageing

Genes linked to ageing that could help explain why some people age at different rates to others have been identified by scientists. The international study using genetic data from more than a million people suggests that maintaining healthy levels of iron in the blood could be a key to ageing better and living longerThe findings could accelerate the development of drugs to reduce age-related diseases, extend healthy years of life and increase the chances of living to old age free of disease, the researchers say.

Scientists from the University of Edinburgh and the Max Planck Institute for Biology of Ageing in Germany focused on three measures linked to biological ageinglifespan, years of life lived free of disease (healthspan), and being extremely long–lived (longevity). Biological ageing – the rate at which our bodies decline over timevaries between people and drives the world’s most fatal diseases, including heart disease, dementia and cancers.

The researchers pooled information from three public datasets to enable an analysis in unprecedented detail. The combined dataset was equivalent to studying 1.75 million lifespans or more than 60,000 extremely long-lived people. The team pinpointed ten regions of the genome linked to long lifespan, healthspan and longevity. They also found that gene sets linked to iron were overrepresented in their analysis of all three measures of ageing.

Source: https://www.thebrighterside.news/

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/