Thrivous

Researchers led by RIKEN Center for Brain Science have shown that the free-energy principle can explain how neural networks are optimized for efficiency. The free-energy principle is a mathematical optimization principle that many systems, including living systems, are thought to follow. These systems are thought to always minimize a mathematical function called free energy. While at this moment the free-energy principle is not rigorously derivable from known science, it seems to work in many important cases. The free-energy principle is based on Bayesian inference. It's a mathematical technique that facilitates probability estimates. And it can help with planning optimization and decision making, as new information becomes available. Living systems are continuously updated by new incoming sensory data. And they remember their own past decisions. This, the researchers have shown, is also the case with neural networks. Biological optimization makes our bodies and behavior as efficient as possible. In the brain, neural networks are optimized to allow efficient control of behavior and transmission of information. This is done while still maintaining the ability to adapt and reconfigure to changing environments. The researchers compared the free-energy principle with well-established rules that control how the strength of neural connections within a network can be altered by changes in sensory input. In his recent and widely praised book, “ Being You: A New Science of Consciousness ” (2021), neuroscientist Anil Seth describes the free-energy principle. He writes that it's “a piece of mathematical philosophy” according to which “organisms maintain themselves in the low-entropy states that ensure their continued existence by actively minimising this measurable quantity called free energy.” And it's “basically the same thing as sensory prediction error.” There's also a forthcoming book, “ Active Inference: The Free Energy Principle in Mind, Brain, and Behavior ” (2022), co-authored by Karl Friston. He introduced the free-energy principle. And his book is likely to provide an end-to-end explanation. The researchers have demonstrated that standard neural networks “perform planning and adaptive behavioral control by taking their previous 'decisions' into account," says researcher Takuya Isomura in a press release issued by RIKEN. "Importantly, they do so the same way that they would when following the free-energy principle." An open access study is published in Communications Biology. It shows how the free-energy principle is the basis for any neural network that minimizes energy cost. Then, as proof-of-concept, it shows how a free-energy minimizing neural network can solve mazes. This research points the way to a better understanding of general neural networks. It suggests a better understanding of brain networks and their impairments and malfunctions in disorders such as schizophrenia. And it may contribute to the development of thinking machines based on neural networks. “Our findings guarantee that an arbitrary neural network can be cast as an agent that obeys the free-energy principle, providing a universal characterization for the brain,” adds Isomura. “Our theory can dramatically reduce the complexity of designing self-learning neuromorphic hardware to perform various types of tasks, which will be important for a next-generation artificial intelligence.”

Scientists at UC San Francisco have found that, when elderly people stay active, their brains have more of a class of proteins that enhances the connections between neurons to maintain healthy cognition. In other words, the benefits of exercise for older adults include brain health, learning, and memory. "It may be that physical activity exerts a global sustaining effect, supporting and stimulating healthy function of proteins that facilitate synaptic transmission throughout the brain," says research leader William Honer in a press release issued by UC San Francisco. Protection from toxic proteins, that cause synapses and neurons to fall apart, promotes synaptic integrity and reduces the risk of neurodegeneration. A research paper is published in Alzheimer's & Dementia. It analyzes data from the Memory and Aging Project at Rush University. That project tracked the late-life physical activity of elderly participants, who also agreed to donate their brains when they died. The UC San Francisco scientists found that active elderly people had higher levels of proteins that facilitate the exchange of information between neurons. Surprisingly, these effects ranged beyond the hippocampus, the brain's seat of memory. They encompassed other brain regions associated with cognitive function. Earlier findings indicated that people who had more of these proteins in their brains when they died were better able to maintain their cognition late in life. "Our work is the first that uses human data to show that synaptic protein regulation is related to physical activity and may drive the beneficial cognitive outcomes we see," says researcher Kaitlin Casaletto. In the paper, the researchers suggest “that [physical activity] may help build synaptic health, even at late ages … but that this is a potentially plastic process that may need to be sustained over time.” According to the researchers, this approach to cognitive functioning and resilience is “of high relevance in our aging population.” "Maintaining the integrity of these connections between neurons may be vital to fending off dementia, since the synapse is really the site where cognition happens," adds Casaletto. "Physical activity - a readily available tool - may help boost this synaptic functioning." I may have mentioned one or two times that I don’t enjoy physical activity too much. I very much prefer brainy activity. But I am not getting any younger. And I guess my brain is not as sharp as it used to be. I can see that physical activity helps my brain stay sharp enough. So yes, I force myself to do regular exercise. And so should you. "In older adults with higher levels of the proteins associated with synaptic integrity, this cascade of neurotoxicity that leads to Alzheimer's disease appears to be attenuated," concludes Casaletto. "Taken together, these two studies show the potential importance of maintaining synaptic health to support the brain against Alzheimer's disease."

Scientists at McGill University have developed a biomaterial tough enough to repair the heart, muscles, and vocal cords. This development combines advances in chemistry, physics, biology, and engineering. According to the scientists, it represents a major advance in regenerative medicine. "Our work highlights the synergy of materials science, mechanical engineering and bioengineering in creating novel biomaterials with unprecedented performance,” says research co-leader Jianyu Li in a press release issued by McGill University. “We are looking forward to translating them into the clinic." A paper is published in Advanced Science. It describes the new biomaterial, which is an injectable hydrogel for wound repair. The hydrogel is a type of biomaterial that provides room for cells to live and grow. Once injected into the body, the biomaterial forms a stable, porous structure allowing live cells to grow or pass through to repair the injured organs. "People recovering from heart damage often face a long and tricky journey. Healing is challenging because of the constant movement tissues must withstand as the heart beats. The same is true for vocal cords. Until now there was no injectable material strong enough for the job," says researcher Guangyu Bao. “The results are promising, and we hope that one day the new hydrogel will be used as an implant to restore the voice of people with damaged vocal cords, for example laryngeal cancer survivors." Physics World explains that “injectable hydrogels are desirable in many areas of regenerative medicine, from drug delivery to lab-on-a-chip disease models.” But many hydrogels break down under stress due to their porous structure. Porosity allows oxygen and nutrients to perfuse through implantable biomaterials. But it often comes at the expense of mechanical strength. Biological tissues such as the heart and the vocal cords are constantly vibrating. And designing synthetic tissue that can survive vibrations remains a challenge in regenerative medicine. The McGill researchers developed a porous “double-network” hydrogel that is able to withstand millions of cycles of mechanical loading better than the “single-network” hydrogels that have been used so far. “Most synthetic materials developed so far for vocal cord repair are based on single-network hydrogels,” Bao told Physics World. “Currently, patients may need periodic injections because those hydrogels do not last long. Our hydrogel offers a 5- to 40-fold increase in toughness, which could potentially improve the retention of the hydrogel after injection.” According to the scientists, this innovation could enable applications like drug delivery, tissue engineering, and the creation of model tissues for drug screening. The scientists are looking to use the hydrogel technology to create lungs to test COVID-19 drugs.

Researchers at Indiana University have developed a silicon device that can change skin tissue into blood vessels and nerve cells. The device has advanced from prototype to standardized fabrication, meaning it can now be made in a consistent, reproducible way. A research paper is published in Nature Protocols. It describes a non-invasive nanochip device, based on tissue nanotransfection technology. This technology can reprogram tissue function by applying a harmless electric spark to deliver specific genes in a fraction of a second. Tissue nanotransfection technology has been developed with the ultimate goal of enabling skin and other tissue to be converted to tissue types necessary for therapy. The technology uses nanotechnology-based chip hardware to deliver biological cargo (genes or drugs) to adult cells in the live body, and convert the cells from one type to another. It is non-invasive, does not require any laboratory-based procedures, avoids the use of stem cells, eliminates the need to use viral vectors, is simple to use, and may be implemented at the point of care. In laboratory studies described in the Nature Protocols paper, the new device successfully converted skin tissue into blood vessels to repair a badly injured leg. The technology is currently being used to reprogram tissue for different kinds of therapies, such as repairing brain damage caused by stroke or preventing and reversing nerve damage caused by diabetes. "This report on how to exactly produce these tissue nanotransfection chips will enable other researchers to participate in this new development in regenerative medicine," said lead researcher Chandan Sen in a press release issued by Indiana University. "This small silicon chip enables nanotechnology that can change the function of living body parts," explained Sen. "For example, if someone's blood vessels were damaged because of a traffic accident and they need blood supply, we can't rely on the pre-existing blood vessel anymore because that is crushed, but we can convert the skin tissue into blood vessels and rescue the limb at risk." The Nature Protocols paper includes engineering details about how the chip is manufactured. "This is about the engineering and manufacturing of the chip," said Sen. "The chip's nanofabrication process typically takes five to six days and, with the help of this report, can be achieved by anyone skilled in the art." The manufacturing information could lead to further development of the chip, which could someday be used clinically in many settings around the world. The researchers plan to seek FDA approval for the chip. Once it receives approval, the device could be used for clinical research in people, including patients in hospitals, health centers and emergency rooms, as well as in other emergency situations by first responders or the military.

Small chemical changes to DNA, known as epigenetic changes, alter how genes are expressed in certain tissues and cells. Some of these changes happen as a person ages. And others may be in response to a person’s environment or life experiences. These epigenetic changes can be used to accurately predict a person’s age from a DNA sample. Or, if a person’s epigenetic age differs from their actual age, it can indicate differences in health, including age-related diseases and early mortality. Therefore, it is possible to develop “aging clocks” based on epigenetic changes. Epigenetic clocks include the Horvath, Hannum, Levine, and Zhang aging clocks, described in previous posts. They measure aging processes at the molecular level. A 2019 study published in PNAS describes a molecular clock that could reshape how pediatricians measure and monitor childhood growth. And it could allow for an earlier diagnosis of life-altering development disorders. The study describes a method specifically designed for children, called the Pediatric-Buccal-Epigenetic (PedBE) clock. It measures chemical changes to determine the biological age of a child’s DNA. "This powerful and easy-to-use tool could be used by clinicians to identify why some children aren't meeting early milestones and potentially diagnose children with developmental disorders earlier in life," said Lisa McEwen, first author on the study, in a press release issued by University of British Columbia. "This would enable doctors and pediatricians to intervene sooner in a child's life leading to better outcomes for kids." The PedBE clock was developed using DNA methylation profiles from 1,032 healthy children, whose ages ranged from a few weeks old to 20 years. DNA methylation is an epigenetic change by which chemical tags are added to the DNA molecule. It can change the activity of a DNA segment without changing the sequence. The researchers found 94 different sites in the genome that, when tested together, could accurately predict a child’s age to within about four months. The researchers also found that children who spent longer in the womb showed an accelerated rate of DNA change by three months, demonstrating that this tool could be used to indicate an infant’s developmental stage. The analysis can be done cheaply and efficiently on cells collected from a cheek swab. "We have a good idea how these DNA changes occur in adults, but until now we didn’t have a tool that was specific for children," said Michael Kobor, senior author of the study. "These DNA changes occur at very different rates in kids and so we adapted this technique for younger ages." In a small pilot study, the researchers also found that children with autism showed a higher PedBE “age” than those considered to be developing typically. This suggests that the clock could be used to screen for autism. “The fact that our pediatric clock was able to distinguish between typically developing children and those with autism in this small experiment demonstrates the powerful potential of this tool,” added Kobor. “Although more research is needed to confirm this, these results show that the PedBE clock could be an important factor in evaluating how children develop.”

Researchers at Arizona State University have reviewed a class of viruses that act to combat rather than cause cancer. They are known as oncolytic viruses. And they have a remarkable ability to target and destroy cancer cells, while leaving healthy cells untouched. "The field of oncolytic virotherapy today is advancing rapidly as clinical trial data accumulates and regulatory approvals continue to accrue," says Grant McFadden in a press release issued by Arizona State University. McFadden is the director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy. A paper is published in Cancers. It reviews oncolytic viruses, which are viruses that selectively target and kill cancer cells while sparing normal ones. And it explores how oncolytic viruses are emerging as key cancer treatment agents. Genetically engineered oncolytic viruses have been developed to work around the therapeutic limitations of naturally occurring ones. The first clues that oncolytic viruses may exist in nature came over a century ago. Physicians noticed that some cancers appeared to regress in patients that also had infections. Many oncolytic viruses can directly attack and kill cancer cells. But their primary strength may be their ability to alert an inactive or disabled immune system to the presence of cancer. Oncolytic viruses can be genetically re-engineered to sharpen their lethality to cancer cells, as well as their ability to stimulate the immune system. The Arizona State University researchers worked with a promising rabbit virus with oncolytic properties. It is called myxoma virus. And it attacks and kills human cancer cells, while being completely harmless to non-cancerous cells. Myxoma virus is an attractive candidate for oncolytic virotherapy because its large genome is amenable to improvements using genetic modification. Scientists may be able to enhance its ability to kill cancer and, at the same time, enhance its ability to trigger a stronger anti-cancer response from the immune system. The researchers suggest that oncolytic virotherapy could be especially successful in combination with a form of cancer immunotherapy based on checkpoint inhibitors. "When patients respond to checkpoint inhibitors, it's often like magic," McFadden says. "They can undergo massive tumor regression and long term, disease-free survival." Cancers exploit proteins called checkpoint proteins to protect themselves from the immune system. And drugs based on checkpoint inhibitors can switch the immune system back on. However, this only works for a minority of cancer patients. "New approaches like immune checkpoint inhibitors are very effective in reducing the tumor burden and improving survival, but it works only in a small number of patients - only 10-20%," cautions researcher Masmudur Rahman. The researchers suggest that the majority of patients never develop an immune response to cancers, leaving nothing for the checkpoint inhibitor to restart. Here is where oncolytic virotherapy can boost cancer immunotherapy based on checkpoint inhibitors. "We believe that if you get an infection going in the tumor bed, you can generate a new kind of immune response to both the tumor and the virus at the same time," McFadden concludes. "That new immune response, we hope, will result in more patients being susceptible to immunotherapies like checkpoint inhibitors." Only four oncolytic viruses have been approved globally for clinical use. But others, including myxoma, are in pre-clinical trials. McFadden recently formed the company Oncomyx Therapeutics to further explore oncolytic virotherapy based on the myxoma virus.

Humans evolved to live many decades after they stopped reproducing. Evolutionary biologists and biomedical researchers at Harvard have presented evolutionary and biomedical evidence showing that we also evolved to be physically active in our later years. "It's a widespread idea in Western societies that as we get older, it's normal to slow down, do less, and retire," says evolutionary biologist Daniel E. Lieberman in The Harvard Gazette. "Our message is the reverse: As we get older, it becomes even more important to stay physically active." A paper is published in PNAS. The researchers argue that physical activity later in life shifts energy away from processes that can compromise health and toward mechanisms in the body that extend it. Physical activity reallocates energy to repair and maintenance processes in the body. This guards against the body's gradual deterioration over the years, against chronic illnesses such as cardiovascular disease and diabetes, and even against some cancers. According to the researchers, the paper is the first detailed evolutionary explanation for why lack of physical activity as humans age increases disease risk and reduces longevity. Why should Darwinian evolution care about what happens to individuals decades after the end of their reproductive age? The researchers argue that Darwinian selection promoted efficient energy allocation mechanisms that slow senescence and reduce vulnerability to many forms of chronic diseases. Physical activity levels have been decreasing worldwide as machines and technology replace human labor. Americans are engaging in less physical activity than they did 200 years ago, and six to ten times less than contemporary hunter-gatherers. This physical inactivity is bad for health. We should be “active grandparents” instead. "The key take-home point is that because we evolved to be active throughout our lives, our bodies need physical activity to age well,” continues Lieberman. “In the past, daily physical activity was necessary in order to survive, but today we have to choose to exercise, that is do voluntary physical activity for the sake of health and fitness." I have always been a typical couch potato who very much prefers reading a good book to any form of physical exercise. But I force myself to exercise regularly to stay in good health. "The key is to do something, and to try to make it enjoyable so you'll keep doing it," concludes Lieberman. "The good news is that you don't need to be as active as a hunter-gatherer. Even small amounts of physical activity - just 10 or 20 minutes a day - substantially lower your risk of mortality." That’s what I do, more or less. I average about 20 minutes of physical activity a day, mostly swimming and hiking. I find this good not only for physical health, but also for mental health.

Researchers investigated whether a perfect DNA methylation-based measure of biological age is theoretically available. And they reported the results of their study in a 2019 paper published in Genome Medicine. Biological age is not always the same as chronological age. In fact, persons with the same chronological age can vary in health, especially in later life. “DNA methylation changes with age,” reads the abstract of the paper. “Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks.’” The lead author of the paper is Qian Zhang, now at Wellcome Sanger Institute. DNA methylation is a biological process by which chemical tags are added to the DNA molecule. It can change the activity of a DNA segment without changing the sequence. The methylation marks fundamentally change the way individual cells use the genome. Epigenetics is the study of chemical and structural modifications made to the genome. The changes do not alter the DNA sequence. But they are still passed along as cells divide. And they can influence how genes are expressed. Epigenetic clocks include the Horvath, Hannum, and Levine aging clocks, described in previous posts. They measure aging processes at the molecular level. The first epigenetic clocks were developed 10 years ago. A recent review article was published by the Simons Foundation. It explains, “scientists have developed dozens of new versions, constructed from different methylation sites and fine-tuned to different purposes.” For this Genome Medicine study, the researchers used thousands of blood samples and hundreds of saliva samples from test subjects of all ages (ranging from 2 to 104). Then the researchers built different age predictors based on DNA methylation analysis. And they trained the predictors with the sample data, using sophisticated statistical techniques. Finally, the researchers ran the predictors over new samples, and compared the results of the predictors. According to the researchers, the results of the study indicate that “a perfect age predictor can in principle be developed based on DNA methylation data.” The researchers found that larger sample sizes lead to a more accurate prediction of age. This seems to indicate that near-perfect epigenetic clocks can be built based on very large data sets. The difference between the chronological age and the biological age measured by the Zhang clock seems to be associated with an increased risk of age-related diseases and death. That is also the case for the Horvath, Hannum, and Levine aging clocks. However, the existing approaches have limitations. And the researchers caution against a strict interpretation of estimates from epigenetic clocks as an indicator of mortality or lifespan.

Researchers at University of Minnesota and Massachusetts General Hospital have shown that it is possible to improve specific human brain functions related to self-control and mental flexibility. They did this by merging Artificial Intelligence (AI) with targeted electrical brain stimulation. "This system can read brain activity, 'decode' from that when a patient is having difficulty, and apply a small burst of electrical stimulation to the brain to boost them past that difficulty," said researcher Alik Widge in a press release issued by University of Minnesota. "The analogy I often use is an electric bike. When someone's pedaling but having difficulty, the bike senses it and augments it. We've made the equivalent of that for human mental function." The researchers conducted a study. It is described in a paper published in Nature Biomedical Engineering. The study included 12 brain surgery (for epilepsy) patients, implanted with hundreds of tiny electrodes throughout the brain. The researchers found that electrical stimulation of a specific brain region improved cognitive control. This was expressed in the ability to to shift from one thought pattern or behavior to another. "An example might include a person with depression who just can't get out of a 'stuck' negative thought,” noted Widge. “Because it is so central to mental illness, finding a way to improve it could be a powerful new way to treat those illnesses." Then the researchers used AI algorithms to track the cognitive control abilities of the patients in realtime and provide boosts of stimulation whenever needed. Some patients suffering from anxiety reported that their anxiety was reduced by the cognitive-enhancing stimulation. They were more able to shift their thoughts away from their distress. This suggests that this method could be used to treat patients with anxiety or depression. "This could be a totally new approach in treating mental illness. Instead of trying to suppress symptoms, we could give patients a tool that lets them take control of their own minds," Widge concluded. "We could put them back in the driver's seat and let them feel a new sense of agency." "The wonderful thing about these findings is that we are now in a position to conduct clinical trials to further demonstrate effectiveness and then hopefully move to helping treatment-resistant patients who are in desperate need for additional interventions to treat their illnesses," added researcher Darin Dougherty. The researchers are now preparing for clinical trials. Because deep brain stimulation is already approved by the U.S. Food and Drug Administration for improving cognitive control, existing tools and devices could be used in clinical trials. And the translation to medical practice could be rapid.

Northwestern University researchers have developed a new injectable therapy that harnesses "dancing molecules" to reverse paralysis and repair tissue after severe spinal cord injuries. The new injectable therapy is based on nanofibers. It is described in a paper published in Science. The therapy has been tested on paralyzed laboratory mice with severe spinal cord injuries. The researchers administered a single injection to tissues surrounding the spinal cords of the paralyzed mice. Just four weeks later, the animals regained the ability to walk. "Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease," said research leader Samuel Stupp, who led the study. "Currently, there are no therapeutics that trigger spinal cord regeneration. I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients.” The new therapy dramatically improved severely injured spinal cords in five ways: Regenerated the severed extensions of neurons, called axons Diminished scar tissue, which can create a physical barrier to regeneration and repair Reformed myelin, the insulating layer of axons around cells that is important in transmitting electrical signals efficiently Formed functional blood vessels to deliver nutrients to cells at the injury site Increased survival of motor neurons How does the new therapy work? A synthetic material is injected as a liquid. It gels into structures of nanofibers that mimic the shape of the spinal cord. And the researchers have been able to control the collective motion of more than 100,000 molecules within the nanofibers. Once connected to cells, the moving molecules trigger signals that promote spinal cord repair. The synthetic signals are short chains of amino acids that survive for weeks. The molecules move, "dance," or even leap temporarily out of these structures. And this enables them to connect more effectively with the cells. "Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often," explained Stupp. "If the molecules are sluggish and not as 'social,' they may never come into contact with the cells." "We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options," announced Stupp. The new therapy could be used to prevent paralysis after major trauma or from diseases. The researchers are persuaded that the underlying technique of controlling and leveraging molecular motion can be applied to other medical cases such as neurodegenerative diseases and stroke. The “fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets," concluded Stupp.