Scientists at the University of Utah report that youthful plasticity has been restored to aging mouse brains by manipulating only a single gene.
Like much of the rest of the body, the brain loses flexibility with age, impacting the ability to learn, remember and adapt. Now, scientists at the University of Utah Health report they can rejuvenate the plasticity of the mouse brain – specifically in the visual cortex – increasing its ability to adapt and change in response to new experiences. Furthermore, manipulating only a single gene is enough to trigger this improvement. The research appears this week in Proceedings of the National Academy of Sciences (PNAS).
"It's exciting because it suggests that by just manipulating one gene in adult brains, we can boost brain plasticity," says lead author Jason Shepherd, Ph.D., Assistant Professor of Neurobiology and Anatomy. "This has implications for potentially reducing normal cognitive decline with aging, or boosting recovery from brain injury after stroke or traumatic brain injury," he says. Additional research will need to be done to determine whether plasticity in humans and mice is regulated in the same way.
In a previous study, Shepherd and his colleagues found that during youth, a "critical window" of brain plasticity is never available to mice lacking a gene known as Arc. Temporarily closing a single eye of a normal young mouse deprived the visual cortex of normal input, and the neurons' electrophysiological response to visual experience changed. By contrast, young mice without Arc could not adapt to the new experience in the same way.
"Given our previous studies, we wondered whether Arc is essential for controlling the critical period of plasticity during normal brain development," explains Shepherd.
Overexpressed Arc in the visual cortex. Credit: Elissa Pastuzyn
If there is no visual plasticity without Arc, then perhaps the gene plays a role in keeping the "critical window" open? In support of this idea, the team's latest investigation finds that in the mouse visual cortex, Arc rises and falls in parallel with visual plasticity. The two peak in teen mice, falling sharply by middle age – suggesting they are linked.
The team probed this connection further in two more ways. First, they tested mice with a strong supply of Arc throughout life. At middle age, these mice responded to visual deprivation as robustly as their juvenile counterparts. By prolonging Arc's availability, the window of plasticity was open for longer.
A second set of experiments raised the bar higher. Viruses were used to deliver Arc to middle age mice, after the critical window had shut. Following this intervention, these older mice responded to visual deprivation just as a youngster would. So even though the window had already closed, Arc enabled it to open once again.
"It was incredible to see that in adult mice, who have gone through normal development and aging, simply overexpressing Arc with a virus restored plasticity," says co-first author Kyle Jenks, a graduate student in Shepherd's lab.
Additional research will now be required to understand precisely how manipulating Arc boosts plasticity. Whether Arc is involved in regulating the plasticity of neurological functions mediated by other brain structures – such as learning, memory, or repair – remains to be tested, but will be examined in the future, says Shepherd.
For the first time, scientists have used the CRISPR system in human embryos to delete faulty DNA responsible for a hereditary heart condition.
Credit: Oregon Health and Science University (OHSU)
Scientists have, for the first time, corrected a disease-causing mutation in early stage human embryos with gene editing. The technique, which uses the CRISPR-Cas9 system, corrected the mutation for a heart condition at the earliest stage of embryonic development so that the defect would not be passed on to future generations.
The work, described today in the journal Nature, is a collaboration between the Salk Institute, Oregon Health and Science University (OHSU) and Korea's Institute for Basic Science. It could pave the way for improved in vitro fertilization (IVF) outcomes, as well as eventual cures for some of the thousands of diseases caused by mutations in single genes.
"Thanks to advances in stem cell technologies and gene editing, we are finally starting to address disease-causing mutations that impact potentially millions of people," says Juan Carlos Izpisua Belmonte, a professor in Salk's Gene Expression Laboratory and a corresponding author of the paper. "Gene editing is still in its infancy, so even though this preliminary effort was found to be safe and effective, it is crucial that we continue to proceed with the utmost caution, paying the highest attention to ethical considerations."
Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden death in otherwise healthy young athletes, and affects approximately 1 in 500 people overall. It is caused by a dominant mutation in the MYBPC3 gene, but often goes undetected until it is too late. Since people with a mutant copy of the MYBPC3 gene have a 50 percent chance of passing it on to their own children, being able to correct the mutation in embryos would prevent the disease not only in affected children, but also in their descendants.
The researchers generated induced pluripotent stem cells from a skin biopsy donated by a male with HCM and developed a gene-editing strategy based on CRISPR-Cas9 that would specifically target the mutated copy of the MYBPC3 gene for repair. The targeted mutated MYBPC3 gene was cut by the Cas9 enzyme, allowing the donor's cells' own DNA-repair mechanisms to fix the mutation during the next round of cell division by using either a synthetic DNA sequence or the non-mutated copy of MYBPC3 gene as a template.
Using IVF techniques, the researchers injected the best-performing gene-editing components into healthy donor eggs newly fertilised with the donor's sperm. Then they analysed all the cells in the early embryos at single-cell resolution to see how effectively the mutation was repaired.
The scientists were surprised by just how safe and efficient the method was. Not only did a high percentage of embryonic cells get repaired, but also gene correction did not induce any detectable off-target mutations and genome instability – major concerns for gene editing. In addition, the researchers developed a robust strategy to ensure the repair occurred consistently in all the cells of the embryo (spotty repairs can lead to some cells continuing to carry mutations – see illustration below).
Professor Belmonte and his colleagues emphasise that, although promising, these are very preliminary results and more research will need to be done to ensure no unintended effects occur.
"Our results demonstrate the great potential of embryonic gene editing, but we must continue to realistically assess the risks as well as the benefits," adds Belmonte.
Future work will continue to assess the safety and effectiveness of the procedure and efficacy of the technique with other mutations.
However, this latest study has already been condemned by Dr David King, from the campaign group Human Genetics Alert, which described the research as "irresponsible" and a "race for first genetically modified baby".
"Perhaps the biggest question, and probably the one that will be debated the most, is whether we should be physically altering genes of an IVF embryo at all," said Darren Griffin, a professor of genetics at the University of Kent. "This is not a straightforward question. Equally, the debate on how morally acceptable it is not to act when we have the technology to prevent these life-threatening diseases must also come into play."
Researchers have discovered that stem cells in the brain's hypothalamus govern how fast aging occurs in the body.
Scientists from the Albert Einstein College of Medicine in New York have discovered that stem cells in the brain's hypothalamus govern how fast aging occurs in the body. This finding, made in mice, could lead to new strategies for warding off age-related diseases and extending lifespan. A paper was published online yesterday in Nature.
The hypothalamus was already known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 paper, researchers from Einstein made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons.
"Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging," says Dongsheng Cai, Professor of Molecular Pharmacology. "But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it's possible to slow and even reverse various aspects of aging throughout the body."
In a series of tests, mice were implanted with stem cells that made fresh neurons, which kept them more physically and mentally fit for months. They had their lives extended by up to 15% compared to untreated animals – the equivalent of boosting a human lifespan from 80 to 92.
"Of course humans are more complex," said Cai, who led the research. "However, if the mechanism is fundamental, you might expect to see effects when an intervention is based on it."
Dr. Cai and his colleagues found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). These are not involved in protein synthesis, but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice.
The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed; and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioural testing that involved assessing changes in the animals' muscle endurance, coordination, social behaviour and cognitive abilities.
"It is a tour de force," said David Sinclair at Harvard Medical School. "It's a breakthrough. The brain controls how long we live. I can see a day when we are implanted with stem cells or treated with stem cell RNAs that improve our health and extend our lives. I would love to know which brain stem cell secretions extend a mouse's lifespan and if human stem cells make them too."
The researchers are now trying to identify the particular populations of microRNAs and perhaps other factors secreted by these stem cells that are responsible for these anti-aging effects – a first step toward possibly slowing the aging process and treating age-related diseases.
Astrophysicists report that tardigrade micro-animals may be one of the most resilient lifeforms on Earth, able to withstand global mass extinctions due to astrophysical events, such as supernovae, gamma-ray bursts, large asteroid impacts, and passing-by stars.
The world's most indestructible species, the tardigrade – an eight-legged micro-animal, also known as the water bear – will survive until the Sun dies, according to a new collaboration between Harvard and Oxford University.
Although much attention has been given to the potential impact of astrophysical events on human life, very little has been published about what it would take to kill the tardigrade and wipe out life on our planet. The new research implies that life will persist for as long as the Sun continues to shine. It also reveals that once life emerges, it is surprisingly resilient and difficult to destroy, boosting the odds of life on other planets.
The study, published in Scientific Reports, shows that the tiny creatures will survive the risk of extinction from all astrophysical catastrophes, and be around for billions of years – far longer than the human race.
Tardigrades are the toughest, most resilient animals on Earth – able to survive for up to 30 years without food or water, and endure temperature extremes of up to 150 degrees Celsius, the deep sea and even the frozen vacuum of space. The water-dwelling micro animal is only 0.5mm (0.02 inches) in size, but can live for up to 60 years. Researchers from the Universities of Oxford and Harvard concluded that they could most likely survive all astrophysical calamities.
Three potential events were considered as part of their research:
There are only a dozen known asteroids and dwarf planets with enough mass to boil the oceans (2x10^18 kg), these include Vesta (2x10^20 kg) and Pluto (10^22 kg). However, none of these objects will intersect the Earth's orbit and pose a threat to tardigrades.
In order to boil the oceans, an exploding star would need to be 0.14 light years away. The closest star to the Sun is 4.2 light years away and the probability of a massive star exploding close enough to Earth to kill all lifeforms on it, within the Sun's lifetime, is negligible.
Gamma-ray bursts are brighter and rarer than supernovae. Much like supernovas, gamma-ray bursts are too far away from Earth to be considered a viable threat. To boil the world's oceans, the burst would need to be within 40 light years, and the likelihood of a burst occurring so close is again, minor.
Gamma-ray burst. Credit: NASA
"Without our technology protecting us, humans are a very sensitive species," said Dr Rafael Alves Batista, Co-author and Post-Doctoral Research Associate in the Department of Physics at Oxford University. "Subtle changes in our environment impact us dramatically. There are many more resilient species on Earth. Life on this planet can continue long after humans are gone. Tardigrades are as close to indestructible as it gets on Earth, but it is possible that there are other resilient species examples elsewhere in the universe. In this context, there is a real case for looking for life on Mars and in other areas of the Solar System in general. If Tardigrades are Earth's most resilient species, who knows what else is out there?"
"A lot of previous work has focused on 'doomsday' scenarios on Earth – astrophysical events like supernovae that could wipe out the human race," explains Dr David Sloan, co-author from the same department at Oxford University. "Our study instead considered the hardiest species – the tardigrade. As we are now entering a stage of astronomy where we have seen exoplanets and are hoping to soon perform spectroscopy, looking for signatures of life, we should try to see just how fragile this hardiest life is. To our surprise we found that although nearby supernovae or large asteroid impacts would be catastrophic for people, tardigrades could be unaffected. Therefore it seems that life, once it gets going, is hard to wipe out entirely. Huge numbers of species, or even entire genera may become extinct, but life as a whole will go on."
In highlighting the resilience of life in general, the research broadens the scope of life beyond Earth, within and beyond the Solar System.
"It is difficult to eliminate all forms of life from a habitable planet," explains Professor Abraham Loeb, co-author and chair of the Astronomy department at Harvard University. "The history of Mars indicates that it once had an atmosphere that could have supported life, albeit under extreme conditions. Organisms with similar tolerances to radiation and temperature as tardigrades could survive long-term below the surface in these conditions. The subsurface oceans that are believed to exist on Europa and Enceladus would have conditions similar to the deep oceans of Earth where tardigrades are found, volcanic vents providing heat in an environment devoid of light. The discovery of extremophiles in such locations would be a significant step forward in bracketing the range of conditions for life to exist on planets around other stars."
Researchers at the University of Tokyo have made a "breathable" nanoscale mesh with an electronic sensor that can be worn on the skin for a week without discomfort, and could potentially monitor a person's health continuously for long periods.
Credit: 2017 Someya Laboratory
A hypoallergenic, electronic sensor can be worn on the skin continuously for a week without discomfort, and is so light and thin that users forget they even have it on, says a group of Japanese scientists. The elastic electrode, constructed of "breathable" nanoscale meshes, holds promise for the development of non-invasive e-skin devices that can monitor a person's health continuously over a long period.
Wearable electronics that monitor heart rate and other health signs have made headway in recent years, with next-generation gadgets employing lightweight, elastic materials attached directly to the skin for more sensitive, precise measurements. However, while the ultrathin films and rubber sheets in these devices adhere and conform well to the skin, their lack of breathability is deemed unsafe for long-term use: dermatological tests show the fine, stretchable materials prevent sweating and block airflow around the skin, causing irritation and inflammation, which could lead to lasting physiological and psychological effects.
"We learned that devices that can be worn for a week or longer for continuous monitoring were needed for practical use in medical and sports applications," says Professor Takao Someya at the University of Tokyo's Graduate School of Engineering. His research group has previously developed an on-skin patch for measuring oxygen in blood.
In their latest research, they developed an electrode constructed from nanoscale meshes containing a water-soluble polymer, polyvinyl alcohol (PVA), and a gold layer – materials considered safe and biologically compatible with the body. The device can be applied by spraying a tiny amount of water, which dissolves the PVA nanofibres and allows it to stick easily to the skin – it will conform seamlessly with curvilinear surfaces of human skin, such as sweat pores and the ridges of fingerprint patterns.
Credit: 2017 Someya Laboratory
The researchers conducted a skin patch test on 20 subjects and detected no inflammation of skin after they had worn the device for a week. The group also evaluated the permeability, with water vapour, of the nanomesh conductor – along with those of other substrates like ultrathin plastic foil and a rubber sheet – and found that its porous mesh structure exhibited superior gas permeability compared to other materials.
Furthermore, the scientists proved the device's mechanical durability through repeated bending and stretching, exceeding 10,000 times, of a conductor attached on the forefinger; they also established its reliability as an electrode for electromyogram recordings when its readings of the electrical activity of muscles were comparable to those obtained through conventional gel electrodes.
"It will become possible to monitor patients' vital signs without causing any stress or discomfort," says Someya about the future applications. In addition to nursing care and medical uses, the new device could enable continuous, precise monitoring of athletes' physiological signals and bodily motion without impeding their training or performance. The team's research is published this week in Nature Nanotechnology.
An array of nanomesh conductors attached to a fingertip, top, and a scanning electron microscope (SEM) image
of a nanomesh conductor on a skin replica, bottom. Credit: 2017 Someya Laboratory.
Researchers have announced the development of a GM banana with higher levels of pro-vitamin A, which could improve the nutritional content of bananas in Africa.
Professor James Dale. Credit: QUT Media
Research by Queensland University of Technology has produced a golden-orange fleshed banana, rich in pro-vitamin A. The decade-long effort, led by Distinguished Professor James Dale, involved extensive laboratory tests at QUT, along with field trials in north Queensland. The results are published in the Plant Biotechnology Journal.
The genetic modification process had resulted in the identification and selection of banana genes that could be used to boost pro-vitamin A in bananas, Professor Dale said. The research, backed with $10 million from the Bill & Melinda Gates Foundation and the UK Government's Department for International Development, ultimately aims to improve the nutritional content of bananas in Uganda, where the fruit is a major staple food in daily diets.
"The East African Highland cooking banana is an excellent source of starch. It is harvested green then chopped and steamed," Professor Dale said. "But it has low levels of micronutrients – particularly pro-vitamin A and iron. The consequences of vitamin A deficiency are severe."
Worldwide, up to 700,000 children die from pro-vitamin A deficiency each year, with a further several hundred thousand going blind, according to the latest available figures.
"What we've done is take a gene from a banana that originated in Papua New Guinea and is naturally very high in pro-vitamin A, but has small bunches, and inserted it into a Cavendish banana," Professor Dale explained. "Over the years, we've been able to develop a banana that has achieved excellent pro-vitamin A levels, hence the golden-orange rather than cream-coloured flesh. Achieving these scientific results, along with their publication, is a major milestone in our quest to deliver a more nutritional diet to some of the poorest subsistence communities in Africa.
"We tried and tested hundreds of different genetic variations here in our lab and in field trials in Queensland until we got the best results. These elite genes have been sent to Uganda in test tubes, where they have been inserted into Ugandan bananas for field trials there."
If all goes according to plan, it is hoped that the new GM bananas could be used commercially in Uganda from 2021.
Scientists at Harvard have used the CRISPR gene-editing system to store a GIF animation in the DNA of bacteria.
For the first time, a primitive movie has been encoded in – and then played back from – DNA in living cells. Scientists funded by the National Institutes of Health say it is a major step toward a “molecular recorder”. In the future, this could make it possible to get read-outs, for example, of the changing internal states of neurons as they develop.
“We want to turn cells into historians,” says neuroscientist Seth Shipman, Ph.D., a post-doctoral fellow at Harvard Medical School, Boston. “We envision a biological memory system that’s much smaller and more versatile than today’s technologies, which will track many events non-intrusively over time.”
This proof-of-concept for a futuristic “molecular ticker tape” was published yesterday in the journal Nature. The ability to record sequential events like a movie at the molecular level could reinvent the concept of recording using molecular engineering, say the researchers. In this scheme, cells themselves could be induced to record molecular events – such as changes in gene expression over time – in their own genomes. Then the information could be retrieved simply by sequencing the genomes of the cells it is stored in.
"If we had those transcriptional steps, we could potentially use them like a recipe to engineer similar cells," added Shipman. "These could be used to model disease – or even in therapies."
The researchers first had to show that DNA can be used to encode not just genetic information, but any arbitrary sequential information into a genome. For this they turned to a revolutionary new gene editing technology, CRISPR. They encoded and retrieved an image of the human hand in DNA inserted into bacteria, before similarly encoding frames from a classic 1870s race horse in motion sequence of photos – an early forerunner of moving pictures.
Over the course of five days, they sequentially treated bacteria with a frame of translated DNA. Afterwards, they were able to reconstruct the movie with 90% accuracy by sequencing the bacterial DNA.
"The sequential nature of CRISPR makes it an appealing system for recording events over time," explained Shipman.
Although this technology could be used in a variety of ways, the researchers ultimately hope to use it to study the brain.
“We want to use neurons to record a molecular history of the brain through development,” said Shipman. “Such a molecular recorder will allow us to eventually collect data from every cell in the brain at once, without the need to gain access, to observe the cells directly, or disrupt the system to extract genetic material or proteins.”
A study of snail neurons, published in Current Biology, suggests memories that trigger anxiety and PTSD could be "erased" without affecting normal memory of past events.
Different types of memories stored in the same neuron of the marine snail Aplysia can be selectively erased, according to a new study by researchers at Columbia University Medical Center (CUMC) and McGill University. Published in Current Biology, the findings suggest that it may be possible to develop drugs to "delete" memories that trigger anxiety and post-traumatic stress disorder (PTSD) without affecting other important memories of past events.
During their experiments, researchers stimulated two sensory neurons connected to a single motor neuron of the snail; one sensory neuron was stimulated to induce an associative memory and the other to induce a non-associative memory. By measuring the strength of each connection, it was found that the increase in the strength of each connection produced by the different stimuli was maintained by a different form of a Protein Kinase M (PKM) molecule (PKM Apl III for associative synaptic memory and PKM Apl I for non-associative). They found that each memory could be erased – without affecting the other – by blocking one of these two molecules.
In addition, they found that specific synaptic memories may also be erased by blocking the function of distinct variants of other molecules that either help produce PKMs or protect them from breaking down.
The researchers say their results could be useful in understanding human memory, because vertebrates have similar versions of the snail proteins that create long-term memories. The PKM-protecting protein KIBRA is also expressed in humans, and mutations of this gene produce intellectual disability.
"Memory erasure has the potential to alleviate PTSD and anxiety disorders by removing the non-associative memory that causes the maladaptive physiological response," says Jiangyuan Hu, PhD, an associate research scientist in the Department of Psychiatry at CUMC and co-author of the paper. "By isolating the exact molecules that maintain non-associative memory, we may be able to develop drugs that can treat anxiety without affecting the patient's normal memory of past events."
"Our study is a 'proof of principle' that presents an opportunity for developing strategies and perhaps therapies to address anxiety," said co-author Samuel Schacher, PhD, a professor of neuroscience in the Department of Psychiatry at CUMC. "For example, because memories are still likely to change immediately after recollection, a therapist may help to 'rewrite' a non-associative memory by administering a drug that inhibits maintenance of non-associative memory."
Future studies in preclinical models are needed, the researchers say, to better understand how PKMs are produced and localised at the synapse before it can be determined which drugs may weaken non-associative memories.
Emma Morano passed away in April. At 117 years old, the Italian woman was the oldest known living human being. Super-centenarians, such as Morano and Jeanne Calment of France – who famously lived to be 122 years old – continue to fascinate scientists and have led them to wonder just how long humans can live for. A study published in Nature last October concluded that the upper limit of human age is peaking at around 115.
Now, however, a new study by McGill University biologists Bryan G. Hughes and Siegfried Hekimi comes to a starkly different conclusion. By analysing the lifespan of the longest-living individuals from the USA, the UK, France and Japan for each year since 1968, Hekimi and Hughes found no evidence for such an upper limit, and if such a maximum exists, it has yet to be reached or identified.
"We just don't know what the age limit might be. In fact, by extending trend lines, we can show that maximum and average lifespans could continue to increase far into the foreseeable future," Hekimi says. Many people are aware of what has happened with average lifespans. In 1920, for example, the average newborn Canadian could expect to live 60 years; a Canadian born in 1980 could expect 76 years, and today, life expectancy has jumped to 82. Maximum lifespan seems to follow the same trend.
It's impossible to predict what future lifespans in humans might look like, Hekimi says. Some scientists argue that technology, medical interventions, and improvements in living conditions could all push back the upper limit.
"It's hard to guess," Hekimi adds. "Three hundred years ago, many people lived only short lives. If we would have told them that one day most humans might live up to 100, they would have said we were crazy."