Posts Tagged ‘genetics’


Patterns of gene expression unite the prairie vole Microtus ochrogaster with other monogamous species, including certain frogs, fish, and birds. YVA MOMATIUK AND JOHN EASTCOTT/MINDEN PICTURES

By Kelly Servick

In the animal world, monogamy has some clear perks. Living in pairs can give animals some stability and certainty in the constant struggle to reproduce and protect their young—which may be why it has evolved independently in various species. Now, an analysis of gene activity within the brains of frogs, rodents, fish, and birds suggests there may be a pattern common to monogamous creatures. Despite very different brain structures and evolutionary histories, these animals all seem to have developed monogamy by turning on and off some of the same sets of genes.

“It is quite surprising,” says Harvard University evolutionary biologist Hopi Hoekstra, who was not involved in the new work. “It suggests that there’s a sort of genomic strategy to becoming monogamous that evolution has repeatedly tapped into.”

Evolutionary biologists have proposed various benefits to so-called social monogamy, where mates pair up for at least a breeding season to care for their young and defend their territory. When potential mates are scarce or widely dispersed, for example, forming a single-pair bond can ensure they get to keep reproducing.

Neuroscientist Hans Hofmann and evolutionary biologist Rebecca Young at the University of Texas in Austin wanted to explore how the regulation of genes in the brain might have changed when a nonmonogamous species evolved to become monogamous. For example, the complex set of genes that underlie the ability to tolerate the presence of another member of one’s species presumably exists in nonmonogamous animals, but might be activated in different patterns to allow prolonged partnerships in monogamous ones.

“We wanted to be bold—and maybe a little bit crazy” in the new experiment, Hofmann says. Instead of doing a relatively straightforward genetic comparison between closely related species on either side of the monogamy divide, he and colleagues wanted to hunt down a gene activity signature associated with monogamy in males across a wide variety of species—frogs, mice, voles, birds, and fish. So in each of these groups, they selected two species, one monogamous and one nonmonogamous.

Rounding up the brains of those animals took an international team and years of effort. Hostile regional authorities and a complicated permitting system confronted the team in Romania as they tried to capture two types of a native songbird. Hofmann donned scuba gear and plunged into Africa’s Lake Tanganyika to chase finger-length cichlid fish into nets. Delicately debraining them while aboard a rocking boat, he says, was a struggle.

Back the lab, the researchers then grouped roughly comparable genes across all 10 species based on similarities in their sequences. For each of these cross-species gene groups, they measured activity based on how much the cells in the brain transcribed the DNA’s proteinmaking instructions into strands of RNA.

Among the monogamous animals, a pattern emerged. The researchers found certain sets of genes were more likely to be “turned up” or “turned down” in those creatures than in the nonmonogamous species. And they ruled out other reasons why these monogamous animals might have similar gene expression patterns, including similar environments or close evolutionary relationships.

Among the genes with increased activity in monogamous species were those involved in neural development, signaling between cells, learning, and memory, the researchers report online today in the Proceedings of the National Academy of Sciences. They speculate that genes that make the brain more adaptable—and better able to remember—might also help animals recognize their mates and find their presence rewarding.

It makes sense that genes involved in brain development and function would underlie a complex behavior like monogamy, says behavioral neuroscientist Claudio Mello of Oregon Health & Science University in Portland. But because the researchers didn’t dissect out specific brain regions and analyze their RNA production independently, they can’t describe the finely tuned patterns of gene expression in areas that are key to reproductive behavior. “It seems to me unlikely that by themselves these genes will be able to ‘explain’ this behavior,” he says.

“The fact that they got any common genes at all is interesting,” adds Lisa Stubbs, a developmental geneticist at the University of Illinois in Urbana. “It is a superb data set and an expert analysis,” she says, “[but] the authors have not actually uncovered many important biological insights into monogamy.”

The study did turn up a curious outlier. Some of the genes with decreased expression in most of the monogamous species showed increased expression in one of them—the poison dart frog Ranitomeya imitator. Young notes that in this species’s evolutionary history, fathers cared for the young before cooperative parenting evolved. As a result, these frogs may have had a different evolutionary starting point than other animals in the study, later tapping into different genes to become monogamous.

Hoekstra, who has studied the genetics of monogamy in mice, sees “a lot of exciting next steps.” There are likely mutations in other regions of DNA that regulate the expression of the genes this study identified. But it will take more work to show a causal relationship between any particular genetic sequence and monogamous behavior.

People also often opt for monogamy, albeit for a complicated set of social and cultural reasons. So, do we share the gene activity signature common to monogamous birds, fish, and frogs? “We don’t know that,” says Hofmann, but “we certainly would speculate that the kind of gene expression patterns … might [show up] in humans as well.”

http://www.sciencemag.org/news/2019/01/monogamy-may-have-telltale-signature-gene-activity

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by ASHLEY YEAGER

A gene drive has successfully caused the collapse of a malaria-carrying mosquito population in the lab, researches report today (September 24) in Nature Biotechnology. This is the first time a gene drive—a genetic element that ensures its own inheritance—has caused a population of mosquitoes to self-destruct, a result that holds promise for combating malaria.

“This breakthrough shows that gene drive can work, providing hope in the fight against a disease that has plagued mankind for centuries,” study coauthor Andrea Crisanti, a molecular parasitologist at Imperial College London, says in a university statement.

In the study, the team targeted a region of a gene called doublesex that is responsible for female development. Female Anopheles gambiae mosquitoes with two copies of the altered doublesex gene did not lay eggs. After eight generations, the drive had spread through the entire population, such that no eggs were laid.

“It’s a really stunning development,” Omar Akbari, an entomologist at the University of California, Irvine who was not involved to the study, tells Wired, noting that mosquitoes are under “huge evolutionary pressure” to resist gene drives that cause the population to collapse. However, Akbari tells Science News that this gene drive might not work well in the wild because resistance will probably pop up.

Crisanti, however, is more confident. “We are not saying this is 100 percent resistance-proof,” he tells The New York Times. “But it looks very promising.” Still, he adds in the university statement, “[i]t will still be at least 5-10 years before we consider testing any mosquitoes with gene drive in the wild.” First, his team will need to test the gene drive in larger containers, where the mosquitoes can act more naturally, Crisanti tells Wired—swarming to find a mate, for instance. Such details were difficult to mimic in the 20 cubic centimeter cages used in this study.

Despite the need for further testing, some researchers hailed the current study as a major success. “With this achievement,” Kevin Esfelt, who studies the evolution of gene drives at MIT, tells The New York Times, “the major barriers to saving [human] lives are arguably no longer mostly technical, but social and diplomatic.”

https://www.the-scientist.com/news-opinion/study–gene-drive-wipes-out-lab-mosquitoes-64849

largest-ever-study-of-genetic-links-to-depression-and-anxiety-launched-309700

The NIHR and King’s College London are calling for 40,000 people diagnosed with depression or anxiety to enrol online for the Genetic Links to Anxiety and Depression (GLAD) Study and join the NIHR Mental Health Bioresource.

Researchers hope to establish the largest ever database of volunteers who can be called up to take part in research exploring the genetic factors behind the two most common mental health conditions – anxiety and depression.

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The GLAD study will make important strides towards better understanding of these disorders and provide a pool of potential participants for future studies, reducing the time-consuming process of recruiting patients for research.

Research has shown 30-40% of the risk for both depression and anxiety is genetic and 60-70% due to environmental factors. Only by having a large, diverse group of people available for studies will researchers be able to determine how genetic and environmental triggers interact to cause anxiety and depression.

Leader of the GLAD study and the NIHR Mental Health BioResource, Dr Gerome Breen of King’s College London, said: “It’s a really exciting time to become involved in mental health research, particularly genetic research which has made incredible strides in recent years – we have so far identified 46 genetic links for depression and anxiety.

“By recruiting 40,000 volunteers willing to be re-contacted for research, the GLAD Study will take us further than ever before. It will allow researchers to solve the big unanswered questions, address how genes and environment act together and help develop new treatment options.”

The GLAD Study, a collaboration between the NIHR BioResource and King’s College London, has been designed to be particularly accessible, with a view to motivating more people to take part in mental health research.

Research psychologist and study lead Professor Thalia Eley, King’s College London, said: “We want to hear from all different backgrounds, cultures, ethnic groups and genders, and we are especially keen to hear from young adults. By including people from all parts of the population, what we learn will be relevant to everyone. This is a unique opportunity to participate in pioneering medical science.”

https://www.nihr.ac.uk/news/nihr-launches-largest-ever-study-of-genetic-links-to-depression-and-anxiety/9201

As the result of a six-year long research process, Fredrick R. Schumacher, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings, published in a research letter in Nature Genetics, contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.

The changes, known as genetic markers or SNPs (“snips”), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The order of these bases determines DNA’s instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are 3 billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.

One in seven men will be diagnosed with prostate cancer during their lifetimes.

“Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions,” said Schumacher. Prostate-specific antigen (PSA) screenings measure how much PSA, a protein produced by both cancerous and noncancerous tissue in the prostate, is in the blood.

Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.

In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn’t have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.

The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. “We probably only need to know 10 percent to 20 percent of these to provide relevant screening guidelines,” continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine.

Currently, researchers don’t know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for “watchful waiting” and monitoring.

The research lays a foundation for determining who and how often men should undergo PSA tests. “In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening,” said Schumacher. “We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every two to five years.” A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. “Someday it may be feasible to target treatments based on a patient’s prostate cancer genetic risk score,” said Schumacher.

In addition to the work in the new study, which targets men of European background, there are parallel efforts underway looking at genetic signals of prostate cancer in men of African-American and Asian descent.

http://thedaily.case.edu/researchers-identify-dozens-new-gene-changes-point-elevated-risk-prostate-cancer-men-european-descent/

Exposure to early life trauma can lead to poor physical and mental health in some individuals, which can be passed on to their children. Studies in mice show that at least some of the effects of stress can be transmitted to offspring via environmentally-induced changes in sperm miRNA levels.

A new epigenetics study raises the possibility that the same is true in humans. It shows for the first time that the levels of the same two sperm miRNAs change in both men and mice exposed to early life stress. In mice, the negative effects of stress are transmitted to offspring. The study is published On May 23rd in Translational Psychiatry.

“The study raises the possibility that some of the vulnerability of children is due to Lamarckian type inheritance derived from their parents’ experiences,” said Larry Feig, Ph.D., professor of Developmental, Molecular and Chemical Biology at Tufts University School of Medicine and member of the Cell, Molecular and Developmental Biology and Neuroscience programs at the Sackler School of Graduate Biomedical Sciences at Tufts.

The human part of the study utilized the Adverse Childhood Experiences (ACE) questionnaire as an indicator of men’s early life trauma. The ACE Study questionnaire includes 10 yes or no questions about one’s experiences until the age of 18, including physical, verbal, or sexual abuse, and physical or emotional neglect. Other questions relate to one’s family members. Four or more yes answers put one at significantly increased risk for future mental and physical health problems. According to a ChildTrends research brief published in 2014, a remarkably high percentage (~10 percent) of the population report scores at or above this cutoff.

miRNAs constitute a newly appreciated type of gene regulator, where each miRNA controls a distinct set of genes. Until recently, sperm from fathers were thought to contribute only DNA to the mother’s egg upon fertilization, but new data in mice indicate that sperm also contribute miRNAs that influence the next generation. Sperm miRNA expression in humans is known to be affected by environmental factors, such as smoking and obesity, but no human study to date has documented the effects of stress.

The new study found that among 28 Caucasian male volunteers, the expression of two highly related sperm miRNAs, miR-449 and miR-34, were inversely proportional to the men’s ACE scores. Men with the most extensive early abuse (highest ACE scores) had as much as a 300-fold reduction in the two sperm miRNAs compared to men with the least abuse.

The idea that these changes can affect the next generation is supported by additional findings in the study, e.g.:

the same sperm miRNA changes that take place in men with high ACE scores also occur in mice exposed to early life social instability stress, which Feig’s lab has shown previously leads to anxiety and sociability defects in female offspring of stressed males for at least three generations;
these two sets of miRNAs are known to work together in mice to allow proper development of the brain and sperm;
in humans, miR-34c has been implicated in promoting early embryo development;
the mouse studies showed that the decline in these sperm miRNA levels is transmitted to the next generation; and
when these embryos mature, these miRNAs are also reduced in the sperm of their male offspring who pass on stress behaviors to their female offspring.
“This is the first study to show that stress is associated with altered levels of sperm miRNAs in humans. We are currently setting up a new, larger study in men, and additional experiments in mice that could yield further support for the idea that changes in these sperm miRNAs do, in fact, contribute to an elevation of stress-related disorders across generations,” said David Dickson, an M.D./Ph.D. student at Tufts and first author of the study.

“Looking to the future, we may be able to figure out a way to restore the low miRNA levels found in men exposed to extreme trauma, because epigenetic changes, such as stress-induced decreases in sperm miRNA expression, are reversible, unlike genetic changes that alter the DNA sequence,” Dickson added.

For example, obesity has been shown to alter specific sperm miRNA levels in men, while bariatric surgery and subsequent weight loss can reverse the changes. In addition, Isabelle Mansuy’s lab has reversed some of the negative effects of stress in mice across generations by exposing mice to an “enriched environment” that involves extensive social interactions, exercise and opportunities to explore their surroundings.

Feig pointed out that in addition to focusing on the potential transgenerational effects of stress, there is a growing appreciation that physicians should collect information on childhood trauma for the sake of the patients who are experiencing this early trauma.

This is because “childhood abuse, trauma and dysfunction adds to the risk of future physical and psychiatric maladies, and significant exposure to abusive and/or dysfunctional families is remarkably common. Moreover, sensitivity to PTSD has been shown to correlate with ACE score, implying the ACE questionnaire could be used as a screening tool to identify people who should take extra precaution to avoid potentially traumatic experiences,” he said.

“However, some people may not answer the ACE survey accurately due to inaccurate recall or because of the sensitive nature of many of the questions, particularly in settings that do not allow anonymity and/or where their answers could affect their future. Thus, discovery of unbiased markers for early trauma, like specific sperm miRNA content, could complement ACE surveys in some clinical settings to bolster preventative medicine,” he concluded.

The authors note that the relatively small sample size limits their ability to more deeply explore the association between ACE scores and miRNA expression. In addition, a longitudinal study with information on behavioral and psychological factors throughout adulthood, with repeated measurements of sperm miRNA content, could allow for further exploration on the effect of cumulative exposure to childhood trauma on miRNA.

Additional authors are Jessica Paulus, Sc.D., Tufts Medical Center as well as Tufts University School of Medicine and the Sackler School; Virginia Mensah, M.D., formerly in Feig’s lab with Women & Infants Hospital and the Warren Alpert Medical School at Brown University and now with the Reproductive Science Center of New Jersey; Janis Lem, Ph.D., Tufts Medical Center; Lorena Saavedra-Rodriguez, Ph.D., formerly a postdoctoral fellow in Feig’s laboratory at Tufts and now with a biopharmaceutical company; and Adrienne Gentry, D.O. and Kelly Pagidas, M.D., University of Louisville School of Medicine.

This study was supported by awards from the National Institute of Mental Health of the National Institutes of Health (R01MH107536), as well as the Tufts Center for Neuroscience Research (National Institute of Neurological Disorders and Stroke of the NIH, P30NS047243). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.

Dickson, D.A., Paulus, J.K., Mensah, V., Lem, J., Saavedra-Rodriguez, L., Gentry, A., Pagidas, K., and Feig, L. A. (2018). Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress. Translational Psychiatry. https://doi.org/10.1038/s41398-018-0146-2

https://now.tufts.edu/news-releases/early-life-trauma-men-associated-reduced-levels-sperm-micrornas

Writing in the journal eLife, the team reveals that this disease is caused by a recessive mutation in CAMK2A – a gene that is well known for its role in regulating learning and memory in animals. The findings suggest that dysfunctional CAMK2 genes may contribute to other neurological disorders, such as epilepsy and autism, opening up potential new avenues for treating these conditions.

“A significant number of children are born with growth delays, neurological defects and intellectual disabilities every year across the world,” explains senior author Bruno Reversade, Research Director at the Institute of Medical Biology and Institute of Molecular and Cell Biology, A*STAR, Singapore, who supervised the study. “While specific genetic mutations have been identified for some patients, the cause remains unknown in many cases. Identifying novel mutations would not only advance our understanding of neurological diseases in general, but would also help clinicians diagnose children with similar symptoms and/or carry out genetic testing for expecting parents.”

The team’s research began when they identified a pair of siblings who demonstrated neurodevelopmental delay with frequent, unexplained seizures and convulsions. While the structure of their bodies developed normally, they did not gain the ability to walk or speak. “We believed that the children had novel mutations in CAMK2A, and we wanted to see if this were true,” says Reversade.

The fully functional CAMK2A protein consists of multiple subunits. Using a genomic technique called exome sequencing, the team discovered a single coding error affecting a key residue in the CAMK2A gene that prevents its subunits from assembling correctly.

Moving their studies into the roundworm Caenorhabditis elegans, the scientists saw that this mutation disrupts the ability of CAMK2A to ensure proper neuronal communication and normal motor function. This suggests that the mutation is indeed the cause of the neurodevelopmental defects seen in the siblings.

To the best of the team’s knowledge, this new disorder represents the first human disease caused by inherited mutations on both copies of the CAMK2A gene. In addition, another report* published recently identified single-copy mutations on both CAMK2A and CAMK2B that caused intellectual disabilities as soon as the mutations occurred. “We would like to bring these findings to the attention of those working in the area of paediatric genetics, such as clinicians and genetic counsellors, as there are likely more undiagnosed children with similar symptoms who have mutations in their CAMK2A gene,” explains co-first author Franklin Zhong, Research Scientist in Reversade’s lab at A*STAR.

“Neuroscientists working to understand childhood brain development, neuronal function and memory formation also need to consider this new disease, since CAMK2A is associated with these processes. In future, it would be interesting to test whether restoring CAMK2A activity can bring therapeutic benefit to patients with this condition, as well as those with related neurological disorders.”

The paper ‘A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability‘ can be freely accessed online at https://doi.org/10.7554/eLife.32451. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

*Küry, S., van Woerden, G.M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., et al. (2017). De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. The American Journal of Human Genetics 101, 768-788.

https://www.technologynetworks.com/neuroscience/news/new-inherited-neurodevelopmental-disease-discovered-303233?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63149617&_hsenc=p2ANqtz-_AJri5fciUzcysqtDye56dm2VpMIbIwRqkV2di9BmqZhzk9xuPEv5CWgKF24BpT8_OB1uWAjitxNXhmduWHyW2XKGlhw&_hsmi=63149617

by Philip Perry

Researchers at the Salk Institute in La Jolla, California have discovered a way to turn back the hands of time. Juan Carlos Izpisua Belmonte led this study, published in the journal Cell. Here, elderly mice underwent a new sort of gene therapy for six weeks. Afterward, their injuries healed, their heart health improved, and even their spines were straighter. The mice also lived longer, 30% longer.

Today, we target individual age-related diseases when they spring up. But this study could help us develop a therapy to attack aging itself, and perhaps even target it before it begins taking shape. But such a therapy is at least ten years away, according to Izpisua Belmonte.

Many biologists now believe that the body, specifically the telomeres—the structures at the end of chromosomes, after a certain time simply wear out. Once degradation overtakes us, it’s the beginning of the end. This study strengthens another theory. Over the course of a cell’s life, epigenetic changes occur. This is the activation or depression of certain genes in order to allow the organism to respond better to its environment. Methylation tags are added to activate genes. These changes build up over time, slowing us down, and making us vulnerable to disease.


Chromosomes with telomeres in red.

Though we may add life to years, don’t consider immortality an option, at least not in the near-term. “There are probably still limits that we will face in terms of complete reversal of aging,” Izpisua Belmonte said. “Our focus is not only extension of lifespan but most importantly health-span.” That means adding more healthy years to life, a noble prospect indeed.

The technique employs induced pluripotent stem cells (iPS). These are similar to those which are present in developing embryos. They are important as they can turn into any type of cell in the body. The technique was first used to turn back time on human skin cells, successfully.

By switching around four essential genes, all active inside the womb, scientists were able to turn skin cells into iPS cells. These four genes are known as Yamanaka factors. Scientists have been aware of their potential in anti-aging medicine for some time. In the next leg, researchers used genetically engineered mice who could have their Yamanaka factors manipulated easily, once they were exposed to a certain agent, present in their drinking water.

Since Yamanaka factors reset genes to where they were before regulators came and changed them, researchers believe this strengthens the notion that aging is an accumulation of epigenetic changes. What’s really exciting is that this procedure alters the epigenome itself, rather than having the change the genes of each individual cell.


The mechanics of epigenetics.

In another leg of the experiment, mice with progeria underwent this therapy. Progeria is a disease that causes accelerated aging. Those who have seen children who look like seniors know the condition. It leads to organ damage and early death. But after six months of treatment, the mice looked younger. They had better muscle tone and younger looking skin, and even lived around 30% longer than those who did not undergo the treatment.

Luckily for the mice, time was turned back the appropriate amount. If turned back too far, stem cells can proliferate in an uncontrolled fashion, which could lead to tumor formation. This is why researchers have been reticent to activate the Yamanaka factors directly. However, these scientists figured out that by intermittently stimulating the factors, they could reverse the aging process, without causing cancer. The next decade will concentrate on perfecting this technique.

Since the threat of cancer is great, terminally ill patients would be the first to take part in a human trial, most likely those with progeria. Unfortunately, the method used in this study could not directly be applied to a fully functioning human. But researchers believe a drug could do the job, and they are actively developing one.

“This study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought,” Izpisua Belmonte said. Of course, mouse systems and human one’s are far different. This only gives us an indication of whether or not it might work. And even if it does, scientists will have to figure out how far to turn back the clock. But as Izpisua Belmonte said, “With careful modulation, aging might be reversed.”