Category Archives: Human Genetics

The first COVID-19 case in Africa was confirmed on February 14th, 2020, in Egypt. The first in sub-Saharan Africa appeared in Nigeria soon after. Health officials were united in a near-panic about how the novel coronavirus would roll through the worlds second most populous continent. By mid-month, the World Health Organization (WHO) listed four sub-Saharan countries on a Top 13 global danger list because of direct air links to China. Writing for the Lancet, two scientists with the Africa Center for Disease Control outlined a catastrophe in the making:

With neither treatment nor vaccines, and without pre-existing immunity, the effect [of COVID-19] might be devastating because of the multiple health challenges the continent already faces: rapid population growth and increased movement of people; existing endemic diseases re-emerging and emerging infectious pathogens and others; and increasing incidence of non-communicable diseases.

Many medical professionals predicted that Africa could spin into a death spiral. My advice to Africa is to prepare for the worst, and we must do everything we can to cut the root problem, Tedros Adhanom Ghebreyesus, the first African director-general of the WHO,warned in March 2020. I think Africa, my continent, must wake up. By spring, theWHO was projecting 44 million or more cases in Africaand the World Bank issued a map of the continent colored in blood red, anticipating that the worst was imminent:

These dire warnings seemed to make sense. After all,two-thirds of the global extreme poor population(63 percent) live in sub-Saharan Africa. According to the World Bank, more than40 percent of the regionlives in extreme poverty and unhygienic environments, conflict, fragmented medical and education systems, and dysfunctional leadershipall factors that was expected to light a match to the tinder of the SARS-CoV-2 outbreak. Scientists say that most African countries lack the capacity and expertise to manage endemic deadly diseases like malaria. Africa seemed ripe for catastrophe.

But disaster never came. Africa has not been affected on anything like the scale of most countries inAsia, Europe, and North and South America.(The major exceptions being China, Taiwan, Australia, and New Zealand, which zealously enforced lockdowns.) In fact, the vast African sub-continent south of the Sahara desert, more than 1.1 billion people, has emerged as the worlds COVID-19 cold spot, as illustrated by anECDC map reproduced by BBC and by graphics like these:

Thelatest statisticsshow about four million cases and 107,000 coronavirus-related deaths, concentrated mostly in the Arab majority countries north of the Sahara. Except for South Africathe most multiracial of the black-majority countriesand Nigeria, sub-Saharan Africa has largely been spared. And these startling low case and death statistics come even asAfrica has the lowest vaccination rate in the worldless than one dose administered per 100 people, and with many countries having given none to the general population.

Europe has less than two-thirds of the population of Africa, but by late-March it had41 million casesand more than 900,000 deaths900 percent more. The US, with less than a third of the population of Africa, has approximately 30.4 million cases and 551,00 deaths as of March 31, thousands of percent more on a per capita basis than Africa. In other words, the US, Europe, and parts of South America are experiencing far more than 1,000 deaths per million while most of sub-Saharan Africa has between 0.5 and 25 deaths per million, according to stats updated regularly byWikipedia.

Journalistsand even somescientistshave beentwisting themselvesinto speculative pretzels trying to explain this phenomenon. Theories range from sub-Saharan Africas quick response (no); favorable climate (which has not protected tropical sections of Brazil, Peru, and other warmer climes in South America); and good community health systems (directly contradicted by WHO and Africa CDC). In each of the articles acknowledging these puzzling statistics, journalists were sure to suggest that Armageddon might be right around the corner.

Experts fear a more devastating second surge,warnedNational Geographicin late December, although there was no first surge and just two weeks before Africas tiny December uptick (driven almost entirely by the mutant variant in South Africa) turned back downward,according to Reuters:

So whats going on here? And why are the media and most scientists so unwilling to engage one of the most plausible science-based factors: that black Africans appear to be protected, at least in part, by their ancestry? Combined with the fact that sub-Saharan Africa is the youngest region in the worldyouth brings fewer co-morbidities and age is the most significant factor in contracting and dying from COVID-19ancestry is likely a significant contributing factor to sub-Saharan Africas comparatively modest case and death count.

With the notable exception of a research project in Hawaii, scientists tend to shy away from exploring the population genetics angle, almost certainly fearful of stirring the embers of race science.It is really mind boggling why Africa is doing so well, while in US and UK, the people of African ancestry are doing so poorly,Maarit Tiirikainen, a cancer and bioinformatics researcher at the University of Hawaii Cancer Center, told us in an email.

Dr. Tiirikainen is a lead researcher in a joint project at the University of Hawaii and LifeDNA in what some believe is a controversial undertaking considering the taboos on race research. They areattempting to identifythose that are most vulnerable to the current and future SARS attacks and COVID based on their genetics.

Blacks (along with other ethnic minorities) in the US and Great Britain who have contracted COVID-19 have generally fared worse than Whites. For the latter, it seems the Western socioeconomics may play a major role, Dr. Tiirikainen wrote. Each individuals risk of dying from a particular disease tends to reflect access to adequate healthcare and underlying health conditions (co-morbidities). Those factors have proved a lethal mix in poorer communities in theUS, UK, and other countries, with lower income groupsoften ethnic and racial minoritiesdying at disproportionately high rates.

But Africa has proven unique. Dr. Tiirikainen, like many candid researchers in this field, is skeptical that social and environmental factors alone can account for the extraordinarily low COVID-19 African infection and death rates. It is not because Africa took extraordinary steps to insulate itself as the pandemic spread. Healthcare remains fragmented at best and COVID information outreach has been limited by scant resources.There may also be genetic differences in immune and other important genes, she said.

At the end of March, 2020, when much was still to be learned about the science of COVID-19, the co-authors of this articlethe Genetic Literacy Projects Jon Entine and contributing science journalist Patrick Whittlediscussed some of the potential reasons in the article Whats race got to do with it? Following discussions with many experts, we decided not to reflexively exclude genetic explanations, which are a taboo subject. Rather, we examined the panoply of likely causes, rejecting thea prioriWestern prejudice that often excludes evidence that might be linked to population-level genetics and group differences for fear of racializing the analysis. We are obviously aware that skin color isnot a recognized science-based population concept. Given theracist historyof biological beliefs about human differences, addressing the fact of ancestrally-based genetic differences must be pursued carefully.

Why even discuss possible genetic factors? Because biases among researchers and public policy officials could undermine the development and deployment of treatments and antiviral vaccines for all of us, but particularly for more vulnerable populations in Africa and in the African diaspora. Blacks and other racial minorities in the US, Latin America, and the UK are more likely to suffer chronic health problems. For example, in the US, blacks aremore than 50 percent likelier to report having poor health as compared to whites, and more than two-thirds of black adult women are overweight. Developing therapies for at-risk populations is critical. Those with genetic resistance to infection or who may be genetically protected in some degree from developing symptoms could help scientists develop treatments for all. Lives are at stake.

So lets dip into these murky waters. Could our ancestry, which defines our genetic make-up, play a role in susceptibility to COVID or other viruses?

. . .

The rest of this article can be read at Quillette. Quillette can be found on Twitter @Quillette

A version of this article originally appeared on the GLP as a two part series. Read those articles here:

Jon Entineis the founding editor of the Genetic Literacy Project, and winner of 19 major journalism awards. He has written extensively in the popular and academic press on population genetics, including two best-sellers,Taboo: Why Black Athletes Dominate Sports and Why Were Afraid to Talk About It,andAbrahams Children: Race, Genetics, and the DNA of The Chosen People. You can follow him on Twitter@JonEntine

Patrick Whittle has a PhD in philosophy and is a New Zealand-based freelance writer with a particular interest in the social and political implications of biological science. You can find him at his websitepatrickmichaelwhittle.comor follow him on Twitter @WhittlePM

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Taboo: Why has Africa emerged as the global coronavirus 'Cold Spot' and why are we afraid to talk about it? - Genetic Literacy Project

Jul 01, 2021 5:30 PM

Author: Doug Dollemore

During his 17-year career with the New York Yankees, Lou Gehrig was famed for his prowess as a hitter and for his durability on the baseball field, which earned him his nickname "The Iron Horse. Then, mysteriously, in 1938, his iron body began to figuratively rust. He couldnt run, hit, or field his position as well as he once did. When doctors finally diagnosed his condition, the news was devastating.

Gehrig had amyotrophic lateral sclerosis (ALS), a rare progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. People who have ALS gradually lose their ability to control muscle movement. Eventually, the condition, now often referred to as Lou Gehrigs disease, leads to total paralysis and death. Then, as now, there is no cure.

In the 80 years since Gehrigs death at age 37, scientists have sought to unravel what causes the disease and develop better treatments for it.

In the latest advance, University of Utah Health researchers have detected a set of genetic mutations that appear to increase a persons risk of developing ALS. They say the discovery of mutations in TP73, a gene that has never been associated with ALS before, could help scientists develop new therapies to slow or even stop the progression of the disease.

Its really a novel discovery that suggests a very different pathway for the onset of at least some cases of ALS that hasnt been explored before, says Lynn Jorde, Ph.D., chair of the Department of Human Genetics at U of U Health and the senior author of the study. From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences.

The study appears in Neurology, the medical journal of the American Academy of Neurology.

"From a scientific standpoint, its going to provide us with a more complete picture of what is going wrong in ALS and expand our understanding of what can be done to mitigate its devastating consequences."

About 85% of ALS cases are sporadic, meaning that no one in a patients family has a history of the disease. However, researchers suspect that up to 61% of sporadic ALS cases are influenced by genetic factors. But detecting those factors has been challenging.

In the past, it has been difficult to determine ALS-causing genes because only recently has sequencing technology advanced enough to feasibly sequence many patients, says Kristi L. Russell, a graduate research assistant at U of U Health and lead author of the study. Additionally, many mutations in a single patient could be considered deleterious, so one must test the candidate mutations in animal models or cell culture, an incredibly time-consuming process.

For this study, Jorde, Russell, and colleagues analyzed blood samples provided by 87 people with sporadic ALS who were being treated at U of U Health. Using a technique called exome sequencing, which zeroes in on the protein-coding regions within genes, they found five people who had rare, deleterious mutations in the TP73 gene, which plays a key role in apoptosis or programmed cell death. Then, the researchers studied data from 2,900 other sporadic ALS patients from the Utah Heritage 1K Project and the ALSdb cohort. Within these groups, they identified 24 different, rare protein-coding variants in TP73.

When the researchers did a similar analysis among 324 people who did not have ALS, the patient mutations in TP73 were not present.

In subsequent laboratory studies, knocking out or disabling TP73 in zebrafish impaired the development of nerve cells in a way that mimicked what appears to occur in ALS. Like in ALS, the zebrafish had fewer motor neurons and shorter axons, nerve fibers that transmit electrical impulses from neurons to muscle cells. This shortening could impede the axons ability to transmit impulses. Shorter axons transmit these impulses far less efficiently.

During their experiments, the researchers also found evidence that mutant TP73, which normally inhibits apoptosis in motor neurons, doesnt work properly. As a result, they suspect that apoptosis is more likely to occur.

It seems that mutant TP73 disrupts apoptosis, which leads to more neuronal death, Russell says. Many biological pathways have been implicated in ALS progression, but our study highlights the underappreciated role of apoptosis in ALS pathology. Apoptosis could potentially become a new focus or target for treatment drug screens.

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Newly Discovered Genetic Mutations May Increase Risk for Lou Gehrig's Disease - University of Utah Health Sciences

An Oxford-led team, working with Cambridge and international scholars, has discovered hundreds of genetic markers driving two of life's most momentous milestones - the age at which people first have sex and become parents.

In a paper published today inNature Human Behaviour, the team linked 371 specific areas of our DNA, called genetic variants (known locations on chromosomes), 11 of which were sex-specific, to the timing of first sex and birth. These variants interact with environmental factors, such as socioeconomic status and when you were born, and are predictors of longevity and later life disease.

The researchers conducted a Genome-Wide Association Study (GWAS), a search across the entire human genome, to see if there is a relationship between reproductive behaviour and a particular genetic variant. In the largest genomic study ever conducted to date, they combined multiple data sources to examine age at first sex (N=387,338) and birth (N=542,901) in men and women. They then calculated a genetic score, with all genetic loci combined explaining around 5-6% of the variability in the average age at sexual debut or having a first child.

Professor Melinda Mills, Director of the Leverhulme Centre for Demographic Science at the University of Oxford and Nuffield College, and the study's first author says, 'Our study has discovered hundreds additional genetic markers that shape this most fundamental part of our lives and have the potential for deeper understanding of infertility, later life disease and longevity.'

The genetic signals were driven by social factors and the environment but also by reproductive biology, with findings related to follicle-stimulating hormone, implantation, infertility, and spermatid differentiation.

Professor Mills adds 'We already knew that childhood socioeconomic circumstances or level of education were important predictors of the timing of reproduction. But we were intrigued to find literally not only hundreds of new genetic variants, but also uncover a relationship with substance abuse, personality traits such as openness and self-control, ADHD and even predictive of some diseases and longevity .'

Professor Mills says, 'We demonstrated that it is a combination of genetics, social predictors and the environment that drives early or late reproductive onset. It was incredible to see that the genetics underlying early sex and fertility were related to behavioural dis-inhibition, like ADHD, but also addiction and early smoking. Or those genetically prone to postpone sex or first birth had better later life health outcomes and longevity, related to a higher socioeconomic status in during childhood.'

Genetic factors driving reproductive behaviour are strongly related to later life diseases such as Type 2 diabetes and cardiovascular disease.

'It is exciting that the genetics underlying these reproductive behaviours may help us understand later life disease.'

Professor Mills concludes, 'Starting your sexual journey early is rooted in childhood inequality but also has links with health problems, such as cervical cancer and depression. We found particularly strong links between early sexual debut, ADHD and substance abuse, such as early age at smoking. We hope our findings lead to better understanding of teenage mental and sexual health, infertility, later life disease and treatments to help.'

Reference: Mills MC, Tropf FC, Brazel DM, et al. Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour. Nature Human Behaviour. Published online July 1, 2021. doi: 10.1038/s41562-021-01135-3.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Genes Can Drive When We Choose To Have Sex, and Become Parents - Technology Networks

Researchers headed by a team at Columbia University Vagelos College of Physicians and Surgeons have linked distinct patterns of genetic mutations with obsessive-compulsive disorder (OCD) in humans. Reporting in Nature Neuroscience on their analysis of exome sequencing data from more than 1,000 individuals with OCD, the scientists say their findings support a contribution of rare damaging coding variation to OCD risk. They suggest the work confirms the validity of targeting specific genes as a potential treatment approach for OCD, and also points to new avenues of study for the commonly debilitating condition.

Senior study author David Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia, and colleagues reported on their study in a paper titled, Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants. The multi-institution collaboration also included scientists from the University of North Carolina at Chapel Hill, the David Geffen School of Medicine in Los Angeles, Harvard Medical School, and SUNY Downstate Medical Center in Brooklyn.

OCD is a neuropsychiatric condition characterized by persistent, intrusive thoughts (obsessions) and repetitive, intentional behaviors (compulsions), the authors explained. The condition, which affects 12% of the population, commonly runs in families, and genes are known to play a large role in determining who develops the disease. Evidence from family-based studies supports a genetic contribution to the disorder, the team wrote. But while strongly acting mutations have been hypothesized to exist in OCD, statistically reliable evidence has been difficult to obtain.

Goldstein stated, Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves. These mutations are individually very rare but important to find because they can provide a starting point for the development of therapeutics that target precise underlying causes of disease.

Most previous studies on the genetics of OCD have used a candidate gene approach, in which researchers focus on plausible genes that might be involved in pathogenesis and look for genetic signatures of risk. Although that approach has had some successes, it can lead to challenges in statistical interpretation and can miss unexpected genes. As a result, both funding agencies and the pharmaceutical industry increasingly focus on genome-wide analyses that can securely implicate genes in disease risk.

But as the researchers noted, Genome-wide association studies of common single-nucleotide polymorphisms (SNPs) have not found variants that were associated with OCD at the genome-wide level of statistical significance, likely owing to insufficient sample size. Goldstein further suggested, The solution to the problem is to study all the genes in the genome at the same time and ask whether any of them have significant evidence of influencing risk. That had not been done yet at scale in OCD.

In collaboration with Gerald Nestadt, MBBCh, a psychiatrist at Johns Hopkins University with access to a cohort of OCD patients, Goldsteins team combined high-throughput sequencing and computational biology techniques to identify relevant genes anywhere in the genome. The investigators looked at genes that encode protein using whole exome sequencing in 1,313 OCD patients, and compared them to similarly large control groups.

The analysis identified a strong correlation between OCD and rare mutations, particularly in a gene called SLITRK5 that had been previously linked to OCD in candidate-gene studies. SLITRK5 is a member of the SLITRK gene family, which influences excitatory and inhibitory synapse formation, the authors wrote. Interestingly, they continued, Slitrk5-knockout mice have been described as having increased OCD-like behaviors, including elevated anxiety and excessive grooming In human samples, a burden of SLITRK5 coding variants that influence synapse formation in vitro has previously been described in OCD cases relative to controls. The study also identified a specific pattern of variation in other genes. Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant. As Goldstein further stated, When you look at genes that do not tolerate variation in the human population, those are the genes most likely to cause disease, and with OCD, we see an overall increased burden of damaging mutations in those genes compared to controls. Thats telling us that there are more OCD genes to be found and where to find them.

The authors concluded, This study is, to our knowledge, the most comprehensive cataloguing of contributions to OCD risk from rare damaging coding SNVs [single nucleotide variants] and indels thus far. Its findings suggest that, like the genetic architecture of other neuropsychiatric disorders, OCD involves contributions to overall risk from these variants.

Goldstein expects that the new data on SLITRK5 will encourage pharmaceutical companies and translational researchers to develop drugs that target this gene. OCD is a disabling disorder that is twice as common as schizophrenia, said H. Blair Simpson, MD, PhD, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and director of the Center for OCD & Related Disorders at New York State Psychiatric Institute, who was not involved with the new study. Two available treatments, serotonin reuptake inhibiting drugs and cognitive-behavioral therapy, are highly effective, Simpson noted, but only work on about half of patients. Thus, these genetic findings are very exciting; they indicate that the promise of precision medicine could include OCD, ultimately transforming how we diagnose and treat this disorder.

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Patterns of Genetic Mutations Linked with Obsessive-Compulsive Disorder in Humans - Genetic Engineering & Biotechnology News

In the first analysis of its kind, researchers at Columbia University Vagelos College of Physicians and Surgeons and several other institutions have linked distinct patterns of genetic mutations with obsessive-compulsive disorder (OCD) in humans.

The work, in Nature Neuroscience, confirms the validity of targeting specific genes to develop new OCD treatments and points toward novel avenues for studying this often debilitating condition.

OCD, which affects 1% to 2% of the population, often runs in families and genes are known to play a large role in determining who develops the disease. However, the identity of many OCD genes remains unknown.

Many neurological diseases are influenced by strongly acting mutations which can cause disease by themselves, saysDavid Goldstein, PhD, director of the Institute for Genomic Medicine at Columbia and a senior author on the new paper. These mutations are individually very rare but important to find because they can provide a starting point for the development of therapeutics that target precise underlying causes of disease.

Although strongly acting mutations have been hypothesized to exist in OCD, statistically reliable evidence has been difficult to obtain.

Most previous studies on the genetics of OCD have used a candidate gene approach, in which researchers focus on plausible genes that might be involved in pathogenesis and look for genetic signatures of risk. Although that approach has had some successes, it can lead to challenges in statistical interpretation and can miss unexpected genes. As a result, both funding agencies and the pharmaceutical industry increasingly focus on genome-wide analyses that can securely implicate genes in disease risk.

The solution to the problem is to study all the genes in the genome at the same time and ask whether any of them have significant evidence of influencing risk. That had not been done yet at scale in OCD, says Goldstein.

In collaboration with Gerald Nestadt, MBBCh, a psychiatrist at Johns Hopkins University with access to a cohort of OCD patients, Goldsteins team took this genome wide approach, which uses high-throughput sequencing and computational biology techniques to identify relevant genes anywhere in the genome.

The investigators looked at genes that encode protein using whole exome sequencing in more than 1,300 OCD patients and compared them to similarly large control groups. The multi-institution collaboration also included scientists from the University of North Carolina at Chapel Hill, the David Geffen School of Medicine in Los Angeles, Harvard Medical School, and SUNY Downstate Medical Center in Brooklyn.

Goldstein expects that the new data on SLITRK5 will encourage pharmaceutical companies and translational researchers to develop drugs that target this gene.

The study also identified a specific pattern of variation in other genes. When you look at genes that do not tolerate variation in the human population, those are the genes most likely to cause disease, and with OCD, we see an overall increased burden of damaging mutations in those genes compared to controls, Goldstein says. Thats telling us that there are more OCD genes to be found and where to find them.

For patients suffering from OCD and their doctors, new treatments cant come too soon. OCD causes uncontrollable, recurring thought patterns and behaviors that interfere with patients daily lives.

OCD is a disabling disorder that is twice as common as schizophrenia, says H. Blair Simpson, MD, PhD, professor of psychiatry at Columbia University Vagelos College of Physicians and Surgeons and director of the Center for OCD & Related Disorders at New York State Psychiatric Institute, who was not involved with the new study.

Two available treatments, serotonin reuptake inhibiting drugs and cognitive-behavioral therapy, are highly effective, Simpson adds, but only work on about half of patients. Thus, these genetic findings are very exciting; they indicate that the promise of precision medicine could include OCD, ultimately transforming how we diagnose and treat this disorder.

Reference: Halvorsen M, Samuels J, Wang Y, et al. Exome sequencing in obsessivecompulsive disorder reveals a burden of rare damaging coding variants. Nat Neurosci. 2021. doi: 10.1038/s41593-021-00876-8.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Genetic Mutations Linked With OCD in Humans - Technology Networks

The same journalist and I have been verifying this opinion for over eight years now indeed, observing the development of a juvenile representative of the Homo sapiens species is a continuous, fascinating adventure.

It's a fact that evolutionary success is determined not by the length of adult individuals' lives, but by the number of their offspring that carry their genes into subsequent generations. More precisely, it's not about the number of one's children, but one's grandchildren: the children need to survive and pass on their genes. Of course, in order to have children, one must beget them, or at least somehow initiate the development of the egg, as it happens in parthenogenetic species, where females don't bother with guys at all, or only rarely. But I've already written before about various original methods of completing that first stage, so let's focus on what happens later.

Ecology differentiates two strategies of reproduction: 'r-selection' and 'K-selection'. The symbols are taken from a complicated formula illustrating population dynamics developed in 1838, which systematized our thinking about animal success for the rest of the 19th century and for almost all of the 20th century. It was developed by Pierre Franois Verhulst (18041849), and its simplified version is as follows: dN/dt = rN (1 N/K), where N is the population, r is its maximum growth rate, K is the carrying capacity of the local environment, and dN/dt is the rate of change of the population with time. According to this model, species that engage in r-selection produce as much offspring as quickly as possible, while K-selection involves an investment in quality rather than quantity. So we either have masses of children that we're not too worried about, hoping that things will work out and some of them will survive; or we have few, but we invest a lot in them and we try to make sure that they do as well as possible. Of course, as is often the case, in nature it's more of a continuum, where not only different species, but also different individuals from the same species, function somewhere between these extremes and we can only say that one is 'more r' or 'more K'.

For example, guppies small fish from South and Central America, popular with both aquarists and evolutionary biologists are very flexible in this regard. Researchers have been studying them for years in Trinidadian streams and it turns out that their strategies vary widely depending on the presence of predators, sometimes within the space of a few metres. In the upper reaches of the streams, where rocks make it impossible for bigger fish to get through, guppies have fewer, but larger and better-fed young, so they're 'more K', and their offspring grow up peacefully in calm waters. Below the rocks (sometimes literally one boulder is all it takes) they choose a strategy more closely aligned with r-selection their offspring are smaller, but they're much more numerous, because in the face of the constant risk of being eaten it makes sense to have as many as possible. So, although science is currently leaving this classic model behind, speaking more often about the diversity of survival strategies, my opinion is that with some reservations these two letters make it easier for us to describe a complex reality.

Still, no matter how much offspring there is to be, they need to be brought into the world somehow. Here, there are fundamentally two methods. You can lay an egg with a yolk (the evolutionary equivalent of a packed lunch) from which after a while, with more or less assistance from the parents, your kids will hatch; or you can nourish the offspring within your own body and give birth to them ready-made. It's an easy guess that apart from oviparity and viviparity there's also a third option: ovoviviparity. It refers to embryos that develop in eggs that hatch while still in the mother's body, which the young leave later.

Let's start ab ovo. The egg must be encased in something, so that it can protect the embryos at least a little from outside danger. Species that lay their eggs in water usually don't have to worry that they'll dry out, so for them a jelly-like membrane is usually enough; it means the contents of the egg stay where they should, instead of sloshing around. But if you live on land, you must like many insects and arachnids, and all reptiles and birds, as well as mammals such as the platypus and the echidna invest in something more watertight. The hard shell of a bird's egg also protects it from at least some predators. For example, the shell of an ostrich egg incidentally, the largest single cell in the world is so thick and strong that even lions have trouble breaking it.

Photo by Anna Sjblom on Unsplash

Still, whatever the eggs are encased in, they all have a better chance of surviving if someone looks after them. We automatically associate incubating eggs with birds; indeed, they either take care of their clutch themselves or, like cuckoos, frame someone else into doing it. But other animals also provide many examples of parental dedication. Female octopuses spend the last weeks of their lives defending their eggs, tucked away in some underwater nook, oxygenating them and cleansing away algae and parasites. This work uses up all the time and energy they've got left after the enormous effort of producing and laying the eggs in a suitable place. When the young octopuses finally hatch, their mum is either already dead or about to die. Although this strategy seems to suit cephalopods, we owe our current position in the world to it I suspect that if a mother octopus could pass her knowledge and experience to her offspring, Earth would be a very different place. As it is, despite their astonishing intelligence, each octopus must re-invent the wheel. Considering that their intelligence precedes ours by a few million years, I really think that if they could accumulate experience from generation to generation, I'd be writing this text for an eight-legged editor-in-chief, had she even been interested in the opinion of an organism as inferior as a human.

Although the sacrifice of the cephalopod mum is impressive, some invertebrates go further. Perhaps the most extreme form of parental devotion is matriphagy, or the consumption of the mother by her newly-hatched offspring. This phenomenon can be observed in some arachnid species: after laying the eggs, the female starts to dissolve the tissues of her body with digestive juices, so that when the adorable spider babies hatch, their mother is nothing more than an eight-legged chitin container filled with nutritious juice. The tots just need to bite through her skin and they can lap it up. Among insects, apart from the obvious examples of the Hymenoptera (i.e. ants, wasps and bees) and termites, earwigs provide another example of exemplary parental care. The Japanese species Anechura harmandi is the only insect known to science in which the mother also dies before the young hatch, to become their first meal. Even the common earwig is no stranger to motherly sacrifice. The females of these rather unpopular fearless vanquishers of aphids and silverfish frequently gather into groups to care for their clutches together, and then to feed their young and bravely defend them from predators.

Laying eggs has its obvious advantages. If they require no care, you can not only produce many, but also expect that they will spread around the world on their own. But carrying their offspring in their own bodies makes it easier for parents to provide suitable conditions for development. No wonder, then, that some animals (including many species of shark and the common European adder) have chosen the compromise of ovoviviparity during their evolution. In others like in the viviparous lizard one or the other method of reproduction dominates depending on environmental conditions. In Southern Europe these lizards, like most lizard species, lay eggs. But in cooler areas the females give birth to their young. Thanks to this flexible strategy, they can live in environments that are inaccessible to many other species, like high up in the mountains and the far north of Europe. It is the only reptile on our continent that also lives beyond the polar circle, although vipers the northernmost of our snakes reach almost as far north as that.

Another interesting issue is laying your eggs in someone else's body, although I'm not sure if that still counts as ovoviviparity. The most banal and drastic example are the many species of parasitoids animals that exploit their host completely, living in it for a time, before killing it like the Alien from the famous science fiction film. Many wasps paralyse their victim (usually a caterpillar or a spider) and lay their eggs in that living larder; the larvae will later gradually bite their way out of it. But laying eggs into the body of one's own partner is even more interesting.

This is what happens in the Hippocampus, or the slowly moving fish known as seahorses. After their mating dance and successful consummation of the relationship, the female lays the fertilized eggs into a special pouch on the male's front. From then on, they will be in his care, so that one day he can give birth to hundreds of miniature seahorses, which he will still take care of after the birth.

But since early childhood, I have been fascinated by another organism. The common Suriname toad a tailless amphibian (i.e. frog-adjacent) from the northern part of South America with the charming Latin name Pipa pipa appeared in my life in the form of an illustration in an ancient animal atlas, and it immediately hopped onto the pedestal as one of my favourite species of all times. Just after the female lays the eggs, the male gathers them up and distributes them evenly on her sticky back. Her skin grows spongy, and the eggs sink into it and develop relatively safely; after a time, fully formed little frogs leave her back. It is undoubtedly one of the most interesting births in nature.

If the young isn't separated from its mother's organism by the egg shell, she usually nourishes it via a placenta. This is, of course, the case in a substantial majority of mammals, but not exclusively. The placenta can also be found in some sharks and lizards, but true viviparity has evolved independently at least 150 times and occurs in many species of fish, amphibians, insects and arachnids. One of these unexpectedly caring parents is the infamous tsetse fly: the female flies around for nine months with a single, increasingly large larva in her abdomen, feeding it with a nutritious milky liquid. A more macabre version of feeding one's young can be observed in some Gymnophiona from the family of common caecilians. Their embryos have special teeth that allow them to feed on the epithelium of the mother's oviduct. After they're born, young common caecilians switch over to the female's outer epithelium and literally flay her, although fortunately she regenerates quickly.

After leaving the mother's body one way or another many young animals still need constant care. Because the physical connection is no longer there, persuading the parents to continue to provide food and shelter requires initiating a psychological bond. The parents must like their newly born or hatched children to keep taking care of them.

And so evolution has equipped young animals with a whole arsenal of signals that leave their carers helpless. In birds, it's frequently a lurid colouration of the inside of the beak and the area around it, visible when it is fully open. Adult birds find this irresistible and stuff food down the open, begging mouth, even if it doesn't belong to their children but, for example, to a fish taking advantage of the situation. It is due to our own primitive instincts that most of us also feel tenderness and an urgent need to take care of young animals (or ones that look young). What's more, the recipients of that care don't even need to be cute, pretty bunnies I still remember how touched I was when, as a student, I discovered a wryneck nest in one of the nest boxes I was checking. The chicks of this woodpecker, with their thin, twisty necks and flat heads, look like mould-infested hallucinogenic mushrooms and they're certainly not pretty, but it works. Their relatively big eyes and squeaky sounds are all it takes. Of course, if the animal meets our criteria of beauty, the effect is even stronger. Cats blatantly exploit this the charm of their small faces, large eyes and the meowing that emulates the voice of a human baby turns out to be so strong that even my geologist friend is unable to resist them. Although due to his profession he is used to communing with nature through the means of a hammer, he can't stop himself and constantly regales everyone with photos of his feline charges on social media.

There's no doubt, however, that in animals such as birds and mammals it's not only the case of a simple reflex. For some time now, researchers have been claiming more and more boldly that other animals also experience feelings and emotions, like fear, anger, boredom and love. And love for one's offspring is probably the easiest to observe. It is the simplest explanation for such dramatic examples as the behaviour of a killer whale called Tahlequah who, two years ago, carried the body of her dead child with her for 17 days. Parental love can also be the explanation because there is no other for more prosaic and happy examples of behaviour, such as the fact that I'm about to walk my daughter to school, even though I've spent all night writing this text.

Translated from the Polish by Marta Dziurosz.

Reprinted with permission of Przekrj. Read the original article.

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Penn scientists correct genetic blindness with single injection into the eye - Big Think

News Release

Thursday, June 24, 2021

NIH scientists discover that bacteria may drive activity of many hallmark aging genes in flies.

To better understand the role of bacteria in health and disease, National Institutes of Health researchers fed fruit flies antibiotics and monitored the lifetime activity of hundreds of genes that scientists have traditionally thought control aging. To their surprise, the antibiotics not only extended the lives of the flies but also dramatically changed the activity of many of these genes. Their results suggested that only about 30% of the genes traditionally associated with aging set an animals internal clock while the rest reflect the bodys response to bacteria.

For decades scientists have been developing a hit list of common aging genes. These genes are thought to control the aging process throughout the animal kingdom, from worms to mice to humans, said Edward Giniger, Ph.D., senior investigator, at the NIHs National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in iScience. We were shocked to find that only about 30% of these genes may be directly involved in the aging process. We hope that these results will help medical researchers better understand the forces that underlie several age-related disorders.

The results happened by accident. Dr. Ginigers team studies the genetics of aging in a type of fruit fly called Drosophila. Previously, the team showed how a hyperactive immune system may play a critical role in the neural damage that underlies several aging brain disorders. However, that study did not examine the role that bacteria may have in this process.

To test this idea, they raised newborn male flies on antibiotics to prevent bacteria growth. At first, they thought that the antibiotics would have little or no effect. But, when they looked at the results, they saw something interesting. The antibiotics lengthened the flys lives by about six days, from 57 days for control flies to 63 for the treated ones.

This is a big jump in age for flies. In humans, it would be the equivalent of gaining about 20 years of life, said Arvind Kumar Shukla, Ph.D., a post-doctoral fellow on Dr. Ginigers team and the lead author of the study. We were totally caught off guard and it made us wonder why these flies took so long to die.

Dr. Shukla and his colleagues looked for clues in the genes of the flies. Specially, they used advanced genetic techniques to monitor gene activity in the heads of 10, 30, and 45-day old flies. In a previous study, the team discovered links between the age of a fly and the activity of several genes. In this study, they found that raising the flies on antibiotics broke many of these links.

Overall, the gene activity of the flies fed antibiotics changed very little with age. Regardless of their actual age, the treated flies genetically looked like 30-day old control flies. This appeared to be due to a flat line in the activity of about 70% of the genes the researchers surveyed, many of which are thought to control aging.

At first, we had a hard time believing the results. Many of these genes are classical hallmarks of aging and yet our results suggested that their activity is more a function of the presence of bacteria rather than the aging process, said Dr. Shukla.

Notably, this included genes that control stress and immunity. The researchers tested the impact that the antibiotics had on these genes by starving some flies or infecting others with harmful bacteria and found no clear trend. At some ages, the antibiotics helped flies survive starvation or infection longer than normal whereas at other ages the drugs either had no effect or reduced the chances of survival.

Further experiments supported the results. For instance, the researchers saw similar results on gene activity when they prevented the growth of bacteria by raising the flies in a completely sterile environment without the antibiotics. They also saw a similar trend when they reanalyzed the data from another study that had raised flies on antibiotics. Again, the antibiotics severed many of the links between aging and hallmark gene activity.

Finally, the team found an explanation for why antibiotics extended the lives of flies in the remaining 30% of the genes they analyzed. In short, the rate at which the activity of these genes changed with age was slower than normal in flies that were fed antibiotics.

Interestingly, many of these genes are known to control sleep-wake cycles, the detection of odorants, and the maintenance of exoskeletons, or the crunchy shells that encase flies. Experiments on sleep-wake cycles supported the link between these genes and aging. The activity of awake flies decreased with age and this trend was enhanced by treating the flies with antibiotics.

We found that there are some genes that are in fact setting the bodys internal clock, said Dr. Giniger. In the future, we plan to locate which genes are truly linked to the aging process. If we want to combat aging, then we need to know precisely which genes are setting the clock.

This study was supported by the NIH Intramural Research Program at the NINDS.

This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.

NINDSis the nations leading funder of research on the brain and nervous system.The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Shukla, A.K. et al., Common features of aging fail to occur in Drosophila raised without a bacterial microbiome, iScience, June 24, 2021, DOI: 10.1016/j.isci.2021.102703

###

Link:
Study suggests scientists may need to rethink which genes control aging - National Institutes of Health

The knowledge and experience of our advisors will help advance our vision of translating novel gene editing medicines.

"Incisive Genetics' platform technology represents a very promising avenue for gene therapy," said Dr. Hayden. "I look forward to leading the Scientific Advisory Board and working with the greater team at Incisive as they continue to expand upon their delivery platform and pipeline."

The Incisive Genetics SAB is comprised of:

Dr. Michael R. Hayden, CM OBC MB ChB PhD FRCP(C) FRSC

Dr. Michael Hayden is a Killam professor at the University of British Columbia and the founder of the Centre for Molecular Medicine and Therapeutics. He is also a Canada Research Chair in Human Genetics and Molecular Medicine. Dr. Hayden previously served as CSO and President of Global R&D at Teva and has co-founded numerous biotechnology companies, including 89Bio, Prilenia Therapeutics, Xenon Pharmaceuticals, and Aspreva Pharmaceuticals. He is a world-renowned scientist who has sat on many boards of private and public companies across the globe. Dr. Hayden is the recipient of numerous awards and is a pioneer in multiple fields, including genetic medicine. Dr. Hayden is the recipient of the Diamond Jubilee Medal (2012) and is a Member of the Order of Canada (2011), and a Member of the Order of British Columbia (2010).

Dr. Leslie Thompson

Dr. Leslie Thompson is a Donald Bren and Chancellor's Professor in the Departments of Psychiatry and Human Behavior and Neurobiology and Behavior at the University of California Irvine (UCI). Dr. Thompson has studied Huntington's disease (HD) for most of her scientific career and was a member of the international consortium that identified the causative gene for HD in 1993. Dr. Thompson is a member of the Hereditary Disease Foundation SAB, HD CARE SAB, Packard Center SAB, Chair of the Huntington's Disease Society of America SAB and is founding Co-Editor in Chief of the Journal of Huntington's Disease. She is also the PI of the OMICS core of the Answer ALS program, which is a precision medicine approach to understand sporadic ALS in over 1000 ALS subjects.

Dr. David Weiner

Dr. David Weiner is a neurologist and neuropharmacologist with over 20 years of experience in the discovery and development of novel therapeutics for neurological disease. He started his career at ACADIA Pharmaceuticals, where, over a ten-year period, he held a series of discovery research and clinical development roles working on multiple therapeutics, most notably Pimavanserin. He subsequently joined EMD Serono in a late clinical development role, ultimately leading early clinical development activities in neurology globally. Dave has extensive experience in neurological and rare disease drug development, serving as CMO and Interim CEO for Proteostasis Therapeutics Inc., CMO at aTYR Pharma and Lumos Pharmaceuticals, and as CEO at Amathus Therapeutics. He has authored numerous scientific publications, multiple patents, and serves on a number of clinical and scientific advisory boards, including the scientific advisory board of the Michael J. Fox Foundation for Parkinson Research.

About Incisive Genetics Inc.

Incisive Genetics, a privately-held biotechnology company based in Vancouver, Canada, was established in 2018. IG is focused on developing its cutting-edge non-viral delivery platform for genetic therapies. This disruptive and transformational delivery platform enables a one-step encapsulation of the active CRISPR components within lipid nanoparticles. The Company's pre-clinical pipeline includes programs addressing neurologic and ocular genetic diseases. IG is actively seeking partnerships with pharmaceutical companies developing gene therapies to be enabled by its novel delivery platform.

For more information, please visit http://www.incisivegenetics.com

FOR MEDIA INQUIRIES:Austin Hill[emailprotected]604-409-0660

SOURCE Incisive Genetics

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Incisive Genetics Announces Formation Of Scientific Advisory Board And Appointment Of Dr. Michael R. Hayden As Chairperson - PRNewswire

Most mornings, Huda Zoghbi, 67, climbs a glass-encased, curling staircase to reach her lab on the top and 13th floor of the Jan and Dan Duncan Neurological Research Institute in Houston, Texas. The twisting glass tower, which she designed with a team of architects, echoes the double helix of DNA a structure that has been central to her career-long quest to uncover genes underlying neurological conditions.

As the institutes director and as a scientist she is known for going beyond the standard job description. Genetics researchers often cast a wide net and sequence thousands of genes at a time. But in her prolific career, Zoghbi has focused on a handful of genes, methodically building up an understanding of their function one careful step at a time.

Thanks to that approach, Zoghbi has made a number of landmark discoveries, including identifying the genetic roots of Rett syndrome, an autism-related condition that primarily affects girls, as well as the genetic mutations that spur spinocerebellar ataxia, a degenerative motor condition. She has authored more than 350 journal articles.

Her accomplishments have earned her almost every major biology and neuroscience research award, including the prestigious Breakthrough Prize in 2017 and the Brain Prize in 2020. Shes clearly the international leader in the field, said the late Stephen Warren, professor of human genetics at Emory University in Atlanta, Georgia.

Zoghbi never set out to lead a large research center, she says her heart is in the lab. That said, she has excelled at it: Since the institutes inception in 2010, it has grown to host more than 200 scientists and fostered more than 70 new disease gene discoveries.

Part of that success may be due to the high expectations she sets for her trainees. They work long hours in what some call the lab that never sleeps, says Vincenzo Alessandro Gennarino, a former postdoctoral fellow in the lab, now assistant professor of genetics and development, pediatrics and neurology at Columbia University. But many say she is also endlessly empathetic and caring toward her lab family, as she describes it. She really kind of sees them as her scientific children in a way, says her son, Anthony Zoghbi, assistant professor of clinical psychiatry at Columbia.

For more than a decade now, this family has worked toward turning the deep biological mechanisms they have uncovered into treatment targets for Rett syndrome and other autism-related conditions. Finding effective therapeutics for such complex conditions is a tall order, Warren said. But shes got good model systems, good ideas, and she attracts very talented people in her lab, so I think she has a crack at it.

Zoghbi grew up in the vibrant city of Beirut, Lebanon, in the 1950s and 60s. Her father filled the familys home with books, which fueled an early passion for Arabic and English literature. She considered studying English literature when she entered the American University of Beirut in 1973, but she switched to biology, swayed by her mother, who saw her talent for the sciences. This path led Zoghbi to medical school at the same institution.

During her first few months of medical training in 1975, the Lebanese Civil War that had erupted earlier that year escalated. Constant bombings made it too dangerous to commute, so Zoghbi and her 62 classmates took shelter on campus. She lived in a closet inside a womens bathroom until the school year ended.

When flying shrapnel injured her 16-year-old brother, Jamal, in the spring, Zoghbis parents decided to send her and her younger siblings to live with their older sister in the United States for the summer. By mid-September, the war had only worsened, and Zoghbi scrambled to find a medical school that would accept a transfer student from another country.

Within weeks, she landed an interview at Meharry Medical College, a historically Black institution in Nashville, Tennessee, and started classes the next day. She spent the rest of the year catching up and feeling achingly homesick, she says, taking solace only in letters from William Zoghbi, a classmate she had started dating before she left Lebanon. Those books were soaked with tears, Zoghbi says. I literally cried my way through that year.

William whom she says she admired for his captivatingly kind smile joined her at Meharry the following year. They later married. (William Zoghbi is now chair of cardiology at Houston Methodist Hospital.)

Zoghbi sought a future in pediatric cardiology at the start of her residency at Houstons Baylor College of Medicine in 1979. And then I rotated in neurology, and everything changed, she says. I fell in love with neurology.

But her excitement wore off soon after she started a neurology fellowship in 1982. It was incredibly frustrating, Zoghbi says, to diagnose children with rare neurological conditions and be unable to provide their families with any information about a cause or hope for a treatment.

This helpless feeling came to a point in October the following year, when she encountered a little girl with a particularly devastating and puzzling condition: Ashley Fry, a 3-year-old girl with sparkling brown eyes, had developed typically for the first 18 months of her life but then suddenly started losing language skills and wringing her hands, rubbing her left hand over and over with her right.

That pain was very tangible to me like, to have a girl, shes healthy, and shes beautiful, and youre enjoying her, and then to see her robbed of that, Zoghbi says. I felt that agony.

Zoghbi and her attending physicians diagnosed Ashley with Rett syndrome. Ashley was the first case diagnosed in Texas and among only a handful identified in the U.S. at the time. But a week later, Zoghbi found another case a girl who arrived at a cerebral palsy clinic wringing her hands. Zoghbi pulled more charts from the clinic describing similar symptoms a stark regression, intellectual disability, seizures and hand-wringing and found a few more cases.

Soon Zoghbi and her colleagues started publishing papers on Rett syndrome, and children with suspected cases came in from all over the country. One after the other they looked the same, and I was like, It has to be a gene, and thats when I decided Im going to go into research, Zoghbi says.

In 1984, she approached the renowned geneticist Arthur Beaudet at Baylor about doing a postdoctoral fellowship in his lab. She had collected blood samples from 200 children with Rett syndrome, and she wanted to try to find the gene underlying the condition. Zoghbi had virtually no laboratory experience, but she was just extremely talented and bright and motivated, says Beaudet, now chief executive officer of the Houston-based prenatal genetic testing company Luna Genetics. She was the kind of trainee every scientist hopes to encounter one day.

Beaudet took Zoghbi on but, to her disappointment, said she couldnt focus on Rett syndrome, which he deemed too difficult to trace genetically. Zoghbi agreed instead to study a family in Texas with spinocerebellar ataxia work that later led to a groundbreaking co-discovery of the gene underlying a subtype of the condition.

Even as Zoghbis spinocerebellar ataxia work accelerated, she continued thinking about Rett syndrome. Her urge to help grew even stronger when she had her first child, a daughter named Roula, in 1985. She did little experiments here and there, sometimes under the radar, searching for clues that the causative gene was on the X chromosome, or X-linked. If so, it would explain why all the cases shed seen so far were girls. If a mutation disrupts a gene on the X chromosome, girls, who have two Xs, still have a functioning copy. But boys, who have only one X chromosome, might not survive.

She was able to pursue her ideas further when she started her own lab at Baylor in 1988. With help from geneticist Uta Francke at Stanford University in California, Zoghbi and her team eventually ruled out more than two-thirds of the genes along the X chromosome. That left hundreds of genes to explore, which they started sequencing one by one, taking about a years worth of work each time. Every gene was a labor of love, Zoghbi says.

Negative results piled up, and funding slowed. But Zoghbi kept at it, persistent as ever. Sometimes, during long weekends in the lab, her two children, Roula and Anthony, tagged along, peering into petri dishes or practicing pipetting while she worked.

One afternoon in August 1999, Zoghbis phone rang just as she and her family were returning home from their annual summer trip to Lebanon. She raced to the phone, and on the other end was Ruthie Amir, a postdoctoral fellow in the lab.

I think I found it, Amir said.

Poring over the data together at Zoghbis house later that day, the pair saw that five girls with Rett syndrome all carried a spontaneous mutation in the same gene on the X chromosome. The gene, MECP2, encodes a protein known as methyl-CpG binding protein 2, which regulates the expression of thousands of other genes throughout the body and brain.

The team published their results two months later in Nature Genetics, 16 years after Zoghbi first met Ashley. Zoghbi invited Ashley and her family to the press conference announcing the discovery. She didnt have to explain why she was asking them to come to Houston, recalls Ashleys father, Clifford Fry. I knew it in my heart that she had found the gene.

Zoghbi has meticulously probed the far-reaching effects of MECP2 ever since, tracking the results of removing the gene from different areas or cell types in the brain. Each of these conditional knockouts has helped to account for a subset of Rett-related traits. Deleting MECP2 from the hypothalamus, for example, produces mice that eat uncontrollably and are aggressive and easily stressed, not unlike traits seen in boys with less severe mutations in MECP2.

Knocking out MECP2 in inhibitory neurons recapitulates almost all the traits of Rett syndrome. The mice even clasp their forepaws repeatedly, which mirrors the girls hand-wringing. And by removing MECP2 from each of two subtypes of inhibitory neurons, or from inhibitory versus excitatory cells, Zoghbi has demonstrated how the gene supports the function of whole brain circuits, not just individual neurons.

Zoghbi and her team also engineered mice with an extra copy of MECP2 to use as controls in Rett experiments. But the animals developed severe seizures, and about a third died prematurely. This unexpected result, published in 2004, showed that a surplus of MECP2 protein can be just as problematic as a deficiency. The following year, another team described some of the first cases of MECP2 duplication syndrome, which causes autism, intellectual disability and seizures mostly in boys.

Zoghbi is particularly attached to her MECP2 duplication work because Tropical Storm Allison nearly washed it away. When the storm slammed into Houston in June 2001, it flooded the animal facility where some of Zoghbis MECP2 duplication mice lived. Zoghbi and one of her graduate students suited up in waders and went searching with a flashlight through the chest-high water for any surviving mice. They found a lone survivor in a top rack of the cages. That mouse is the founder of one of the MECP2 duplication colonies the lab studies to this day.

I learned a lesson from that, Zoghbi says. Always go back and take a second look. You never know.

Zoghbi holds a steady focus on finding what will truly help people with Rett syndrome and the other conditions she studies. Its clear that her approach is not Okay, Ive discovered the gene, Ive done my job, says Michela Fagiolini, associate professor of neurology at Harvard University, who also studies Rett syndrome. And that drive is Zoghbis true legacy: She has built not just an empire in Texas but also created a school of thinking.

In one ongoing line of work, Zoghbis team has used snippets of genetic material, called antisense oligonucleotides, to silence the extra MECP2 gene copy in duplication mice. A drug delivering these genetic strands reverses problems with movement, learning and memory in mice with two human copies of MECP2, suggesting that it might also be effective in people.

The key to these types of treatments, Zoghbi says, will be titrating the dosage of MECP2 expression so that it normalizes protein levels without tipping them too far in the direction of Rett syndrome. As such, Zoghbi is searching for biomarkers that signal when MECP2 levels have reached a safe zone.

Zoghbi has also worked with colleagues at Baylor to show that deep brain stimulation applied to the hippocampus improves learning and memory in a mouse model of Rett. They are exploring whether stimulating motor circuits can similarly ease motor deficits in the mice. And Zoghbi has also tried mimicking the effects of deep brain stimulation in the form of intensive behavioral training to activate some of the same circuits.

Training Rett mice on motor and memory tasks early in life postpones the onset of difficulties in these areas, according to results published in March. If the same holds true in human clinical trials, it would help build the case to offer genetic screening for Rett syndrome in newborns, Zoghbi says. Lets give these girls the maximum opportunity, and lets hopefully delay the disease onset by a year or year and a half or two, until more effective genetic treatments become a reality, she says.

Zoghbi stopped working as a clinician a couple of years ago, but a photo of Ashley, now 41, sits on the windowsill in her office, reminding her of where it all started and what shes working toward. When Ashley and her family are in town, Zoghbi sometimes meets them at their hotel, just to say hi to Ashley and give her a hug and a gift, such as an ornate purple and gold shawl.

Giving people like Ashley a chance to fully engage in their world is at the heart of Zoghbis inexhaustible work ethic, says Laura Lavery, a postdoctoral associate who has worked with Zoghbi for the past seven years. Shes the most driven person Ive ever met, and underlying all of that is really her love and empathy for humankind. She is just not going to stop until she figures out how to help.

Cite this article: https://doi.org/10.53053/THWT9489

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Huda Zoghbi: Taking genetic inquiry to the next level - Spectrum

LONDON, June 28, 2021 (GLOBE NEWSWIRE) -- Treos Bio Limited (Treos), a clinical stage biotechnology company using data science and proprietary biomarkers to develop precision off-the-shelf and personalized peptide cancer immunotherapies, today announced the publication of a peer-reviewed article titled A Peptide Vaccine Candidate Tailored to Individuals Genetics Mimics the Multi-Targeted T Cell Immunity of COVID-19 Convalescent Subjects in Frontiers in Genetics. The paper reviewed the potential of PolyPEPI-SCoV-2, the Companys peptide vaccine candidate, to potentially address all four structural proteins of the COVID-19 virus in order to generate long-term immunity in virtually all human subjects, independent of ethnicity.

We are gratified to see these promising results published in Frontiers in Genetics, providing another scientific validation for our novel approach to match patients genetic background to T cell responses, which was already successfully applied for the design of our off-the-shelf cancer vaccines. We believe long-term immunity to coronaviruses will likely originate from targeted and broad T cell responses and we think that our technology has the potential to produce long-lasting immunity against this variable virus, said Dr. Christopher C. Gallen, M.D., Ph.D., Chief Executive Officer of Treos. Overall, with the downstream physiological activation shown, these data have compelling implications for the development of highly immunogenic, T cell-focused global vaccines against various pathogens and diseases. We look forward to leveraging our proprietary data science and therapeutic platform to continue investigating this program.

Article highlights include:

The full article is accessible at https://www.frontiersin.org/articles/10.3389/fgene.2021.684152/full and at http://treosbio.com/index.php/publications-2/.

About Treos Bio LimitedTreos Bio uses computational data science and proprietary biomarkers to develop precision off-the-shelf and personalized peptide-based cancer immunotherapies. The Company has developed a unique ability to match the antigens expressed by a specific cancer to the individual patients target recognition mechanism (HLA). This technology aims to address the challenge of the variability of an individual patients clinical responses to cancer immunotherapies. Treos lead candidate is PolyPEPI-1018, an off-the-shelf immunotherapy for the treatment of metastatic colorectal cancer, co-developed with a candidate companion diagnostic. Treos is also developing off-the-shelf personalized immunotherapies (PEPI Panel) for several types of solid tumors and has completed preclinical development of PolyPEPI immunotherapies in ovarian, breast, bladder, gastric and lung cancers and melanoma. The Company is also developing an investigational COVID-19 peptide vaccine, PolyPEPI-SCoV-2. Treos launched in February 2017 and has raised $28 million Series A funding led by shareholders of BXR Group and recently closed a $14 million investment round led by Outsized Ventures (formerly known as Luminous Ventures). More information can be found at http://www.treosbio.com.

Media Contact:

Solebury TroutZara Lockshin +1-646-378-2960zlockshin@soleburytrout.com

Investor Contact:

Solebury TroutAlan Lada +1-646-378-2927alada@soleburytrout.com

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Treos Bio Announces the Publication of Preclinical Data in Frontiers in Genetics Showing its COVID-19 - GlobeNewswire