Category Archives: Genetic Medicine

President Trumps illness from a coronavirus infection last month was the most significant health crisis for a sitting president in nearly 40 years. Yet little remains known about how the virus arrived at the White House and how it spread.

The administration did not take basic steps to track the outbreak, limiting contact tracing, keeping cases a secret and cutting out the Centers for Disease Control and Prevention. The origin of the infections, a spokesman said, was unknowable.

But one standard public health technique may still shed some light: tracking the clusters genetic fingerprints.

To better understand the outbreak, The New York Times worked with prominent geneticists to determine the genetic sequence of viruses that infected two Times journalists believed to have been exposed to the coronavirus as part of their work covering the White House.

The study reveals, for the first time, the genetic sequence of the virus that may have infected Mr. Trump and dozens of others, researchers said. That genome is a crucial clue that may allow researchers to identify where the outbreak originated and whether it went on to infect others across the country.

The White House has not disclosed any effort to conduct similar genetic testing, but the studys results show that it is still possible, even weeks after positive tests. Additional sequencing could help establish the path of the virus through the White House, the role of a possible super-spreading event for Judge Amy Coney Barrett and the origin of an outbreak among the staff of Vice President Mike Pence in the last week or so.

The journalists, Michael D. Shear and Al Drago, both had significant, separate exposure to White House officials in late September, several days before they developed symptoms. They did not spend any time near each other in the weeks before their positive tests.

Mr. Shear traveled with Mr. Trump and other staff on Air Force One on Sept. 26, when Mr. Trump approached within five or six feet without a mask. Mr. Drago covered the Judge Barrett event that day and a news conference the next day near officials who were not wearing masks and later tested positive. Both journalists wore masks.

The viral genomes of the two journalists shared the same distinct pattern of mutations, the research found. Along with their exposure history, the findings suggest that they were infected as part of the broader White House outbreak, said Trevor Bedford, a geneticist at the Fred Hutchinson Cancer Research Center and the University of Washington who led the research team.

These mutations that are possessed by these viruses are quite rare in the United States, Dr. Bedford said. I am highly convinced that these viruses come from the same outbreak or cluster based on their genomes.

The study, which has been posted online but not yet peer reviewed or published in a science journal, followed academic protocols that require genetic samples to be anonymous. Mr. Shear and Mr. Drago chose to disclose their identities for this article.

Viruses constantly mutate, picking up tiny, accidental alterations to their genetic material as they reproduce. Few mutations alter how a virus functions. But by comparing patterns of mutations across many genetic sequences, scientists can construct family trees of a virus, illuminating how it spreads.

The genomes believed by these researchers to be connected to the White House outbreak do not identify a recent geographic source, in part because they are unusual. The ancestors of those viruses spread to the United States from Europe and were circulating widely across the country in April and May, but the trail goes cold after that, according to Dr. Bedford.

Geneticists said the genomes are a key piece of the puzzle that may spur future research to determine where the White House outbreak originated and where it may go next. Scientists collect and publish tens of thousands of new sequences of the coronavirus every month, and additional testing may fill in the picture.

The results show that even weeks after it was identified, the White House outbreak would be better understood by sequencing samples of more people who were infected. Swabs used in positive tests are often kept in labs for months after an initial infection, and genetic material for the coronavirus is stable if stored appropriately.

The C.D.C. routinely relies on genetic testing to help understand Covid-19 outbreaks elsewhere across the country. In a study released on Thursday, the C.D.C. cited genetic sequencing and intensive contact tracing that documented an super-spreading event at a high school retreat in Wisconsin.

But the Trump administration is not known to have conducted its own genetic analysis of people infected in the outbreak. The White House declined to respond to questions on genetic sequencing of Mr. Trump and the cluster of aides and officials who tested positive or became ill.

There is still a remote possibility, Dr. Bedford said, that a previously unseen version of the virus had been circulating undetected in Washington or Northern Virginia and infected both journalists independently from the White House cluster. More testing of the outbreak could eliminate that possibility entirely, he said.

Scientists not involved in the research who reviewed the results agreed with the conclusion that the two samples sharing rare mutations strongly suggested they are part of the same outbreak.

These genomes are probably going to be identical or nearly identical to the genome that infected the president, said Michael Worobey, head of the department of ecology and evolutionary biology at the University of Arizona.

Dr. Worobey disputed the White Houses characterization that the source of the outbreak could not be known.

A lot of things are unknowable if you make no effort to know anything about them, and this falls into this category, Dr. Worobey said. All of these things actually can be known if you make the effort and you have the transparency that scientists are desperately trying to promote as we sequence hundreds of thousands of these genomes around the world.

For months, the White House minimized the threat of the virus and eschewed basic safety precautions at official events, like wearing a mask or keeping people six feet apart.

At least 11 people who attended a Rose Garden celebration on Sept. 26 for Judge Barrett, which included an indoor event without masks, became infected with the coronavirus, including Mr. Trump. Additional genetic testing could help more clearly establish the role of that event.

Dr. Bedford and his colleagues were able to obtain a full genetic sequence for the virus that infected Mr. Shear and a partial sequence of the virus that infected Mr. Drago. Several unusual mutations matched in the two samples, sufficient evidence to determine with a very high probability that they were essentially the same genome, Dr. Bedford said.

The work was carried out by a multidisciplinary team of researchers at the University of Washington School of Medicine, the Hutchinson Center and the Brotman Baty Institute for Precision Medicine in Seattle.

The work is convincing, and it is the best way to piece together the progression of such an outbreak, said David Engelthaler, head of the infectious disease branch of the Translational Genomics Research Institute in Arizona, where he and colleagues have sequenced thousands of genomes to track the spread of the coronavirus, including devastating outbreaks at Native American reservations in the state.

Its critical no matter where we are to sequence this virus, Dr. Engelthaler said. Not just at the White House, but at the White Mountain Apache Reservation here in Arizona.

Carl Zimmer contributed reporting.

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Tests Show Genetic Signature of Coronavirus That Likely Infected Trump - The New York Times

Researchers from the US and Canada believe that fingolimod represents an exciting novel therapy for HIV infection. In the scientific review PLOS Pathogens, Dr Rachel Resop and her colleagues from the George Washington University and the University of Montreal demonstrate through extensive test tube experiments that without affecting the viability of human cells, the drug can hinder several key steps of the HIV life cycle.

Known commercially as Ginleya, fingolimod is an oral medicine used in the treatment of multiple sclerosis, a disease where the central nervous system is attacked by the bodys own immune system.

Fingolimod is an immunomodulatory drug that directly targets a component of the immune system called Sphingosine-1-phosphate, or S1P.

S1P has multiple roles in the cell-signalling system, including cell proliferation and migration, survival, apoptosis (programmed self-destruction) and inflammation. None of these processes could exist without the binding of S1P to its specific receptors (proteins located on the cell surface), which are numbered S1PR1 to S1PR5.

S1PR1 and S1PR4 are present on several subsets of CD4 T cells. They can be modulated by drugs (called agonists) that bind to receptors and produce an effect within cells and also by drugs (antagonists) that block those receptors to agonists. However, the full scope of S1P signalling in CD4 T cells, as well as the impact of HIV-1 on the S1P receptors are not fully understood. Moreover, although the S1P involvement in inflammation and diseases such as diabetes is established, little is known on the role of S1P in HIV-1 pathogenesis.

Previous research has shown that fingolimod downregulates S1PR1 in lymphocytes, modulates S1P signalling and, consequently, changes the natural migration, proliferation and cycle state of lymphocytes and other cells.

Resop and colleagues therefore decided to see if the molecule had any impact on the establishment of both active and latent HIV infection. In other words, the investigators were assuming that because it is an immunomodulatory compound, fingolimod could inhibit HIV infection.

Previous studies that brought them to test their hypothesis had also shown that:

The researchers looked at how the S1P signalling was involved in the establishment of productive HIV infection. For this, they used CD4 T cells from HIV-negative individuals that they expanded in culture, then activated. Then, they treated the cells with different doses of fingolimod, before infecting them with either an X4 or R5 tropic HIV-1. It was important to proceed this way because HIV attaches to the CD4 receptor on the cell, but also selectively to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (R4-tropic), or both (dual-tropic).

Small pharmacological molecules that could help uncover where HIV is hiding in the cells of HIV-positive persons whose viral load had been suppressed below the level of detection (or reverse HIV latency). Researchers are investigating these molecules hoping they may be part of a combination approach to eradicating HIV (kick HIV out of latently infected cells to suppress it with ARVs).

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a host cell), HIV binds to the CD4 receptor and its coreceptor.

The HIV reservoir is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapycan reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped.

When HIV selectively attaches to a particular coreceptor on the surface of a host CD4 cell. HIV can attach to either the CCR5 coreceptor (R5-tropic) or the CXCR4 coreceptor (X4-tropic) or both (dual-tropic).

Results from this cell-free experiment show that pre-treatment of cells with fingolimod reduced HIV-1 infection, with the greatest reduction (55%) seen with the highest dose. Moreover, fingolimod did not render the cells less viable, and its inhibitory effect was observed regardless of HIV-1 tropism.

This provided evidence that fingolimod does have an impact on the establishment of productive HIV-1 infection through interfering with the S1P signalling.

The drug also proved to have an inhibitory effect on the cell-to-cell transmission of HIV: in line with the cell-free results described above, the investigators observed a marked decrease in productive infection. Again, this was seen with both X4 and R5-tropic HIV, and cell viability was not reduced.

Further experiments suggested that the fingolimod inhibitory effect during cell-to-cell transmission is due to failure of HIV to infect new cells, rather than the inability of infected cells to produce virions.

Proviral HIV-1 DNA is the chemical form in which the virus genetic information is stored within infected cells that form the latent reservoir. Latent infections are established during cell-to-cell transmission of the virus and their magnitude directly correlates with productive infection. Could fingolimod help reduce proviral DNA harboured in target cells and perhaps even limit the establishment of infection?

Infected cells were treated with fingolimod from day 10 to 13 of infection, after which the drug was removed from the culture and replaced by two antiretrovirals until day 17.

At day 17, latent HIV infection was assessed in the mixture of uninfected and latently infected cells obtained, and the investigators found that fingolimod had significantly reduced the levels of total and integrated proviral DNA (by 51% and 60%, respectively). This led to a 66% reduction in production of new virus by reactivated reservoir cells.

However, adding fingolimod, once the latently infected cells had been established, had no effect. This indicates that, in this study at least, latency was established prior to antiretroviral therapy and that following the use of antiretrovirals, the latent reservoir was not impacted by fingolimod.

But since latently infected cells are established during cell-to-cell transmission of HIV, this also indicates that the brunt of the role of fingolimod is likely a consequence of the reduction in productive infection. This effect is carried over into a reduced incidence of latently infected CD4 T cells.

It was also important to investigate the mechanisms by which fingolimod inhibits HIV infection.

While comparing fingolimod-pre-treated cells with untreated ones, the investigators observed a reduction of the surface density of the CD4 molecule. They also found that virion binding and viral fusion were reduced in the treated cells. They suggest that the reduction in the surface density supported the decrease in both binding and fusion.

However, these reductions (average 23%) could only partially account for the larger reductions in HIV DNA already mentioned. Fingolimod probably alters additional steps in the viral life cycle.

After observing that fingolimod promotes a non-cycling (resting) state in memory cells and a reduction in HIV DNA, the researchers hypothesised that the drug may also favour the activity of innate (present at birth) HIV restriction factors. These are cellular proteins that, among several roles, act as a first line of defence to block viral replication and propagation, and may promote antiviral cellular immunity to combat viruses. One of them is SAMHD1, known to impair reverse transcription specifically.

Following treatment of cells for 24 hours with fingolimod, a relative increase in SAMHD1 was seen, which may be associated with a decline in levels of Cyclin D3, a protein known to regulate SAMHD1.

Finally, the investigators evaluated whether fingolimod could reactivate latent HIV on its own or in combination with one or more latency reversing agents. These are molecules that have the potential to help uncover where HIV is hiding in cells of people whose viral load is present but undetectable with standard tests. They are being investigated as part of the shock and kill HIV cure strategies, based on reactivating latent cells, then killing them with antiretrovirals.

In the same in vitro model already used in the study, CD4 T cells were treated for 48 hours with fingolimod, either on its own or together with various combinations of six latency reversing agents. Then the frequency of reactivated cells was measured. Fingolimod was found to not hinder the ability of these latency reversing agents and even to have a moderate latency reversal activity when used on its own.

In summary, this study shows that fingolimod:

Hence the enthusiasm of Resop and colleagues who say that fingolimod may be useful as a strategy to limit the size of the latent reservoir if used prior to ART initiation, such as in acute infection. They also suggest it could have a role in strategies aimed toward viral reactivation and eradication of the latent HIV reservoir.

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Could a multiple sclerosis medication be used against the HIV reservoir? - aidsmap

The research, conducted by scientists at the University of Cambridge and the Institut Pasteur, was published today in the leading journalNature. It highlights how large COVID-19 outbreaks in European nursing homes, and the potential for missing deaths in some Asian and South American countries, have skewed COVID-19 death data for older age groups, rendering cross-country comparisons of the scale of the pandemic inaccurate.

The researchers say that reporting of deaths from COVID-19 among those under the age of 65 is likely to be far more reliable, and can therefore give clearer insights into the underlying transmission of the virus and enable better comparisons between countries crucial in guiding government strategies to try to get COVID-19 under control.

Simply comparing the total number of deaths across countries can be misleading as a representation of the underlying level of transmission of SARS-CoV-2. Most deaths are in older people, but they are the least comparable across countries, said Megan ODriscoll, a PhD researcher in the University of Cambridges Department of Genetics and first author of the paper.

In countries including the UK, Canada and Sweden, the COVID-19 pandemic has disproportionately affected nursing home residents, who account for over 20% of all reported COVID-19 deaths. The level of SARS-CoV-2 transmission among the general population can be difficult to disentangle from these large outbreaks.

By contrast, some countries in Asia and South America have far fewer reported COVID-19 deaths in older people than expected. One potential explanation for these missing deaths is that causes of deaths in elderly populations may be less likely to be investigated and reported as countries struggle to contain the epidemic.

Nursing homes are enclosed communities of people, and once the virus gets in it can spread quickly resulting in higher levels of infection than in the general population. Were seeing an excessively large number of deaths from COVID-19 in this older age group, particularly in countries that have many nursing homes, said Dr Henrik Salje in the University of Cambridges Department of Genetics, the senior author of the report.

He added: Its not just that residents are older than the general population, they are also generally more frail, so a 70-year old living in a nursing home is often more likely to die of COVID-19 than a 70-year old in the general population. To reduce the overall number of COVID-19 deaths it is vital to protect vulnerable elderly communities.

In their new model, the researchers integrated age-specific COVID-19 death data from 45 countries with 22 national-level seroprevalence surveys. Governments of many countries are using seroprevalence surveys to estimate the number of people in a population with antibodies against the coronavirus. Antibodies indicate if a person has been infected with SARS-CoV-2 at some point, so are a good indicator of population-wide infection rates.

Our model shows that the number of COVID-19 deaths by age, in people under 65 years old, is highly consistent across countries and likely to be a reliable indicator of the number of infections in the population. This is ofcritical use in a context where most infections are unobserved, said ODriscoll.

The model can be used at a country-wide level to predict a persons likelihood of dying from COVID-19 following infection, depending on their age. It also works in reverse, to estimate a countrys total number of infections given its number of COVID-19 deaths in an age group, which is particularly useful in places where seroprevalence studies have not been conducted.

Using death data from under-65 age groups only, which is most representative of transmission in the whole population, it shows that by the 1 September this year an average of 5% of the population of a country had been infected with SARS-CoV-2. However, in some places it was much higher, especially South America.

For example, using Perus COVID-19 death figures, which equate to 0.01% of the countrys population, the model suggests that over half of the population of Peru has now been infected with SARS-CoV-2 a figure far higher than expected. This indicates particularly high rates of transmission of the virus in Peru.

But even after excluding data from the over 65s, the model shows that COVID-19 death rates cannot be compared between some countries, because the relationship between infections and deaths is not consistent when other widespread co-morbidity factors are involved.

It seems that people living in places such as Slovenia and Denmark have a low probability of death following infection with SARS-CoV-2, even after accounting for the ages of their populations, which is very different to what weve seen in New York, for example. There are likely to be fundamental differences in the populations across countries, which might include their underlying health, said Salje.

The model also revealed a strong pattern across countries in the 5-9 year age group, which consistently has the lowest probability of death following SARS-CoV-2 infection.

The work demonstrates how age-specific death data alone can be used to reconstruct the underlying level of SARS-CoV-2 infection in a country and how it has changed over time. The researchers say this approach could be applied at sub-national scale, and may be of particular use in settings where large seroprevalence studies might not be feasible.

This research was funded by the University of Cambridge COVID-19 Rapid Response Grant.

Reference

ODriscoll, M. et al: Age-specific mortality and immunity patterns of SARS-CoV-2. Nature (2020). DOI: 10.1038/s41586-020-2918-0

ENDS

About the University of Cambridge

The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 110 affiliates of the University have won the Nobel Prize.

Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America.

The University sits at the heart of the Cambridge cluster, which employs 60,000 people and has in excess of 12 billion in turnover generated annually by the 4,700 knowledge-intensive firms in and around the city. The city publishes 341 patents per 100,000 residents.

http://www.cam.ac.uk

About the Institut Pasteur and the Institut Pasteur International Network

The Institut Pasteur, a non-profit foundation with recognized charitable status set up by Louis Pasteur in 1887, is today an internationally renowned center for biomedical research with a network of 32 institutes worldwide. In the pursuit of its mission to prevent and control diseases in France and throughout the world, the Institut Pasteur operates in four main areas: research, public health, education and training, and development of research applications.

More than 2,700 people work on its Paris campus. The Institut Pasteur is a globally recognized leader in infectious diseases, microbiology, and immunology. Other avenues of investigation include cancer, genetic and neurodegenerative diseases, genomics and developmental biology. This research aims to expand our knowledge of the living world in a bid to lay the foundations for new prevention strategies and novel therapeutics. Since its inception, 10 Institut Pasteur scientists have been awarded the Nobel Prize for Medicine, including two in 2008 for the 1983 discovery of the human immunodeficiency virus (HIV) that causes AIDS.

http://www.pasteur.fr/en

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Focus on COVID-19 deaths in under-65s for better insights into infection rates across populations, say researchers - Newswise

Genetic associations between inflammatory bowel disease (IBD) and stress related to depression have been uncovered by a novel study that combined 3D genomic mapping with publicly available data from genome-wide association studies (GWAS). Carried out by researchers at Childrens Hospital of Philadelphia (CHOP), the study further implicated new genes involved in IBD risk that are enriched in both derived hypothalamic neurons and organoids grown from colon cells. The former has a vital role in controlling stress and depression, the colon, meanwhile, is directly affected by IBD.

The findings were published earlier this month inCellular and Molecular Gastroenterology and Hepatology. DOI: 10.1016/j.jcmgh.2020.10.004. This work builds upon an earlier study by the group which implicated a subset of IBD loci as conferring an effect via the hypothalamus.

Our results implicate a role for the hypothalamus in the genetic susceptibility to IBD, said senior author Struan Grant, Ph.D., a director of the Center for Spatial and Functional Genomics at CHOP and the Daniel B. Burke Endowed Chair for Diabetes Research. Epidemiological data has previously shown overlap between IBD and stress and depression, and now we have generated genomics data to support that association. Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.

IBD comprises Chrons disease (CD) and ulcerative colitis. It is an immune-mediated condition marked by dysregulated inflammation of the gastrointestinal tract. More than three million people, or approximately 1.3% of all adults, suffer from this condition in the US alone.

Multiple genetic and environmental factors are known to contribute to the pathogenesis of IBD, and more than 230 loci for the disease have been uncovered using GWAS analyses. Many of the genes residing at these loci have been implicated in pathways related to the immune system and the microbiome.

The CHOP team first established whether there were genetic correlations between IBD and depression to assess the degree of genetic commonality between the two conditions. (Depression was used as a proxy for stress because of the limited number of published GWAS efforts that have focused on stress and used a consistent definition of it.) To do this, they analyzed eleven autoimmune diseases. They found that among those, IBD was most strongly statistically correlated positively with depression.

Next, the researchers validated the correlation between IBD and depression. First, they measured the enrichment of IBD-associated genetic variants in the 3D genomic patterns within hypothalamic-like neurons (HNs) and colonoids from rectal biopsies. They found a highly significant four-fold increase in HNs and a seven-fold increase in the colonoids. A proprietary variant-to-gene mapping approach, was then used to determine which genes are implicated in the pathogenesis of IBD at these enriched signals. By assessing those genes, the researchers then looked for pathways potentially influenced by IBD-associated genetic variants.

Using this variant-to-gene mapping effort, the researchers implicated 25 genes in HNs that conferred risk for IBD. Eleven of those genes have known functions in the brain, in particular CREM, CNTF and RHOA, which are genes that encode key regulators of stress. Seven of those genes were also implicated in the colonoids. The researchers observed an overall enrichment for hormonal signaling pathways as well as the expected enrichment in immune and microbiome signaling pathways.

We propose that some IBD-associated variants alter the hypothalamus-pituitary-adrenal axis and stress responses, which could in turn play a role in predisposing patients to this disease and exacerbating its presentation, Grant said. Future studies are warranted to refine our understanding of the role of the hypothalamus in IBD onset.

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GWAS Links Genetic Associations Between IBD and Stress Regulated by the Hypothalamus - Clinical OMICs News

Scientists in Vienna have developed a new human tissue screening technique that has identified previously unknown genes involved in causing microcephaly, a rare genetic disorder, and that could one day be used to identify unknown genes tied to other conditions.

In a study published Thursday in Science, researchers screened lab-grown human brain tissues for 172 genes thought to be associated with microcephaly, a condition in which babies are born with smaller-than-normal brains and have severe mental impairments. The search revealed 25 new genes linked to this rare neurological condition, adding to the 27 already known genes tied to microcephaly. The researchers also uncovered the involvement of certain pathways that were previously unknown to be connected to the disease.

This is a proof of concept, said Jrgen Knoblich, a molecular biologist at the Austrian Academy of Sciences Institute of Molecular Biotechnology and co-author of the study. With our ability to query many diseased genes at the same time and ask which ones are relevant in a human tissue, we can now study other diseases and other organs.

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For decades scientists have relied on small animals as models to make sense of how a human brain develops. But it turns out that our brains are not blown-up versions of a rodent brain. Mice and rat brain surfaces, for instance, are smooth, unlike the shrivelled walnut look of a human brain, with its countless folds. Also, these rodents are born with a somewhat complete brain, in which most neurons are in place, although they continue to form new connections after birth. In a human child, on the other hand, there are a massive number of neurons that form and populate the cortex after birth.

There are some processes that happen in our brain and not in mice brains that are responsible for human brains becoming so big and powerful, Knoblich said. This generates a very big medical problem, which is how do we study processes that are only happening in humans.

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To address this problem, several scientists including Knoblich developed human brain organoids that are no bigger than a lentil, created from stem cells, and function just like a working human brain. With an interest in studying neurodevelopmental disorders like microcephaly, Knoblichs team used these miniature substitute brains to look for clues about the genes that may hamper brain development.

Typically, scientists conduct genetic screening by inactivating select genes one by one to understand their contribution to bodily functions. But screens of human genes are restricted to cells grown in petri dishes in two dimensions, in which cells dont interact very much.

Microcephaly is a tissue disease and we couldnt really study it in 2D, said Christopher Esk, a molecular biologist at the Austrian Academy of Sciences Institute of Molecular Biotechnology and co-lead author of the study.

So, the researchers developed a technique called CRISPR-Lineage Tracing at Cellular resolution in Heterogeneous Tissue, which uses the gene-editing technology to make cuts in DNA and knockout genes in combination with a barcoding technology that tracks parent stems and their progeny cells as the 3D brain organoid develops.

Using an organoid developed from cells of a microcephalus patient, they kept an eye out for mutations that gave rise to fewer cells and thus a small brain in comparison with a healthy one.

The researchers used CRISPR-LICHT to simultaneously screen 172 potential microcephaly causing gene candidates and found 25 to be involved.

Among them was a gene called Immediate Early Response 3 Interacting Protein 1 in the endoplasmic reticulum, which is the protein processing station within a cell. This protein processing is required to properly process other proteins, among them extracellular matrix proteins, which are in turn important for tissue integrity, and thus brain size, Esk said.

Kristen Brennand, a stem cell biologist at the Icahn School of Medicine at Mount Sinai in New York, who wasnt involved in the study, said she appreciated how the research captured this causal link. Clinical genetics can identify mutations in patients, but fall short of identifying causal mutations that definitively underlie disease risk, she said.

Going forward, Knoblich and his colleagues hope to use CRISPR-LICHT to screen many more genes that may be associated with other brain development disorders. Weve done it for microcephaly, and were already doing it for autism, he said. But the method can be applied to any type of organoid or any type of disease and any cell type.

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New screening tool could turn up genes tied to developmental disorders - STAT

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

New York City COVID-19 Outbreak Began Earlier Than Thought

Investigators with NYU Langone Health/NYU School of Medicine leveraged gene testing to trace the origins of COVID-19 through the New York City region in the spring. Their data demonstrated that the virus first developed in late February, seeded by a minimum of 109 different sources that then spread, instead of from a single patient zero. They also found that more than 40% of people who tested positive did not have any known contact with another person before contracting the disease. They published their research in the journal Genome Research.

Our findings show that New Yorks early screening test methods missed the onset and roots of the outbreak by several days at the minimum, said study co-lead author Matthew Maurano, assistant professor in the Department of Pathology at NYU Langone Health. The work strongly suggests that to nip future outbreaks in the bud, we need a system of rapid, plentiful real-time genetic surveillance as well as traditional epidemiologic indicators.

The study also showed that more than 95% of New Yorkers with COVID-19 had a viral strain that was highly contagious, which explains why it spread so aggressively. The research team collected viral genetic data on 864 nasal swabs collected from New Yorkers who tested positive for COVID-19 between March 12 and May 10. They were mostly from Manhattan, Brooklyn, and Nassau County on Long Island. They then compared the gene sequences of the virus from those samples to ones observed in the original strain analyzed last winter from patients in Wuhan, China. They found that the New York strains more closely matched those originating from Europe or the U.S. instead of from China. They also found some of the early infection chains, meaning person to person infections, ran at least 50 people long.

The sequences analyzed in this study made up about 10% of COVID-19 patients within a single hospital system in New York. The community infection scale was probably much higher, with the original introduction of the virus to New York City possibly earlier.

The Evolution of COVID-19 Viral Mutations

Researchers at the University of Illinois College of Agricultural, Consumer and Environmental Sciences tracked the mutation rate of the SARS-CoV-2 proteins, the proteome, through time, beginning with the first genome published in January 2020 and ending more than 15,300 genome iterations later in May. The team discovered some regions are still actively mutating, while the mutation rate in other regions appears to be slowing, with primarily single versions of key proteins continuing to mutate. On the one hand, the higher mutation rate appears to be bad news, suggesting that the virus is continuing to change and adapt to its environment. But the slower mutation rate in some regions suggests that the stabilization of specific proteins may be good news for the development of treatment. The team did observe what appeared to be a general slowing of the mutation rate beginning in April, which included stabilization within the spike (S) protein.

How Cancer Remodels Chromosomes

Studies by scientists at the University of Virginia found that cancer remodels the architecture of chromosomes so cancer can establish itself and spread. They found that cancer depends on a protein known as CCCTC-binding factor (CTCF), which occurs naturally in cells. In normal, healthy cells CTCF maintains chromosome structure and plays a role in turning genes on and off as needed. Cancer highjacks CTCF, causing it to appear in locations where it shouldnt and inhibiting its binding. This changes the three-dimensional structure of chromosomes and how genes function. They identified CTCF remodeling in six different cancers, including T-cell acute lymphoblastic leukemia, acute myeloid leukemia, breast cancer, colorectal cancer, lung cancer, and prostate cancer.

Potent Antibody Against COVID-19 Virus Mapped

Quite a number of therapeutic antibodies are in clinical trials against SARS-CoV-2, the virus that causes COVID-19, including those being developed by Eli Lilly and Regeneron Therapeutics. Both of those companies have requested emergency use authorization from the U.S. Food and Drug Administration. Investigators at Fred Hutchinson Cancer Research Center in Seattle have mapped a potent antibody from a COVID-19 survivor, describing how it interferes with the spikes on the viruss surface and induces pieces of those spikes to break off. They also indicate that the antibody, CV30, was 530 times more potent than any of the others they identified. The antibody functions in two ways, overlapping the viruss target site on human cells, and the second to induce dissociation of part of the spike. They plan to begin preclinical tests with hopes of moving it to human trials.

How Exercise Stalls Cancer Growth

Anecdotally, people who exercise have been observed to have a better cancer prognosis than inactive people. But why that was the case wasnt really understood. Researchers at Swedens Karolinska Institutet believe they have found an explanation. Physical exercise changes the metabolism of cytotoxic T cells in the immune system, which improves their ability to attack cancer cells. Cytotoxic T cells specialize in killing cancer cells. Working in laboratory mice, one group that exercised regularly on a spinning wheel and another that did not, they then studied the cytotoxic T cells in the animals by injecting antibodies that remove the T cells in both groups of mice. They also transferred cytotoxic T cells from the fit mice into unfit mice with tumors and found it improved their prospects compared to the cancerous mice who received cells from unfit mice.

Our research shows that exercise affects the production of several molecules and metabolites that activate cancer-fighting immune cells and thereby inhibit cancer growth, said Helene Rundqvist, senior researcher at the Department of Laboratory Medicine, Karolinska Institutet, and the studys first author. We hope these results may contribute to a deeper understanding of how our lifestyle impacts our immune system and inform the development of new immunotherapies against cancer.

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