Category Archives: Genetic Medicine

Vitamin B12, or cobalamin, is a dietary nutrient essential for normal human development and health and is found in animal-based foods but not in plant-based foods, unless they have been supplemented. Mutations in the genes encoding the proteins responsible for the metabolic processes involving vitamin B12result in rare human inborn errors of cobalamin metabolism.

Vitamin B12diseases can present a complex landscape of characteristics, and to better understand themDr. Ross A. Poch, associate professor ofmolecular physiology and biophysicsat Baylor College of Medicine, and his colleagues have studied two rare inherited vitamin B12conditions that affect the same gene but are clinically distinct from the most common genetic vitamin B12disorder.

Meet three distinct inherited vitamin B12diseases

Patients with the most common inherited vitamin B12disease, calledcblC, suffer from a multisystem disease that can include intrauterine growth restriction, hydrocephalus (the build-up of fluid in the cavities deep within the brain), severe cognitive impairment, intractable epilepsy, retinal degeneration, anemia and congenital heart malformations. Previous work had shown that mutations in theMMACHCgene causecblCdisease.

It also was known that some patients presenting with a combination of typical and non-typicalcblCcharacteristics do not have mutations in theMMACHCgene, but rather in genes that code for proteins called RONIN (also known as THAP11) and HCFC1. The resulting changes in these proteins lead to reducedMMACHCgene expression and a more complexcblC-like disease.

In this study, Poch and his colleagues looked for other genes that also might be affected byHCFC1andRONINgene mutations.

Tackling the complexity oftwoinherited vitamin B12diseases

We developed mouse models carrying the exact same mutations that the patients withcblC-like disease have inHCFC1orRONINgenes, and recorded the animals characteristics, Poch said. We confirmed that they presented with the cobalamin syndrome as expected, but in addition we found that they had ribosome defects. Ribosomes form the protein-building machinery of the cell.

What the findings may mean for patients

The findings have potential therapeutic implications. SomecblC-like patients may respond to some extent to cobalamin supplementation, but we anticipate that will not help the issues due to ribosome defects, said Poch, member of theDan L Duncan Comprehensive Cancer Center.

One step toward designing effective ribosomopathy therapies is to better understand what the defects in the ribosomes are. We plan to functionally characterize the altered ribosomes at the molecular level to identify how their function is disrupted, Poch said.

There are many exciting aspects of this study, from the clinical implications to the basic science. The beauty is in how the work in patients is symbiotic with the work in the mouse model and how each system informs the other, said co-authorDr. David S. Rosenblatt,professor in the departments of human genetics, medicine, pediatrics, and biology at McGill University and senior scientist at the Research Institute of the McGill University Health Centre.

Would you like to learn more about this study? Find it in the journalNature Communications.

Other contributors to this work include co-first authors Tiffany Chern and Annita Achilleos, Xuefei Tong, Matthew C. Hill, Alexander B. Saltzman, Lucas C. Reineke, Arindam Chaudhury, Swapan K. Dasgupta, Yushi Redhead, David Watkins, Joel R. Neilson, Perumal Thiagarajan, Jeremy B. A. Green, Anna Malovannaya and James F. Martin. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine; University of Nicosia Medical School, Cyprus; Michael E. DeBakey Veterans Affairs Medical Center, Houston; the Francis Crick Institute, London; Kings College London; McGill University Health Centre, Montreal and Texas Heart Institute, Houston.

This work was supported by the Dan L Duncan Comprehensive Cancer Centers National Institutes of Health (NIH) award P30CA125123 for BCM Mass Spectrometry Proteomics Core, CPRIT Core Facility Award (RP170005) and the following NIH grants: R01 EY024906, R01 DE028298, T32 EY007102, T32 HL007676, R01 HL127717, R01 HL130804 and R01HL118761. Additional support was provided by the Vivian L. Smith Foundation, State of Texas funding and Foundation LeDucq Transatlantic Networks of Excellence in Cardiovascular Research (14CVD01).

ByAna Mara Rodrguez, Ph.D.

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Unraveling the complexity of vitamin B12 diseases - ScienceBlog.com - ScienceBlog.com

image:The Blood Proteoform Atlas (BPA) compiles ~56,000 proteoforms identified from 21 human cells types and plasma view more

Credit: Please credit Kelleher and Levitsky labs at Northwestern University

Northwestern University scientist have discovered families of proteins in the body that could potentially predict which patients may reject a new organ transplant, helping inform decisions about care.

The advancement marks the beginning of a new era for more precise study of proteins in specific cells.

Scientists tend to look at shifting patterns of proteins as if through goggles underwater, taking in just a fraction of available information about their unique structures. But in a new study to be published January 27 in the journal Science, scientists took a magnifying glass to these same structures and created a clarified map of protein families. They then held the map up in front of liver transplant recipients and found new indicators in immune cell proteins that changed with rejection.

The result, the Blood Proteoform Atlas (BPA), outlines more than 56,000 exact protein molecules (called proteoforms) as they appear in 21 different cell types almost 10 times more of these structures than appeared in similar previous studies.

Scratching the surface of potential

Were working to create the protein equivalent of the Human Genome Project, said Neil Kelleher, a leading expert in proteomics and co-corresponding author of the paper. The BPA is a microcosm of that, including a specific-use case.

Kelleher is the Walter and Mary Glass Professor of Molecular Biosciences and professor of chemistry in NorthwesternsWeinberg College of Arts and Sciencesand a professor of medicine inNorthwestern University Feinberg School of Medicine.He is also the director of theChemistry of Life Processes Institute(CLP) and faculty director ofNorthwestern Proteomics, a center of excellence within CLP that develops novel platforms for drug discovery and diagnostics.

Each human gene has at least 15 to 20 unique forms of processed proteins (proteoforms). And with 20,300 individual genes in the human body, there are millions of proteoforms created by genetic variation, modification or splicing. Kelleher said with a complete roadmap of each genes family of proteinsthe goal of a major science initiative known as the Human Proteoform Project discoveries about disease, aging and new therapeutics will accelerate.

The Kelleher lab uses state-of-the-art mass spectrometry and data analysis to identify proteofoms in cells and blood efficiently, keeping proteoforms intact in a form of top-down analysis rather than cutting them up into tiny pieces as with the industry standard.

Were starting to see the complexity, he said. In this paper, we demonstrate patient-, cell type- and proteoform-specific measurements, which allows us to get to better biomarkers.

A blood test for liver transplant rejection

Having team members across disciplines allows the project to conceptualize a move from lab bench to bedside. As Kelleher probes the scientific basis for phenomena in the cell, co-corresponding author and Northwestern Medicine transplant hepatologist Josh Levitsky works with him to understand how these could be applied to a specific system.

Levitsky, professor of medicine, surgery and medical education at Feinberg, originally connected with Kelleher through his leadership in the biomarkers space, in which measurable signs in the blood are used to predict health metrics in patients facing disorders and in this instance, liver transplant rejection.

It was really important for Neil that there was a biologically relevant example to contextualize how these proteoform panels can identify diseases non-invasively as markers, Levitsky said. And theres also a need in my field to have mechanistic biomarkers that are more relevant to their immune biological pathways. This could be the start of a new era in cell-specific markers.

Physicians must suppress the immune system with drug therapy and monitor liver transplant recipients for signs of rejection, often only responding after an episode has begun. Guesswork throughout this process could be eliminated with specific knowledge about whats happening at the most granular level.

With the BPA as a reference map, the team took blood samples from participants in one of Levitskys biomarker collection studies. They examined which proteoforms seemed to activate in response to the transplant and identified those that changed compared to patients without rejection.

Next, the Levitsky and Kelleher team developed a panel of 24 proteoforms from the initial study and looked at them in transplant recipient samples from across the country. They found the same proteoforms lit up as in the first trial.

Moving the field forward

The promise here is to be able to use this panel moving forward to be able to identify patients who have no signs of rejection versus those who have very early evidence of rejection, Levitsky said. If we can pick up on this several weeks before rejection actually happens, we might be able to modify immunosuppression.

Levitsky continues to examine how proteoforms change in transplant recipients over time to develop additional biomarkers that may inform how he treats patients down the line. Kelleher said as the number of cell types in the atlas grows, so too will potential ways to use it. In addition to broadening understandings of human biology, the BPA could have similar applications across immune disorders.

The study, The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells, was conducted across six institutions with 26 scientists. Rafael D. Melani, a research assistant professor in the Kelleher Group, was the first author of the paper, along with Vincent R. Gerbasi, also from Northwestern, and Lissa C. Anderson from Florida State University.

The research was supported by the National Institute of General Medical Sciences of the National Institutes of Health (award numbers: P41 GM107569, R21LM013097, T32 GM105538 and R21 AI135827), the Human Biomolecular Atlas Program (award number: UH3 CA246635-02), Paul G. Allen Frontiers Program Award (award number 11715), the Knut and Alice Wallenberg Foundation grant (2016.0204) and the Swedish Research Council grant (2017-05327). Work performed at the National High Magnetic Field Laboratory is supported by the National Science Foundation Division of Materials Research and Division of Chemistry and the State of Florida.

The Blood Proteoform Atlas: A reference map of proteoforms in human hematopoietic cells

28-Jan-2022

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Researchers identify proteins that could predict liver transplant rejection - EurekAlert

Dr. Johan V. Hultin, a pathologist whose discovery of victims of the 1918 flu pandemic buried in Alaskan permafrost led to a critical understanding about the virus that caused the outbreak, died on Saturday at his home in Walnut Creek, Calif. He was 97.

The death was confirmed by his wife, Eileen Barbara Hultin.

Dr. Hultins discovery was crucial to finding the genetic sequence of the virus, allowing researchers to examine what made it so lethal and how to recognize it if it came again. The virus, which was 25 times more deadly than ordinary flu viruses, killed tens of millions of people and infected 28 percent of Americans, dropping the average life span in the United States by 12 years.

Dr. Hultins quest to find victims of the 1918 flu was sparked in 1950 by an offhand remark over lunch with a University of Iowa microbiologist, William Hale. Dr. Hale mentioned that there was just one way to figure out what caused the 1918 pandemic: finding victims buried in permafrost and isolating the virus from lungs that might be still frozen and preserved.

Dr. Hultin, a medical student in Sweden who was spending six months at the university, immediately realized that he was uniquely positioned to do just that. The previous summer, he and his first wife, Gunvor, spent weeks assisting a German paleontologist, Otto Geist, on a dig in Alaska. Dr. Geist could help him find villages in areas of permafrost that also had good records of deaths from the 1918 flu.

After persuading the university to provide him with a $10,000 stipend, Dr. Hultin set off for Alaska. It was early June 1951.

Three villages seemed like they might have what he wanted, but when he arrived at the first two, the victims graves were no longer in permafrost.

The third village on his list, Brevig Mission, was different. The flu had devastated the village, killing 72 out of 80 Inuit residents. Their bodies were buried in a mass grave with a large wooden cross at either end.

When Dr. Hultin arrived and politely explained his mission, the village council agreed to let him dig. Four days later, he saw his first victim.

She was a little girl, about 6 to 10 years old. She was wearing a dove gray dress, the one she had died in, he recalled in an interview in the late 1990s. The childs hair was braided and tied with bright red ribbons. Dr. Hultin called for help from the University of Alaska Fairbanks, and the group eventually found four more bodies.

They stopped digging. We had enough, Dr. Hultin said.

He removed still-frozen lung tissue from the victims, closed the grave and took the tissue back to Iowa, keeping it frozen on dry ice in the passenger compartment of a small plane.

Back in the lab, Dr. Hultin tried to grow the virus by injecting the lung tissue into fertilized chicken eggs the standard way to grow flu viruses. He was caught up in the excitement of his experiment, he said, and had not thought about the possible danger of introducing a deadly virus into the world.

I remember the sleepless nights, he said. I couldnt wait for morning to come to charge into my lab and look at the eggs.

But the virus was not growing.

He tried squirting lung tissue into the nostrils of guinea pigs, white mice and ferrets, but again he failed to revive the virus.

The virus was dead, he said.

Dr. Hultin never published his results but bided his time, working as a pathologist in private practice in San Francisco and hoping for another opportunity to resurrect that virus.

His chance came in 1997, when, sitting by a pool on vacation with his wife in Costa Rica, he noticed a paper published in Science by Dr. Jeffery K. Taubenberger, now chief of the viral pathogenesis and evolution section at the National Institute of Allergy and Infectious Diseases.

It reported a remarkable discovery. Dr. Taubenberger had searched a federal repository of pathology samples dating to the 1860s and found fragments of the 1918 virus in snippets of lung tissue from two soldiers who had died in that pandemic. The tissue had been removed at autopsy, wrapped in paraffin and stored in the warehouse.

Dr. Hultin immediately wrote to Dr. Taubenberger, telling him about his trip to Alaska. He offered to return to Brevig to see if he could find more flu victims.

I remember getting that letter and thinking: Gosh. This is really incredible. This is amazing, Dr. Taubenberger said in an interview this week. He thought the next step would be to apply for a grant for Dr. Hultin to return to Brevig. If all went well, Dr. Hultin might go back in a year or two.

Dr. Hultin had a different idea.

I cant go this week, but maybe I can go next week, he told Dr. Taubenberger.

He added that he would go alone and pay for the trip himself so that there would be no objections from funding agencies, no delays, no ethics committees and no publicity.

Mrs. Hultin told her husband that the village council would never allow him to disturb the grave again. I told him it was a fools errand, she recalled on Tuesday.

Dr. Hultin, though, found an ally in a council member, Rita Olanna, whose relatives had died during the flu pandemic and were buried in that grave. Her grandmother had met Dr. Hultin when he arrived in 1951. Ms. Olanna told Dr. Hultin, My grandmother said you treated the grave with respect.

He was allowed to open the grave again. This time, four young men from the village helped him dig.

At first, every body they found had decomposed. Then, toward the end of the afternoon, when the hole was seven feet deep, they saw the body of a woman that was mostly intact, with lungs that were still preserved. He extracted lung tissue and placed it in a preservative solution.

After closing the grave, he made two wooden crosses to replace the original ones, which had rotted. Later, he had two brass plaques made with the names of the Brevig flu victims, which had been recorded, and returned to the village to attach them to the new crosses flanking the grave.

When he returned to San Francisco, Dr. Hultin sent the lung tissue to Dr. Taubenberger in four packages two with Federal Express, one with UPS and one more with the U.S. Postal Servicess Express Mail. He didnt want to take any chances of losing the tissue.

Dr. Taubenberger got all of the packages. The lung tissue from the Brevig woman was invaluable, he said, because the snippets of lung from the soldiers had so little virus that, with the technology at the time, the effort to get the complete viral sequence would have been delayed by at least a decade.

Using the tissue Dr. Hultin provided, Dr. Taubenbergers group published a paper that provided the genetic sequence of a crucial gene, hemagglutinin, which the virus had used to enter cells. The group subsequently used that tissue to determine the complete sequence of all eight of the viruss genes.

Johan Viking Hultin was born on Oct. 7, 1924, into a wealthy Stockholm family. His father, Viking Hultin, had inherited an export business. When Johan was 10, his parents divorced and his mother, Eivor Jeansson Hultin, married Carl Naslund, a pathologist and virologist at the Karolinska Institute in Stockholm.

He had two sisters; one died of sepsis at 6, and the other died in auto accident at 32. After high school, Johan went to Uppsala University to study medicine.

He married his childhood sweetheart, Gunvor Sande, when he was completing medical school. The couple divorced in 1973, and he married Eileen in 1985.

Along with his wife, Dr. Hultin is survived by his children, Peder Hultin, Anita Hultin and Ellen Swensen; three stepdaughters, Christine Peck, Karen Hill and Deborah Kenealy; 12 grandchildren; and seven great-grandchildren.

Before results from the study of the Brevig womans virus were published, Dr. Hultin asked the villagers if they wanted the village to be identified in a news release and a journal article. They might be besieged by media. Maybe you wont like that, he warned them.

The Brevig residents came to a consensus: Publish the paper and identify the village. Dr. Hultin was listed as a co-author.

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Johan Hultin, Who Found Frozen Clues to 1918 Virus, Dies at 97 - The New York Times

Introduction

The Code on Genetic Testing and Insurance (the Code) was published in October 2018, replacing the Concordat and Moratorium on Genetics and Insurance. The Code is a voluntary agreement between government and the Association of British Insurers (ABI), whereby insurers who are signed up to the Code will never require or pressure any applicant to undertake a predictive or diagnostic genetic test, and will only consider the result of a predictive genetic test for a very small minority of cases. To date, there is only one test for which insurers can request disclosure of results, which is a predictive genetic test for Huntington's disease, in applications for life insurance cover which total over the financial limit of 500,000.

The government is of the view that it is important everyone has access to good insurance at the right price. The Code aims to provide reassurance to the public about how and whether genetic testing could affect their access to life, critical illness and income protection insurance products in the UK. A Consumer Guide to the Code and responses to FAQs were published alongside the Code.

The Code is open-ended with no expiry date. To ensure that the Code remains fit for purpose, the government and ABI have agreed to publish annual reports to provide commentary on the state of the insurance market and developments in genomic technologies, as well as details on compliance with the Code. A 3-yearly review will allow for the Code to be kept up to date.

This is the government's second annual report under the Code and provides an update on the changes in the genomics policy landscape since the publication of the first annual report in June 2020. It sits alongside the ABI's annual report which includes information on compliance as well as additional relevant information on the insurance market.

Perhaps the biggest impact on the UK genomics landscape during the reporting period has been the COVID-19 pandemic. Although many healthcare services have been disrupted due to the effects of the virus, the pandemic has also raised the profile of genomics and highlighted its significant potential in public health, through government-funded initiatives such as the GENOMICC study (looking at factors in patient genomes which could influence the severity of viral infections), and the COVID-19 Genomics UK (COG-UK) consortium, which has sequenced more than 1.9 million SARS-CoV-2 genomes since its inception in March 2020, enabling the identification of viral variants, monitoring of viral transmission and the development of freely available bioinformatics and data sharing tools. The transfer of COG-UK's national sequencing role to the 4 UK public health agencies, in August 2021, serves as further confirmation of the ongoing importance of genomics as a tool for protecting and improving the nation's health.

Despite the disruptions caused by the pandemic, significant breakthroughs continue to be made in improving the diagnosis and treatment of patients through genomics, particularly in the areas of cancer and rare diseases. The sequencing phase of the 100,000 Genomes Project, completed in December 2018, resulted in actionable findings for between 1 in 4 and 1 in 5 rare disease patients, and approximately half of cancer cases. As part of their consent for the project, participants were offered the option to receive additional health information contained in their genome sequence. These additional findings are currently in the process of being returned, with all consenting participants expected to receive their results by spring 2022.

The success of the 100,000 Genomes project proved the value of Whole Genome Sequencing (WGS) in clinical care. It also laid the foundations to launch the NHS Genomics Medicines Service (GMS) in 2018, which is now rolling out the world's first WGS service for patients with a suspected rare disease and certain cancers.

The government published its 10-year strategy to extend the UK's leadership in genomic healthcare and research in September 2020. Genome UK: the future of healthcare sets out a vision to create the most advanced genomic healthcare system in the world, using the latest scientific advances to deliver better health outcomes at lower cost.

The strategy focuses on 3 main pillars: diagnosis and personalised medicine, prevention, and research; alongside the 5 cross-cutting themes of public engagement, workforce development, supporting industrial growth, maintaining trust and delivering nationally coordinated approaches to data and analytics. The strategy is UK-wide and has support from all 4 administrations of the UK. It recognises that health policy is devolved and that decisions about whether and how to implement specific elements of the strategy will necessarily be made separately by the 4 administrations. These decisions will differ to accommodate the different needs of the populations in the 4 administrations and the structures and systems of the NHS in each administration.

In May 2021, the government published the first of several phased implementation plans, covering the period 2021 to 2022. This first phase plan was focused on implementation in England. Work is underway to ensure that in future implementation plans all parts of the UK will benefit from the Genome UK vision.

The government's commitment to incorporate the latest genomics advances into routine healthcare includes the further development of the NHS GMS. Through the GMS, NHS England and Improvement has committed to sequence 500,000 whole genomes by 2023 to 2024, as part of their world-first WGS service for patients. This has the potential to enable faster diagnosis and more effective use of therapies, resulting in increased survival rates and a reduction in adverse drug reactions. Progress to date includes the introduction of rapid whole exome sequencing (a part of the whole genome) in newborn and paediatric intensive care units (in October 2019), and in foetal medicine (October 2020). Additionally, live clinical testing for whole genome sequencing as part of routine care commenced in November 2020 across the NHS.

With genomic testing set to become part of routine clinical care, it is important to note that the Code states that insurance companies cannot require or pressure any applicant to undertake a predictive or diagnostic genetic test in order to obtain insurance.

Genome UK highlights 2 key areas in which genomics may be harnessed to enabling predictive and preventative care, namely, the expansion of genomic testing in the screening of newborns, and targeted screening using genomics to improve population health.

The world-first NHS-Galleri trial led by NHS England in partnership with GRAIL, aims to improve early detection of more than 50 types of cancer, using high intensity sequencing of circulating cell-free DNA (cfDNA). The trial, launched in September 2021, aims to recruit 140,000 volunteers to determine how well GRAIL's Galleri blood test works in the NHS, with the ultimate goal of improving outcomes through faster diagnosis and earlier intervention. Initial results are expected by 2023.

The Our Future Health programme (formerly the Accelerating Detection of Disease challenge) is also a major focus of this preventative pillar of the strategy. With the goal of recruiting up to 5 million diverse, healthy participants, Our Future Health will provide a resource for research into early detection, next generation diagnostics and smart clinical trials. The programme will be used to evaluate the clinical utility of polygenic risk scores (PRS), which calculate the combined impact of many variations across the genome in order to create an overall risk score. PRS may then be used in the future, in combination with other risk factors, to identify those at higher risk of certain diseases, potentially enabling earlier clinical and lifestyle interventions.

Whole genome sequencing of newborns could significantly increase the diagnoses of genetic conditions, offering the opportunity for early intervention through pre-symptomatic treatment. In July 2021, Genomics England released the findings of a large-scale dialogue, commissioned with the UK National Screening Committee and with support from the government's Sciencewise programme, looking at public attitudes to whole genome sequencing as part of newborn screening. Dialogue participants were broadly supportive of the potential use of WGS for newborn screening, provided that due consideration was given to the design and planning of any use of this technology, that the public was involved, and that appropriate resources, investment and safeguards were in place. These results will be used to support further scoping and decisions on whether whole genome screening should be used for newborns in the future.

When considering genomics research, it should be noted that under the Code, any predictive genetic test result obtained exclusively in the context of scientific research does not need to be disclosed to an insurer, regardless of the test or the level of cover. This includes the Galleri and Our Future Health initiatives mentioned above.

The UK has long been at the forefront of translational genomics research. Building on the pioneering work of the UK Biobank (which at 500,000 participants, is now the largest and most intensively genetically and phenotypically described cohort in the world), the government's vision is to create a secure, integrated system of diverse genomic and phenotypic datasets which can be used to drive new genomics research. This in turn will enable earlier interventions, better diagnostics, and innovative therapies for patients from all backgrounds across the UK.

Sequencing of all 500,000 participants was completed on time in December 2021, through work funded by UK Research and Innovation (UKRI)-MRC, Wellcome Trust, Amgen, AstraZeneca, GSK, and Johnson & Johnson. Sequencing data is being made securely available to researchers via the UK Biobank Research Analysis Platform, enabling the study of the impact of genetic variation on disease in unprecedented detail and scale.

To facilitate genomic research within the NHS GMS, the newly established NHS Genomic Medicine Research Collaborative will bring together NHS England and NHS Improvement, Genomics England and the National Institute for Health Research (NIHR) to support academic and industry projects, with insights being rapidly adopted into the NHS.

A core ambition for the future of genomic research will be to address the historic underrepresentation of data from ethnic minority groups in genomic datasets, which without action will lead to further entrenchment of health inequalities. A number of activities will be required to improve the diversity of genomic data, including bespoke sequencing programmes, community engagement activities and development of novel digital tools to analyse diverse genomic datasets.

The UK also continues to drive global genomics research into COVID-19, including research into the genetics of symptom severity, and the identification and tracking of new virus variants. A collaboration between GenOMICC and Genomics England, examining the genetic mechanisms of critical illness in COVID-19, was recently published in the journal Nature, with the findings informing the selection of drugs for inclusion in trials. This work is ongoing, with the goal of analysing whole genome sequences of approximately 20,000 participants severely affected by COVID-19 and comparing these with the whole genome sequences of 15,000 participants mildly affected, to identify genetic factors which may underpin variations in susceptibility. There are also links to research projects focused on 'long COVID' and infections involving vaccinated patients.

A collaboration between Genomics England and COG-UK also aims to secure viral genome sequences generated from viral isolates from GenOMICC participants, with a view to identifying virus and host factors, as well as any potential interplay of these factors, which may alter the host response to infection.

Since its publication, the Code has been widely disseminated among genetic counsellor professional bodies, key healthcare professionals and organisations, as well as being signposted to participants in the 100,000 Genomes project and Our Future Health. Efforts to raise awareness of the Code will continue as a constant activity.

Despite the fast pace of advances in genomic technologies, it is important that the public feel confident that their data is secure and that it is used to deliver the best possible care. The government's previous annual report on the Code highlighted the findings of a 2019 public dialogue on genomic medicine, commissioned by Genomics England. This report found that despite widespread enthusiasm for its potential applications, participants had clear red lines on the use of data, including the inappropriate use of genetic information for insurance purposes, and questions about how compliance with the Code would be enforced. The government's commitment to annual reports and 3-yearly reviews on the Code assures that these concerns are being considered.

In terms of data protection, Genomics England is currently working to develop a next-generation Trusted Research Environment to provide secure access to genomic and linked data to researchers (subject to patient consent, confidentiality and relevant data protection provisions). The Global Alliance for Genomics and Health (GA4GH), is also working to develop standards and policies for sharing genomic and related health data, as part of a 5-year project funded by the NIHR, MRC and Wellcome Trust.

With the cost of genetic testing continuing to fall, increasing numbers of tests are being marketed directly to the public. Following an extensive consultation with stakeholders, the House of Commons Science and Technology Select Committee published a report on direct-to-consumer (DTC) genomic testing in June 2021. This report described the benefits and risks of DTC genomic testing, including concerns regarding the future use of genomic data, insurance, and consent, and provided a series of recommendations for government. The government's response to the report was published in November 2021, welcoming many of the Select Committee's recommendations. The response described planned and ongoing work in the area, such as the Medicines and Healthcare Products Regulatory Agency's (MHRA) public consultation on medical devices regulation including in-vitro diagnostic testing the category which encompasses DTC genomic testing. It is important to note that the provisions of the Code apply both to tests obtained in healthcare settings, as well as those marketed directly to consumers. Therefore, individuals do not have to share the results of any DTC genomic tests with their insurer, unless it is a diagnostic result of a predictive genetic test for Huntington's disease, in applications for life insurance cover which totals over the financial limit of 500,000.

In tandem with the government's report, the ABI will also be publishing their annual report which includes information on compliance as well as additional relevant information on the insurance market.

Accompanying their report, the ABI have commissioned an independent research report produced by the Cambridge Centre for Health Services Research (CCHSR). This study assessed the potential impact of predictive genetic testing on insurers who provide life, health, and critical illness protection by using 6 groups of exemplar conditions. The study highlighted that assessment of the risk to the insurance industry presented by genetic tests and associated conditions is determined by a complex interplay of factors related to the genetic test itself, engagement with testing, the genetic architecture of the condition, the capacity for reducing risk and the cost of treatment. While an interesting assessment, the study was not designed to determine whether the exemplar conditions, or any other tests and conditions, should be considered as being exempt from the current Code. This evidence, amongst others, will inform the 3-yearly review of the Code which the government has committed to conduct this year.

In all aspects of the Code, the ABI and its members continue to work closely with government and other stakeholder groups to achieve a balanced relationship regarding the fair and transparent use of genetic test results for insurance purposes. It should be noted, however, that while all ABI members are automatically bound by the Code, not all insurers offering life, income protection and critical illness insurance are signed up to the Code. A full list of insurance companies who have signed up to the Code will be published on the ABI website.

The significant developments in genomic testing, medicine and research over the past year provide exciting opportunities for improving diagnosis, prevention and treatment of disease. However, as these advances do not alter the landscape of predictive testing in the UK for the foreseeable future, they have no direct impact on the terms of the Code, which remain relevant and effective.

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Code on genetic testing and insurance: the government's annual report 2021 - GOV.UK

The immune system is made up of much more than antibodies. Although most of the news about the effectiveness and endurance of COVID-19 vaccines has focused on antibody titers, not as much has been reported on their effect on other parts of the immune system that offer longer-term protection, such as T cells. For that and more, continue reading.

4 Vaccines Teach T Cells to Fight the Omicron Variant of COVID-19

Investigators atLa Jolla Institute for Allergy and Immunologyfoundthat four COVID-19 vaccinesthePfizer-BioNTech, Moderna, Johnson & Johnson/JanssenandNovavaxall caused the immune system to create effective, long-lasting T cells against SARS-CoV-2. They can also recognize other variants of concern, including Delta and Omicron. All the data was in fully vaccinated adults who had not yet received booster shots. The research team plans to investigate T-cell responses in people who received booster shots and those who have had the so-called breakthrough infections. That means they were vaccinated but were infected anyway. One finding was that fully vaccinated individuals have fewer memory B cells and neutralizing antibodies against the Omicron variant, consistent with early reports from other laboratories about waning immunity.

Most studies about the long-lasting effectiveness of vaccines have focused only on antibody responses. But this is only a part of the human immune response.

Dr. Alessandro Sette, professor and co-leader of the study, said, The vast majority of T-cell responses are still effective against Omicron.

These cells wont stop you from getting infected, said Dr. Shane Cortty, LJI Professor, but in many cases, they are likely to keep you from getting very ill.

This appears true for all the vaccines studiedand for up to six months after vaccination. The relative lack of neutralizing antibodies does suggest that the Omicron variant is more likely to cause a breakthrough infection. Additional neutralizing antibodies are created slower with fewer memory B cells.

Most of the neutralizing antibodies, i.e., the antibodies that work well against SARS-COV-2, bind to a region called the receptor binding domain, or RBD, said LJI instructor Dr. Camila Coelho, who was co-first author of the study. Our study revealed that the 15 mutations present in Omicron RBD can considerably reduce the binding capacity of memory B cells, compared to other SARS-CoV-2 variants such as Alpha, Beta and Delta.

Treating Alzheimers Using Ultrasound Stimulation

Researchers at theGwangju Institute of Science and Technology (GIST)in South Koreautilizedexternal ultrasound pulses at gamma frequency to reduce protein accumulation in the brain. The technique involves syncing a persons (or animals) brain waves above 30 Hz, called gamma waves, with an external oscillation of a given frequency. Earlier work in mice showed that this technique, gamma entrainment, could slow the formation of beta-amyloid plaques and tau proteins. The GIST group demonstrated it was possible, in mice, to apply the technology using ultrasound pulses at 40 Hz. The mice exposed to ultrasound pulses for two hours a day for two weeks had decreased beta-amyloid plaque concentration and tau protein levels in the brain. Electroencephalographic data on the mice showed functional improvements and did not cause micro bleeding.

2 Blood Proteins Point to Poor Longevity and Health

Scientists with theUniversity of Edinburghanalyzed datafrom six large genetic studies into human aging, each of which held genetic data on hundreds of thousands of people. They analyzed 857 proteins and identified two that had significant negative effects across various measures of aging. People with genes that resulted in increased levels of these proteins were frailer, had poorer self-rated health, and were less likely to live exceptionally long lives. The first protein is apolipoprotein (LPA), which is believed to be involved in blood clotting. High levels of LPA increase the risk of atherosclerosis, resulting in heart disease and possible stroke. The second is vascular cell adhesion molecule 1 (VCAM1), primarily found on the surface of endothelial cells that line blood vessels. These control the expansion and retraction of blood vessels involved in blood clotting and the immune response.

Some Genes Protect the Obese from Some Diseases

Although obesity is, in general, bad for your health, some people with obesity seem to stay relatively healthy. Adiposity is related to how fat is distributed throughout the body. For example, fat under the skin, like a paunch or double chin, appears less harmful than fat stored around organs like the heart and liver. And it is genes that determine how and where the fat is stored. Geneticists at theUniversity of Exeterused atechniquedubbed Mendelian randomization. Of the 37 diseases they tested, they found that 12 were directly associated with genes that determine if a person has a favorable adiposity. The 12 included coronary artery disease, stroke and type 2 diabetes. Nine other diseases were classified as unrelated to adiposity and were probably due to carrying too much weight, such as deep vein thrombosis or arthritis in the knees. However, they point out that regardless of favorable or unfavorable adiposity, obesity is a serious risk to an individuals health, and even obese people with favorable adiposity are at increased risk for diseases such as gallstones, adult-onset asthma, and psoriasis. On the other hand, they also found that some conditions that were thought to be associated with weight, such as Alzheimers, didnt seem to be.

Super Immunity Against COVID-19

A laboratory study out of theOregon Health & Science Universityidentifiedtwo types of immunity against COVID-19: breakthrough infections after vaccination or natural infection after vaccination. They both provide approximately equivalent levels of enhanced immune protection. The so-called super immunity was previously used to describe very high levels of immune responses after breakthrough infections. The new research leveraged multiple live SARS-CoV-2 variants to assay cross-neutralization of blood serum from breakthrough cases. Essentially, the study found either are good at providing super immunity and the likely reason there are so many cases of breakthrough infections is that the virus is present in so much of the population.

It makes no difference whether you get infected-and-then-vaccinated, or if you get vaccinated-and-then-a-breakthrough infection, said Dr. Fikadu Tafesse, co-senior author and assistant professor of molecular microbiology and immunology in the OHSU School of Medicine. In either case, you will get a really, really robust immune responseamazingly high.

The problem, of course, is that both cases require you to get infected. Dr. Marcel Curlin, senior co-author and associate professor of medicine (infectious diseases) in the OHSU School of Medicine and director of OHSU Occupational Health, noted, Immunity from natural infection alone is variable. Some people produce a strong response and others do not. But vaccination combined with immunity from infection almost always provides very strong responses.

See the article here:
Research Roundup: How COVID-19 Vaccines Train T Cells and More Research News - BioSpace

image:Left: During midgestation, CLIP cells residing in the Caudal ganglionic eminence (CGE) generate interneurons that migrate into the cortex. Right: In Tuberous Sclerosis Complex (TSC), CLIP cells generate brain tumors and cortical tubers. Heterozygous mutations in TSC2 result in excessive proliferation of CLIP cells, generating cell types of cortical tubers (blue) as well as brain tumors (purple). view more

Credit: Knoblich/IMBA

With the help of cerebral organoids, IMBA scientists were able to ascertain that Tuberous Sclerosis, a rare neurodevelopmental genetic disorder, arises developmentally rather than only genetically. With these patient-derived laboratory models of the human brain, they pinpointed the origin of the disease to progenitor cells specific to humans. The findings, now published in Science, further show that the pathology of diseases affecting the human brain could only be well understood using human-derived brain organoid models.

The complexity of the human brain is largely due to its development involving processes unique to humans, many of which are still lurking in the darkest corners of our current scientific knowledge. Tuberous Sclerosis Complex (TSC) is no exception in this respect, as it has long been described as a chiefly genetic disorder based on data obtained from animal models. Now, breakthrough research from the Knoblich lab at IMBA Institute of Molecular Biotechnology of the Austrian Academy of Sciences uses patient-derived cerebral organoid models to pierce the mysteries of this rare neurodevelopmental disease. Our findings on the root cause of TSC led us to a progenitor cell type specific to the human brain. This explains why the pathology of this disease could not be well established with other laboratory models, explains IMBA Scientific Director Jrgen Knoblich, co-corresponding author on the publication.

In many affected patients, TSC manifests in the form of severe epilepsy and psychiatric symptoms like autism and learning difficulties. Morphologically, TSC is characterized by well-described signs often found in the brains of patients. Among those are benign tumors present in a defined area of the brain, as well as lesions in the brain cortex, or cerebral mantle, called tubers. For a long time, both morphological aberrations have been attributed to a genetic cause. However, results from the analysis of patient samples diverged from the prevalent theory, mainly with regards to tubers. To study Tuberous Sclerosis, we developed cerebral organoid models of the disease: three-dimensional cell cultures that we use to model the brain and that we can derive from any patient, explains co-corresponding author Nina Corsini, Research Associate in the Knoblich Group at IMBA.

For the study led by Corsini and Knoblich, the team grew brain organoids from several affected patients, a method that allows to investigate molecular and cellular mechanisms that existed in the patients brains at some point during development. With this approach, we found that, like in the patients brains, the organoids grew tumors and had disorganized areas that resembled patient tubers, explains Oliver Eichmller, the first author on the study. However, recapitulating the pathophysiology of a disease is only the first step towards designating the culprit: By digging further into the causes, we found that both of these abnormalities were triggered by the excessive proliferation of a cell type specific to the human brain, states Eichmller. These cells were termed Caudal Late Interneuron Progenitors, or CLIP cells. They are cells found during the developmental stage of human brains but not in animals like mice. Our study shows that our brain is very complex much more complex than the brains of most animals., says Corsini.

The scientists draw parallels to other neurodevelopmental and neuropsychiatric diseases, but also to malignant diseases affecting human brains, speculating that these could also be caused by human-specific developmental processes. Our findings on human-specific principles in brain development and pathology could also apply to other known diseases for which no therapies exist to this date, states Knoblich.

Having made headlines worldwide in 2013 for establishing human brain organoids at IMBA, the Knoblich lab already adapted this revolutionary technology to studying hidden processes of human brain development, as well as several diseases affecting the human brain. With their current findings, the team is now able to shed light on one of the shady slopes of neuroscience and medicine. We will clearly not stop here!, exclaims Knoblich. As a next step, we aim to investigate further neuropsychiatric diseases by adapting our technology further. We are confident that this human-derived laboratory model will finally help us identify human-specific mechanisms that have been overlooked for far too long!

Original publication:Eichmller O.L., Corsini N.S., et al., Amplification of human interneuron progenitors promotes brain tumors and neurological defects, Science, 2022. DOI: https://doi.org/10.1126/science.abf5546

About IMBAIMBA - Institute of Molecular Biotechnology - is one of the leading biomedical research institutes in Europe focusing on cutting-edge stem cell technologies, functional genomics, and RNA biology. IMBA is located at the Vienna BioCenter, the vibrant cluster of universities, research institutes and biotech companies in Austria. IMBA is a subsidiary of the Austrian Academy of Sciences, the leading national sponsor of non-university academic research. The stem cell and organoid research at IMBA is being funded by the Austrian Federal Ministry of Science and the City of Vienna.

Experimental study

Lab-produced tissue samples

Amplification of human interneuron progenitors promotes brain tumors and neurological defects

28-Jan-2022

The authors declare no competing interests.

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