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Detailed genetic road map will guide research into TB treatments, vaccines

A new study led by Washington University School of Medicine in St. Louis lays out a genetic road map of immune responses to tuberculosis (TB) infection across three species. Pictured is a TB-infected human lung. TB is shown in green, and immune cells surrounding the TB bacteria are shown in red and white.

Tuberculosis (TB) is one of the worlds most vexing public health problems. About 1.5 million people died from this bacterial lung infection in 2018, and the World Health Organization (WHO) estimates that one-quarter of the worlds population some 2 billion people, mostly in developing countries are infected with the bacteria that causes TB.

For decades, scientists have been studying the deadly disease in mice and other animal models to develop drug therapies and vaccines to treat or prevent the infection. But findings in animals with TB dont always translate well to people with the disease, leaving scientists puzzled by the discrepancies.

Now, a new study led by Washington University School of Medicine in St. Louis offers a genetic road map detailing the similarities and differences in immune responses to TB across three species mice, macaques and humans. According to the researchers, the insight into the immune pathways that are activated in diverse models of TB infection will serve as a valuable tool for scientists studying and working to eradicate the disease.

The research, appearing Jan. 29 in the journal Science Translational Medicine, is a collaboration between Washington University; the Texas Biomedical Research Institute in San Antonio; and the University of Cape Town in South Africa.

For many years, scientists have been frustrated by the fact that animal models of TB especially the genetically identical mice so often studied dont really reflect what we see in people with TB infections, said co-senior author Shabaana A. Khader, PhD, a professor of molecular microbiology at Washington University. This study is important because now we show in great detail where these animal models overlap with humans with TB and where they dont.

Unlike many previous mouse studies, the new research involved genetically diverse mice that more closely recapitulate the wide range of TB infection severity in humans: Some infected individuals show no symptoms; others show intermediate degrees of severity; and still others develop extreme inflammation of the lungs.

With co-author Deepak Kaushal, PhD, at the Texas Biomedical Research Institute, the researchers compared the genetic and immune responses to TB infection in these diverse mice with the responses of TB-infected macaques in the Kaushal lab. And with co-author Thomas J. Scriba, PhD, of the University of Cape Town, the research team analyzed blood samples from adolescents in Western Cape, South Africa, who are enrolled in a clinical trial investigating TB infection. The samples from people allowed the researchers to analyze and compare data from the mice and macaques with a range of responses to TB infection in young people.

Past research from this long-running clinical trial identified a group of 16 genes whose activation patterns predicted the onset of TB disease more than a year before diagnosis. These genes called a human TB gene signature differed significantly in their activation patterns between young people who developed symptoms of TB and those who didnt.

In macaques, primates closely related to humans, scientists have long assumed that TB infection closely resembles such infection in people.

Our data demonstrate that 100% of the genes previously identified as a human TB gene signature overlap in macaques and people, said co-senior author Makedonka Mitreva, PhD, a professor of medicine and of genetics at Washington University and a researcher at the universitys McDonnell Genome Institute. Its important to have the definitive data showing it to be true.

There was significant overlap between humans and mice as well, according to the researchers, including co-first authors Mushtaq Ahmed, PhD, an assistant professor of molecular microbiology in Khaders lab; Shyamala Thirunavukkarasu, PhD, a staff scientist in Khaders lab; and Bruce A. Rosa, PhD, an assistant professor of medicine in Mitrevas lab. But they also identified genetic pathways that differed between mice and humans, providing detailed analysis of areas where TB in mice is unlikely to point to meaningful insight into human TB infection.

Until now, we have studied mouse models to understand TB disease progression, not knowing where the mouse disease translates to human disease and where it doesnt, Khader said. Now, we have shown that many areas do translate but that there are important aspects of TB infection that dont. If you are using mouse models to develop TB vaccines or other therapeutics that target areas that dont overlap, you likely wont succeed.

Added Mitreva, Our study will inform researchers when they may need to move to a different animal model to study their genetic or molecular pathways of interest.

The researchers studied in detail the genes that increase in expression in people who develop severe TB disease. Of 16 such genes identified in people, they were able to study 12 in mice. Four of the genes could not be studied because mice dont have equivalent versions of such genes or, when such genes were eliminated, the mouse embryos died during development.

The scientists found that the 12 genes fall into three categories: those that provide protection against TB infection; those that lead to greater susceptibility to TB infection; and those that had no effect either way. Such information will be useful in seeking future therapeutics that could, for example, boost effects of protective genes or shut down harmful ones.

According to Khader and Mitreva, their team plans to use the new knowledge to better understand TB infections that have become drug-resistant, a growing problem in places where the disease is endemic. In addition, they will harness the information to help understand why the TB vaccine often administered to high-risk groups of people works well in some individuals but not others.

With the studys raw data publicly available, Khader and Mitreva said they are hopeful it will serve as a valuable resource to TB research and immunology communities worldwide.

This work was supported by Washington University in St. Louis; the National Institutes of Health (NIH), grant numbers HL105427, AI111914-02, AI123780, AI134236-02, U19 AI91036 and U19AI106772; the Department of Molecular Microbiology at Washington University; and a Stephen I. Morse Fellowship; the Department of Medicine at the University of Rochester Medical Center.

Scriba is a co-inventor of a patent of the 16-gene signature for TB susceptibility from the Adolescent Cohort Study (ACS).

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Immune responses to tuberculosis mapped across 3 species - Washington University School of Medicine in St. Louis

Meet Lea Starita, a Seattle-based genome scientist who is working to understand how our individual genes impact our health. Here, she answers some questions about her work.

What do you do? I am a research assistant professor of genome sciences at the University of Washington School of Medicine, and I co-direct the advanced technology lab at the Brotman Baty Institute for Precision Medicine (or the BAT-lab).

One of the main goals for precision medicine is to be able to practice genome-guided medicine. However, as a field, we are really good at reading DNA sequences of people, but we are really bad at understanding the health risks or benefits associated with any given DNA change. At the BAT lab, we are developing production-scale molecular-profiling technologies that we hope will accelerate our understanding of the impact of genetic variation on human development, human health and in treating disease.

The BATlab team also helped to build the worlds premier respiratory pathogen surveillance platform as part of the Seattle Flu Study.

How did you get started in this specialty?Ive been on this trajectory since I took an awesome molecular biology lab class in college. They handed us the New England Biolabs catalog to use instead of a textbook. To this day, that catalog contains nearly any enzyme you could need for cutting and pasting pieces of DNA together. I fell in love with the puzzle posed by molecular biology.

Whats a typical day like?I am lucky enough to get to spend the day with my colleagues, collaborators, staff and trainees who are all brilliant and creative scientists. My favorite times are when someone is at the white board drawing up a new idea or an improvement on an old idea. On the best days, I actually get in the lab to do some molecular biology myself. I love to play with DNA.

Whats the best part of the job?Dreaming up new technologies to answer tough biological questions with students, staff and collaborators. We try to answer questions like these: What is unique about each of the cell types in a human or animal? How do we understand the effect of a small change in a human or viral genome on health and disease? Although, I even find small process improvements exciting.

What surprises people about what you do? They are surprised when we talk about how important creativity and communication are in being successful as a scientist. I think people think we are these nerdy automatons, and that is totally not true. Well, the automaton part isnt true, anyway.

Do you have a cool job or know someone in the Seattle area who does? Email Michelle Archer with your recommendations for people to feature in Cool Job.

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Seattle-based genome scientist gets to play with DNA - Seattle Times

BOSTON--(BUSINESS WIRE)--Akouos, a precision genetic medicine company developing gene therapies to potentially improve and preserve hearing, announced today that data from its inner ear gene therapy platform will be presented during the 43rd Annual Midwinter Meeting of the Association for Research in Otolaryngology (ARO), being held January 25 to January 29, 2020 in San Jose, CA.

Akouos continues to advance our platform for inner ear disorders, and we are excited to share our progress with the scientific community, said Greg Robinson, Ph.D., chief scientific officer of Akouos. The data presented at ARO further substantiates Akouoss use of AAVAnc80 vector technology and its potential to address many forms of hearing loss.

SYMPOSIUM

Title: The Adeno-associated Viral Anc80 (AAVAnc80) Vector - Precision Genetic Medicines to Address Hearing LossPresenter: Michelle Valero, Ph.D., Director, Anatomy & Physiology, AkouosSession: Symposium 11Date and Time: Saturday, January 25, 3 p.m. (PST)

POSTER PRESENTATIONS

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Olive Baboons (Papio anubis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: The Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Cynomolgus Macaques (Macaca fascicularis)Day and Time: Monday, January 27, 1 p.m. (PST)

Title: Dual Adeno-associated Viral Anc80 Vector Efficiently Transduces Inner Ear Cells in Non-human PrimatesDay and Time: Monday, January 27, 1 p.m. (PST)

About Akouos

Akouos is a precision genetic medicine company dedicated to developing gene therapies with the potential to improve and preserve hearing. Leveraging its adeno-associated viral (AAV) vector-based gene therapy platform, Akouos is focused on developing precision therapies for forms of sensorineural hearing loss. Headquartered in Boston, the Company was founded in 2016 by world leaders in the fields of neurotology, genetics, inner ear drug delivery, and AAV gene therapy. Akouos has strategic partnerships with Massachusetts Eye and Ear and Lonza, Inc. For more information, please visit http://www.akouos.com.

About AAVAnc Technology

Ancestral AAV (AAVAnc) technology was developed in the laboratory of Luk Vandenberghe, Ph.D., Director of the Grousbeck Gene Therapy Center at Harvard Medical School. AAVAnc technology uses computational and evolutionary methods to predict novel conformations of the adeno-associated viral particle. AAVAnc80, one of 40,000 AAVAnc vectors, has demonstrated preliminary safety and effective gene delivery in both mice and non-human primates in numerous preclinical studies.

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Akouos Announces New Data at the Association for Research in Otolaryngology Midwinter Meeting - Business Wire

A new analysis of available data has convinced a panel genomic experts that nine genes previously believed to be associated with a rare, genetic heart conditionlong QT syndromewere an erroneously linked to the condition, as revealed in a new study funded by the National Human Genome Research Institute (NHGRI), a division of the National Institutes of Health (NIH).

Geneticists and heart specialists around the world had previously reported 17 genes to cause long QT syndrome. However, the Clinical Genome Resources (ClinGen) expert panel has critically reevaluated the scientific evidence for all 17 reported genes, and has concluded at least nine of the genes cannot be linked to the disease, and only three of the genes can be definitively associated with the most common form of the disease.

Long QT syndrome is caused by mutations in genes that regulate the hearts electrical activity. These mutations can cause the heart to have sudden, irregular heart rhythms, or arrhythmias. People with long QT syndrome can have arrythmias that are both unprovoked or as a result of stress and exercise. These arrythmias can be fatal.

Many people with long QT syndrome may be unaware they have the condition, unless they get an unrelated electrocardiogram, know their family history, and have undergone genetic testing.

Ever since the syndrome was described in 1957, researchers have engaged in a genetic race to identify the genes associated with it, which currently includes the 17 genes. By using such a standardized, evidence-based framework, the international ClinGen panel experts on long QT syndrome were able to classify the 17 genes into specific groups.

Three genes, KCNQ1, KCNH2 and SCN5A, had sufficient evidence to be implicated as definitive genetic causes for typical long QT syndrome. Four other genes had strong or definitive evidence supporting their role in causing atypical forms of long QT syndrome, particularly if they presented in the newborn period with associated heart block, seizures or delays in development.

The remaining ten genes were deemed to not have sufficient evidence to support a causal role in the syndrome. In fact, nine of these 10 remaining genes were placed in the limited or disputed category. The study authors suggest that these genes not be routinely tested in clinical settings when evaluating patients and families with long QT syndrome, because they lack sufficient scientific evidence as a cause for the condition.

This removal of genes from the testing list impacts genetic testing providers, who use research papers to determine which genes to include in their testing panels for diagnostic reporting to physicians. Published papers reporting gene-disease associations vary widely in their study design and strength of evidence to support their conclusions. Until recently, standard guidelines that can differentiate between genes found with strong and valid scientific approaches versus those with insufficient evidence did not exist. Clearly, this is a problematic approach, and led to several studies drawing early conclusions.

ClinGens expert panels include researchers, clinicians, and genetic counselors who apply an evidence-based framework in evaluating the available data from research papers to place gene-disease relationships into definitive, strong, moderate, limited, disputed, or refuted categories.

ClinGen is an impressive community effort. With over 1,000 researchers and clinicians from 30 countries volunteering their time and expertise, ClinGen is providing much needed clarity for the clinical genomics community regarding which gene-disease pairs have sufficient evidence to be used clinically, said Erin Ramos, Ph.D., project scientist for ClinGen and program director in the Division of Genomic Medicine at NHGRI.

Our study highlights the need to take a step back and to critically evaluate the level of evidence for all reported gene-disease associations, especially when applying genetic testing for diagnostic purposes in our patients. Testing genes with insufficient evidence to support disease causation only creates a risk of inappropriately interpreting the genetic information and leading to patient harm, says Michael Gollob, M.D., senior author of the paper and researcher at the Toronto General Hospital Research Institute.

Moreover, testing for genes not definitively associated with long QT syndrome can result in inappropriate and costly medical interventions such as implanting of a cardioverter-defibrillator.

This is not the first time a team at ClinGen has clarified published research for clinicians. The same team of researchers published a similar study in 2018, covering another heart condition called Brugada syndrome. In 2019, the American Society of Human Genetics considered the paper as one of the top 10 advances in genomic medicine.

ClinGen is an NHGRI-funded resource created to define the clinical relevance and validity of genes associated with various genetic disorders. It comprises more than 20 expert panels working on a variety of genetically influenced diseases, ensuring the reliability of gene-disease linkage. This work is also instrumental in determining which specific genes should be targeted for further study in precision medicine and research.

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Genes Previously Linked to Heart Condition Disputed - Clinical OMICs News

Eisai and Personal Genome Diagnostics (PGDx) will use liquid biopsy to accelerate Next-Generation drug discovery and development

Japanese firm Eisai Co., Ltd., has entered into a joint research and development agreement with Personal Genome Diagnostics Inc., Maryland, for cancer genetics panel test, and it has initiated the research.

In this joint research and development, Eisai and PGDx will create a kitted cancer gene panel test that enables comprehensive analysis of mutation in more than 500 cancer gene using liquid biopsy with blood samples. Additionally, the kit will be used in our drug discovery and development.

In Eisai's medium term business plan EWAY2025, Eisai is pursuing creating innovation focused in neurology area and oncology area aimed at realizing prediction / prevention and cure. Aiming to acquire next-generation sequencing technology for realizing personalized cancer medicine, Eisai has concluded a joint research and development agreement with PGDx, a US bio-venture with liquid biopsy genomic expertise.

By analyzing the circulating tumor DNA (ctDNA) in the blood using its own created gene panel testing technology, Eisai will investigate the Cancer Evolution, which is a series of process such as developments of cancer cells, recurrence / metastasis and the appearance of acquired drug resistance. Eisai will also identify genetic abnormalities of drug resistance to existing anti-cancer agents that will be the targets of a new drug discovery and use a kitted cancer gene panel test for clinical trials to develop new anticancer drugs. Eisai will continue to work on cancer genome medicine for realizing early detection of cancer, and providing personalized cancer medicine and cures for cancer patients in the future.

In addition to accelerating cancer genome medicine based on the latest liquid biopsy technology, Eisai aims to build an oncology ecosystem, in which a longitudinal trajectory of cancer patients will be monitored, to lead to the creation of cures for cancer patients as well as diagnosis for prediction and prevention of cancer. Eisai will make continuous efforts to meet diversified needs of, and increasing the benefits provided to, patients with cancer, their families, and healthcare professionals.

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Eisai and PGDx jointly start R&D of cancer genetics panel test - BSA bureau

The rate of new mutations in the human genome appear to be consistent across diverse populations, except onethe Old Order Amish of Lancaster, Pennsylvania. This group has a lower rate of developing new mutations, according to a study published January 21 in PNAS.The lower mutation rate does not appear to have a genetic component, pointing to a possible role for environmental factors in modifying how fast human genomes accrue new mutations.

It really looks like environmental differences might actually [have] the most significant effect on the number of mutations that you pass on to your offspring, rather than . . . there being some sort of gene causing mutations, says Aylwyn Scally, a geneticist at the University of Cambridge who was not involved in the work. In a larger study than this one, researchers might be better able to detect a genetic contribution if there is one, he says. But still its surprising that it hasnt jumped out, and instead theres this curious effect thats bolstered by their finding about the Amish. Maybe different environments are actually the biggest factor.

Mutation rates are a source of genetic variation within populations. Knowing more about these rates in humans can help researchers better understand disease and evolution. Before this study, mutation rates had really only been looked at in Europeans, and so we wanted to be able to look in a much broader, diverse population, evolutionary geneticist Timothy OConnor of the University of Maryland, a coauthor on the new paper, tells The Scientist.

To this end, he and his colleagues leveraged a dataset of whole genomes from more than 1,400 parent-child trios from the National Heart, Lung, and Blood Institutes TOPMed (Trans-Omics for Precision Medicine) program. The team found that the rate of de novo mutations was similar across populations of African, Latino, and European ancestry. That finding was intriguing because previous work had suggested that populations with high levels of genetic diversity, such as those of African descent, would have higher mutation rates.

Even more unexpected was the mutation rate detected in the 59 Amish families in the cohort. These Amish families are of European descent but have been genetically isolated from other populations since the 1700s and all descended from about 700 individual founders. They had a seven-percent-lower mutation rate compared with the other populations.

We were pretty surprised, says OConnor. Initially the team thought the lower mutation rate had to be an artifact of the sequencing or analysis. We did basically everything we could to try and figure out what kind of artifact would be causing it, and we couldnt find one.

The research team next tried to pinpoint what caused the Amish to have a lower incidence of new mutations. OConnor and his colleagues determined that the lower mutation rates were not heritable, which led the team to speculate that environmental factorssuch as the typical Amish diet and limits on technologymay contribute.

The findings are novel in that the reduced mutation rate hasnt been previously shown with so much sequencing data, says Heather Wheeler, a geneticist at Loyola University Chicago who was not involved in the study. The caveat is that it was still just in one group, and there were only 59 families in the Amish population, she notes. If this is a real effectthe clean-living hypothesis they proposewe definitely want to see it validated in other populations that have similar environments to the Amish.

M.D. Kessler et al., De novo mutations across 1,465 diverse genomes reveal mutational insights and reductions in the Amish founder population,PNAS,doi:10.1073/pnas.1902766117, 2020.

Abby Olena is a freelance journalist based in Alabama. Find her on Twitter@abbyolena.

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Human Mutation Rates Steady Across GroupsExcept in the Amish - The Scientist

BOSTON--(BUSINESS WIRE)-- Decibel Therapeutics, a development-stage biotechnology company developing novel therapeutics for hearing loss and balance disorders, today announced a new strategic research focus on regenerative medicine approaches for the inner ear. The company is also announcing a collaboration and option agreement that gives Decibel exclusive access to novel compounds targeting proteins in a critical regenerative pathway.

Decibels research focus on regeneration will be powered by the companys research and translation platform. The company has built one of the most sophisticated single cell genomics and bioinformatics platforms in the industry to identify and validate targets. Decibel has also developed unique insights into regulatory pathways and inner ear delivery mechanisms that together enable precise control over gene expression in the inner ear and differentiate its AAV-based gene therapy programs.

Our deep understanding of the biology of the inner ear and our advanced technological capabilities come together to create a powerful platform for regenerative medicine therapies for hearing and balance disorders, said Laurence Reid, Ph.D., acting CEO of Decibel. We see an exciting opportunity to leverage this platform to address a broad range of hearing and balance disorders that severely compromise quality of life for hundreds of millions of people around the world.

The first program in Decibels regeneration portfolio aims to restore balance function using an AAV-based gene therapy (DB-201), which utilizes a cell-specific promoter to selectively deliver a regeneration-promoting gene to target cells. In collaboration with Regeneron Pharmaceuticals, Decibel will initially evaluate DB-201 as a treatment for bilateral vestibulopathy, a debilitating condition that significantly impairs balance, mobility, and stability of vision. Ultimately, this program may have applicability in a broad range of age-related balance disorders. There are currently no approved medicines to restore balance. Decibel expects to initiate IND-enabling experiments for this program in the first half of 2020.

Decibel is also pursuing novel targets for the regeneration of critical cells in both the vestibule and cochlea of the inner ear; these targets may be addressable by gene therapy or other therapeutic modalities. As a key component of that program, Decibel today announced an exclusive worldwide option agreement with The Rockefeller University, which has discovered a novel series of small-molecule LATS inhibitors. LATS kinases are a core component of the Hippo signaling pathway, which plays a key role in regulating both tissue regeneration and the proliferation of cells in the inner ear that are crucial to hearing and balance. The agreement gives Decibel an exclusive option to license this series of compounds across all therapeutic areas.

The agreement also establishes a research collaboration between Decibel and A. James Hudspeth, M.D., Ph.D., the F.M. Kirby Professor at The Rockefeller University and the director of the F.M. Kirby Center for Sensory Neuroscience. Dr. Hudspeth is a world-renowned neuroscientist, a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and a Howard Hughes Medical Institute investigator. Dr. Hudspeth has been the recipient of numerous prestigious awards, including the 2018 Kavli Prize in Neuroscience.

Rockefeller scientists are at the leading edge of discovery, and we are excited to see the work of Dr. Hudspeth move forward in partnership with Decibel, said Jeanne Farrell, Ph.D., associate vice president for technology advancement at The Rockefeller University. The ambitious pursuit of harnessing the power of regenerative medicine to create a new option for patients with hearing loss could transform how we address this unmet medical need in the future.

In parallel with its new research focus on regenerative strategies, Decibel will continue to advance key priority preclinical and clinical programs. DB-020, the companys clinical-stage candidate designed to prevent hearing damage in people receiving cisplatin chemotherapy, is in an ongoing Phase 1b trial. Decibel will also continue to progress DB-OTO, a gene therapy for the treatment of genetic congenital deafness, which is being developed in partnership with Regeneron Pharmaceuticals. The DB-OTO program aims to restore hearing to people born with profound hearing loss due to a mutation in the otoferlin gene and is expected to progress to clinical trials in 2021.

To support the new research focus, Decibel is restructuring its employee base and discontinuing some early-stage discovery programs.

About Decibel Therapeutics, Inc. Decibel Therapeutics, a development-stage biotechnology company, has established the worlds first comprehensive drug discovery, development, and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200129005162/en/

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Decibel Therapeutics Announces Strategic Research Focus on Regenerative Medicine for the Inner Ear - BioSpace

Image: Professor Chris Lord andDr Stephen Pettitt next to the olaparib display in the Science Museum's medicine galleries

The Science Museum's new 24 millionmedicine galleriesshowcases pioneering research from The Institute of Cancer Research, London, as part of its story of modern medicine.

The new galleries, which have transformed the first floor of the world-famous museum, explore humanity's relationship with medicine and health through more than 500 years of history.

Included in the exhibition are extraordinary medical artefacts from the collections of Henry Wellcome and the Science Museum Group, including the world's first MRI scanner, Fleming's penicillin mould, a professional pianist's prosthetic arm and robotic surgery equipment.

Science MuseumLatesare adults-only, after-hours theme nights that take place in the museum on the last Wednesday of every month. Tonight's (Wednesday 29 January) Lates event isMedicine Lates.

Follow #smLates on Twitter

The museum chose to showcase the ICR's pioneering research underpinning the development of targeted drug olaparib, which has transformed the lives of tens of thousands of women with breastand ovariancancers.

Olaparib's origins lie in ICR research into the BRCA genes in the 1990s, when our scientists tracked down the BRCA2 gene.

A decade after the identification of BRCA2, ICR researchers found that targeting a DNA repair protein called PARP was a potential way to kill cancer cells with a faulty BRCA gene. This helped lead to the development of olaparib, and other so-called PARP inhibitors.

The gallery features plates which replicate the original ICR experiment to successfully show that olaparib specifically kills cancer cells with defects in their BRCA genes, while leaving healthy cells unaffected.

You can see these in the Medicine and Bodies gallery, which explores how the search to understand more about the human body has transformed medicine.

Displayed alongside Crick and Watson's molecular DNA model, the plates represent how understanding the genetic basis of cancer has transformed our ability to treat it through the creation of targeted therapies.

Professor Chris Lord,Deputy Head of the Breast Cancer Now Toby Robins Research CentreandDivision of Breast Cancer Researchat the ICR (pictured above), said:

"The fact that the Science Museum have chosen to highlight PARP inhibitors in their new gallery is a real testament to how cancer research can genuinely lead to improvements in the treatment of the disease. We are immensely proud of this, as are the other labs across the world who also contributed to these discoveries."

"Despite PARP inhibitors now being highlighted in Science Museum, this is not the end for us we are still working very hard at the ICR to think about how we can improve the effectiveness of these drugs and to make sure that each patient receives the best possible treatment approach."

Daisy Henesy, the ICRs Public Engagement Officer, said:

"It's a thrill to see the ICR's research showcased alongside other huge advances in modern medicine, and richly deserved.

"I urge everyone to visit the new Science Museum galleries and have a look for yourself and don't forget to tweet us with any pictures @ICR_Londonand let us know what you think!"

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ICR research showcased in major new Science Museum gallery documenting history of medicine - The Institute of Cancer Research

A cruel twist of genetic fate brought Alzheimers disease to a sprawling Colombian family. But thanks to a second twist, one member of the clan, a woman, managed to evade the symptoms for decades. Her escape may hold the key to halting, or even preventing, Alzheimers.

The inherited version of Alzheimers disease erodes peoples memories early, starting around age 40. In this family and others, a mutation in a gene called presenilin 1 eventually leaves its carriers profoundly confused and unable to care for themselves. Locals around the Colombian city of Medelln have a name for the condition: la bobera, or the foolishness.

The woman in the afflicted family who somehow fended off the disease carried the same mutation that usually guarantees dementia. And her brain was filled with plaques formed by a sticky protein called amyloid. Many scientists view that accumulation as one of the earliest signs of the disease. Yet she stayed sharp until her 70s.

Researchers were stumped, until they discovered that the woman also carried another, extremely rare genetic mutation that seemed to be protecting her from the effects of the first one. This second mutation, in a different Alzheimers-related gene called APOE, seemed to slow the disease down by decades, says Joseph Arboleda-Velasquez, a cell biologist at Harvard Medical School.

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There was this idea of inevitability, he says. But the womans circumstances bring a different perspective one in which amyloid buildup no longer guarantees problems. Arboleda-Velasquez and colleagues reported the details of the womans exceptional case November 4 in Nature Medicine, omitting the womans name and precise age to protect her privacy.

Although the discovery is based on one person, it points to a biological weak spot in the degenerative disease that affects an estimated 5.8 million people in the United States alone. So far, nearly every clinical trial designed to slow or stop the disease has failed. Those heartbreaking disappointments have prompted scientists to expand their search for treatments.

Perhaps this unusually resilient woman in Colombia shows a way to halt the disease, or at least slow it down. Can we come up with a drug that does this to people who dont have a mutation? asks Arboleda-Velasquez. The potential for that is tremendous.

The vast majority of people with Alzheimers have a sporadic form of the disease with no clear genetic culprit. These people often reach their 70s or 80s before signs of dementia appear. Mutations that cause trouble much earlier, such as the Paisa mutation found in the Colombian family, are unusual. But despite their different origins and different timelines, these two versions of Alzheimers are thought to progress in somewhat similar ways.

Normally, presenilin 1 makes a protein that helps chop up the long, sticky amyloid precursor protein. One of the resulting small bits is called amyloid-beta. Those smaller pieces are harmlessly washed out of the brain. The mutated presenilin 1 gene found in the Colombian family, however, creates a kink in the chopping process that leads to an abundance of a version of amyloid that knits itself into plaques between brain cells.

This pileup is already visible in brain scans of people in their 20s who carry the mutation. By their mid-40s, many of these people have trouble remembering; they typically develop full-blown dementia by age 50.

Inheriting just one copy of the mutation is enough to lead to excess amyloid, and ultimately dementia. The mutations powerful effect in this family is one of the strongest arguments for the fact that amyloid plays a critical role in Alzheimers, says immunologist and aging expert Richard J. Hodes, director of the National Institute on Aging in Bethesda, Md. Since taking on the role in 1993, Hodes has helped set the course for U.S.-funded Alzheimers research, allocating support for promising projects, including studies happening in Colombia.

The Colombian family, 5,000 members strong, includes an estimated 1,000 or so people who carry the Paisa mutation in the presenilin 1 gene. Their involvement in the research has been invaluable. Access to hundreds of people known to be at high risk for the disease allows scientists to study how Alzheimers unfolds, particularly at its earliest stages, and has led to reports of early signs of Alzheimers, both in the brain and the blood. Family members have gone to great lengths to help, walking or taking a bicycle to the nearest bus stop, and then taking a bus to a train, for many hours, to come to the clinic, Hodes says.

During Hodes recent visit to the Medelln area, a resident told him how the disease is just a part of their lives: If I have the disease, I know that my family, my brother and my sister, will take care of me. And if I dont, I will take care of them.

When Colombian researchers learned of the woman who stayed sharp until her 70s, they arranged for her to travel to Boston in the summer of 2016, accompanied by family members and a research assistant. There, neuroimaging researcher Yakeel T. Quiroz and her colleagues used brain scans to measure levels of amyloid and other markers of brain health, including another Alzheimers-related protein called tau, which can tangle up inside nerve cells.

Those scans revealed a brain loaded with amyloid, says Quiroz, of Harvard Medical School. This woman had most likely been accumulating amyloid for decades. On a scale commonly used to quantify amyloid in the brain, she scored 1.96, well above the threshold of 1.2 that signifies extensive amyloid buildup. Her score was, pretty much the highest that we have seen in anybody we have scanned so far, Quiroz says.

Genetic analyses revealed that the woman had whats called the Christchurch mutation in both copies of her APOE gene. Further tests suggested that this mutation, named for the New Zealand city where it was first found, was shielding her from the disease. The fact that the woman had huge amounts of amyloid in her brain, yet didnt seem impaired until her 70s, is extremely surprising, interesting, provocative and potentially very, very informative, Hodes says.

Scientists need to do more work to confirm that the APOE Christchurch mutation protected her brain. Still, the results reveal a simple truth, Hodes says. Amyloid itself is not necessarily sufficient to cause dementia.

Studies outside of the Colombian family also make clear that amyloid isnt the whole story. Other cellular actors contribute to the death of nerve cells and memory loss that Alzheimers brings. Nerve cellclogging tangles of tau and other signs of brain illness are tightly linked to brain decline, research from many studies has shown. Thats reflected in observations from a study of 480 people age 60 and older who live around Rochester, Minn.

These people, none of whom showed signs of dementia, were randomly chosen to be invited into the study, an unbiased selection that offered researchers a glimpse of brain health in the wider population.

To find out which brain changes best predict future memory loss, neuroradiologist Clifford R. Jack Jr. of the Mayo Clinic in Rochester and colleagues tested volunteers memory performance while measuring their amyloid levels and other brain signals. Amyloid seemed to be closely involved in memory decline over about five years but only in the right context, the team reported in June 2019 in JAMA.

Without either of two other troublesome markers tau tangles or brain shrinkage amyloid didnt predict memory loss. In other words, amyloid might be setting up the shot, but then it passes the ball.

Amyloid in the head is the first stage of what will ultimately lead to full-blown Alzheimers disease, Jack says. But there can be a lot of time between that early stage of amyloid accumulation and the development of symptoms.

Among the Colombian family members, that interval lasts around 10 to 15 years. The same is roughly true for people with the sporadic form of Alzheimers. But for the woman described in the report in Nature Medicine, that lag seemed twice as long.

That suggests that at least its possible to live with amyloid not just for 15 years, but for many decades, says Paul Aisen, director of the University of Southern Californias Alzheimers Therapeutic Research Institute in San Diego. Living healthy longer: Thats very exciting.

The protective effect of the womans mutation seems to come from an extremely specific change. In the Christchurch variant, a single spot in the APOE gene is tweaked. The resulting protein has a serine amino acid swapped in for the standard arginine.

The swap prevents the APOE protein from binding to some sugar-dotted proteins called heparan sulfate proteoglycans, or HSPGs, experiments on the isolated proteins revealed. Earlier studies showed that HSPGs may promote amyloid accumulation and nudge nerve cells to slurp up more toxic tau.

But to misbehave, HSPGs might need to partner with the APOE protein. The Christchurch mutation could have protected the womans brain by scrambling that nefarious relationship, the researchers suspect. Without that specific connection between APOE and HSPGs, the disease process gets stalled, Arboleda-Velasquez says. This really puts a block on the cascade of events.

Fleshing out the APOE proteins normal biological cascade, and how that changes with the Christchurch mutation, is going to allow for much more finely targeted drug development, says Aisen, who also works as a consultant for Biogen, a biotechnology company in Cambridge, Mass. The company is developing an amyloid-targeting drug called aducanumab and is expected to apply for approval from the U.S. Food and Drug Administration this year (SN: 1/18/20, p. 8).

As one of the strongest genetic risk factors for dementia, the APOE gene has long been scrutinized as a possible target for Alzheimers drugs. People who carry a version of the gene called APOE4 have a higher risk of Alzheimers.

The APOE2 version dramatically lowers the risk, Quiroz, Arboleda-Velasquez and colleagues report in preliminary research posted online November 2 at medRxiv.org. APOE3 usually brings an average risk of Alzheimers, with the notable exception of the version with the Christchurch mutation carried by the Colombian woman.

In the general population, old age is the biggest risk factor for Alzheimers. As the number of older people balloons, so too will the number of people with dementia. By 2050, an estimated 13.8 million people in the United States will have Alzheimers. Worldwide, an estimated 50 million people have dementia; Alzheimers accounts for the bulk of those cases.

The family in Colombia continues to help. A clinical trial testing a drug that is designed to lower amyloid is under way in Colombia. People who have the Paisa mutation but have not shown Alzheimers symptoms, as well as people without the mutation, are receiving the drug. The drug, crenezumab, is an antibody thats thought to mark amyloid for destruction by immune cells. Its being developed by Roche/Genentech.

Quiroz and her colleagues also plan to follow the Colombian woman and other members of the family over time, as part of a research exchange between Fundacin Universidad de Antioquia in Medelln, which has led the studies on this family, and Massachusetts General Hospital in Boston.

Each month, the project, called COLBOS, for Colombia-Boston, flies a new group of about five adult participants to Boston for extensive evaluation, including thinking and memory tests, brain scans and measurements of smelling ability, fitness and music perception. Participants being studied in Colombia are as young as 9 years old.

The project may yield insights about how Alzheimers takes hold early on. But in a way, the initial trigger might not even matter. It could be that the cause or more likely, causes of Alzheimers might ultimately be poor targets for drugs, Arboleda-Velasquez says.

People with loved ones suffering from Alzheimers, including the Colombian family, dont necessarily care what causes the disease, Quiroz says. They are more interested in seeing if there is anything that can help them to get better. Thats what the patients and families are waiting for.

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How one woman became the exception to her familys Alzheimers history - Science News