Daily Archives: October 31, 2020

Oct. 26, 2020 10:00 UTC

SAN DIEGO--(BUSINESS WIRE)-- Boundless Bio, a biotechnology company developing innovative therapeutics directed to extrachromosomal DNA (ecDNA) in aggressive cancers, today will present research highlighting powerful components of its proprietary Spyglass platform at the 2020 American Society of Human Genetics (ASHG) Annual Meeting.

The poster, titled A Robust Imaging and Single-Cell Sequencing Platform to Characterize Tumor Extrachromosomal DNA (ecDNA) in Response to Therapeutic Intervention, describes elements of Boundless Bios broad platform for interrogating ecDNA biology. These elements couple automated cellular imaging with comprehensive single-cell genomic sequencing. The tools are part of an essential toolkit for understanding how ecDNA responds when cancers are treated with various therapeutic pressures and can be broadly applied to track how oncogenes amplify and where they are expressed following therapeutic intervention. Tumors driven by oncogene amplification are aggressive, have poor prognosis, and have proven elusive for targeted therapies. ecDNA frequently harbor oncogene amplifications and promote resistance to cancer treatment by enhancing genomic diversity and enabling cancer cells to rapidly adapt in response to therapeutic pressures.

We are building our Spyglass platform to serve as the first robust, objective, and high-resolution tool for characterizing ecDNA and how they respond to therapeutic pressures, said Jason Christiansen, Chief Technology Officer of Boundless Bio. This new research presented at ASHG demonstrates that our platform can successfully track how the behavior of ecDNA in cancer shifts in the face of treatment; these insights are enabling us to develop more effective, highly-targeted treatments for patients with cancers driven by ecDNA.

Study Details

Utilizing key analytical tool elements of the Spyglass platform, scientists studied colorectal cancer cells with amplified oncogenes in the presence and absence of cytotoxic chemotherapy, demonstrating the ability to robustly characterize changes in ecDNA and chromosomally-amplified genes at the phenotypic and molecular level.

The researchers studied Colo320DM cells, containing a mixture of the MYC oncogene on ecDNA and chromosomally amplified gene populations; Colo320HSR cells with a pure chromosomally amplified MYC population; and DLD1 cells as a non-amplified control. Each arm was treated for 2 weeks with a cytotoxic chemotherapeutic agent. Cells in metaphase were collected, stained with DAPI and probed for the MYC oncogene by Fluorescence In Situ Hybridization (FISH). Whole-slide images (~10mm2) were collected using automated imaging; and custom-built software was used to automatically identify and quantify ecDNA in individual metaphase spreads. Relative changes in MYC FISH signal and localization were used to quantify the changes in ecDNA and chromosomal amplification populations before and after drug treatment.

In addition, single-cell sequencing techniques revealed molecular level information about the amplified gene regions that is complementary to the spatial information provided by image analysis. Regions of increased gene expression and open chromatin around the MYC gene are indicative of ecDNA and were not identified in the chromosomally amplified line. Further, although chromosomally amplified regions exist in both model lines, molecular level evidence demonstrated divergence in this region not discernable by imaging. When treated with cytotoxic chemotherapy, the ecDNA population was reduced and the chromosomally amplified region was selected. Together these tools demonstrated Boundless Bios ability to monitor and quantify dynamic changes in ecDNA in cancer cells under selective pressure.

About ecDNA Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA containing functional genes, including oncogenes, that are separated from tumor cell chromosomes. ecDNA rapidly replicate within cancer cells, causing high numbers of oncogene copies and can be passed to daughter cells asymmetrically during cell division, driving tumor heterogeneity. Cancer cells have the ability to increase or decrease copy number of oncogenes located on ecDNA to enable survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells primary mechanisms of recurrence and treatment resistance. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

About Boundless Bio Boundless Bio is a next-generation precision oncology company interrogating a novel area of cancer biology, extrachromosomal DNA (ecDNA), to deliver transformative therapies to patients with previously intractable cancers.

For more information, visit http://www.boundlessbio.com.

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About Boundless Bios Spyglass Platform Boundless Bios Spyglass platform is a comprehensive suite of proprietary ecDNA-driven and pair-matched tumor models along with proprietary imaging and molecular analytical tools that enables Boundlesss researchers to interrogate ecDNA biology and maintain a robust pipeline of novel oncotargets essential to the function of cancer cells that are enabled by ecDNA. The Spyglass platform facilitates Boundless innovation in the development of precision therapeutics specifically targeting ecDNA-driven tumors, thereby enabling selective treatments for patients whose tumor genetic profiles make them most likely to benefit from our novel therapeutic candidates.

View source version on businesswire.com: https://www.businesswire.com/news/home/20201026005101/en/

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Boundless Bio Presents Research Showcasing its Imaging and Single-Cell Sequencing Platform for Extrachromosomal DNA (ecDNA) Detection at the 2020...

Counting the years: Older parents are no more likely than younger ones to pass on large genetic mutations to their children.

10,000 Hours / Getty Images

Most of the large, spontaneous genetic mutations tied to autism are passed down from fathers. But, unlike with smaller mutations, a mans age is unlikely to significantly up the rate at which they occur.

Researchers presented the unpublished work today at the 2020 American Society of Human Genetics conference, which is taking place virtually because of the coronavirus pandemic.

Spontaneous, or de novo, mutations can occur in a sperm or egg cell, or very early on in an embryos development. Many of these changes involve a single DNA letter, or base pair, and are known as point mutations. They tend to accumulate over time in sperm and eggs and may contribute to higher rates of autism among children born to older parents, especially older fathers.

Larger mutations, such as deletions or duplications of DNA sequences, have also been linked to autism, but they are rarer and require sizeable cohorts to study. The new work examined structural variants involving 50 or more base pairs in two large groups of autistic people and their families.

Its likely that studies of even larger groups will find that parental age does raise the odds of passing down structural variants, says co-lead investigator Aaron Quinlan, professor of human genetics and biomedical informatics at the University of Utah in Salt Lake City. But the new findings from his lab make it clear that age plays a much smaller role for them than it does for point mutations.

The results are fairly good evidence that if there is a parental age effect, it is weak, he says.

The researchers analyzed the genomes of 2,363 people with autism, as well as 1,938 of their non-autistic siblings and both parents. They compared rates of structural variants, excluding those that involve entire chromosomes. The families have no known history of autism.

They found that more than one in five autistic people has a structural variant, compared with fewer than one in six non-autistic people.

In both autistic people and controls, about three-quarters of the mutations occurred in DNA passed down by the fathers cells rather than the mothers.

But the fathers of children with and without structural variants do not differ significantly in age, the researchers found.

They did not analyze the relationship between a mothers age and likelihood of mutations, but because mothers and fathers in the cohort were of similar ages, the researchers can infer a similar effect.

In a smaller group of 165 autistic people and 85 unaffected people all carrying structural variants the researchers confirmed an association between paternal age and the number of point mutations in people with autism and in controls.

Point mutations and structural variants have different underlying mechanisms: The former tend to occur randomly during cell division and genome replication, whereas the latter are the result of cells repairing breaks in the chromosome.

The rate at which those [chromosome breaks] occur dont really change as a function of age, Quinlan says.

The findings may lead to a better understanding of the role of structural variations in autism and other complex conditions in which genetics play a large role, says Jonathan Belyeu, a graduate student in Quinlans lab. Belyeu presented the findings.

Theoretically, if we can identify where these variants are occurring, it will point us to genes that are important for the overall [condition], Belyeu says.

For more reports from the 2020 American Society of Human Genetics annual meeting, please click here.

Originally posted here:
Parental age plays small role in large mutations tied to autism - Spectrum

At least 10% of patients with life-threatening coronavirus diseases 2019 (COVID-19) pneumonia have antibodies that attack their own interferons, according to a new study by a team of international investigators.

The study, published in Science, found that 101 out of 987 patients with severe COVID-19 pneumonia had IgG autoantibodies that neutralize the ability of type 1 interferons to block SARS-CoV-2 infection.

This was a huge surprise, much unexpected, corresponding author Paul Bastard, affiliated with Inserm, University of Paris Imagine Institute and St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University, told Contagion. Very surprising how it mimics genetic inborn errors of immunity. Extremely surprising too that individuals with complete genetic defects in key interferon genes (as described in Zhang Q and al., Science, 2020) were adult patients who had not suffered previously from severe viral infections.

In a separate study, the team detailed genetic variants contributing to life-threatening COVID-19 pneumonia. Loss-of-function variants at 13 human loci known to govern TLR3- and IRF7-dependent type 1 interferon immunity to influenza virus were examined. Genetic defects leading to impaired production or response to type 1 interferons were reported in 23 patients (3.5%).

The twin studies come from lab of Jean-Laurent Casanova, MD, PhD, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at the Rockefeller University, and the COVID Human Genetic Effort, a international collaboration aiming to determine how human genetics determine severe COVID-19.

The antibody study included 987 patients with critical COVID-19, 663 asymptomatic or pauci-symptomatic patients with COVID-19, and 1227 healthy controls. Autoantibodies were found in none of the patients with asymptomatic or mild COVID-19 and in only 4 of the healthy participants. Based on this, the estimated prevalence of these autoantibodies in the general population is 0.33%.

The study also could help explain why men have been more adversely affected by COVID-19 than women, finding that 95 of the 101 patients with the autoantibodies were men.

The neutralizing autoantibodies are believed to have been present before SARS-CoV-2 infection and caused the severity of the disease. They were identified in 2 patients before infection and 3 patients with APS-1, a serious but rare immune diseased marked by a high concentration of antibodies against interferons, had life-threatening COVID-19.

It would be important to implement routine testing for auto-antibodies in all patients infected with COVID-19 to be able to implement adequate treatments and preventive measures. And perform genetic testing in the patients with unexplained severe COVID-19, Bastard said.

Treatment could include early injected or nebulized IFN- because autoantibodies that work against that type of interferon are rare among those affected, while treatment with IFN- is unlikely to be affective, the study said.

Early intervention might be key. Once patients are hospitalized, it might be too late for treatment to show benefits. The World Health Organization Solidarity Trial recently released results indicating that interferon-beta therapy didnt lower mortality nor the need for ventilation among more than 2,000 people who received the drug.

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Autoantibodies Block Interferons in 10% of Severe COVID-19 Cases - Contagionlive.com

Insitro founder and CEO Daphne Koller (left) and CFO Mary Rozenman (right). Photo courtesy of Insitro.

San Francisco-based Insitro announced today that it has entered a five-year discovery collaboration agreement with Bristol Myers Squibb to discover and develop novel therapies for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Through this collaboration, Insitro will utilize its proprietary platform, Insitro Human (ISH), to create induced pluripotent stem cell (iPSC) derived disease models for both diseases. This platform applies machine learning, human genetics and functional genomics to create predictive in vitro models. ISH can potentially provide insight into how these diseases progress within patients. Bristol Myers Squibb will have the option to select from targets identified by Insitro to advance through clinical development and commercialization.

Neurodegenerative disorders like ALS and FTD have historically been a challenging therapeutic area, with no disease modifying treatments today. We are excited to partner with Bristol Myers Squibb and its world-class neuroscience leaders, who share our vision of leveraging human genetics, machine learning, and high-throughput biology and chemistry in order to identify and provide new treatments for patients suffering from these devastating diseases, said Daphne Koller, founder and chief executive officer of Insitro. Since founding Insitro just over two years ago, we have demonstrated our capabilities in building predictive models to discover novel targets and patient segments. We have also developed new approaches to machine-learning-enabled therapeutics design, which we look forward to deploying to discover treatments for novel targets emerging from this collaboration.

Insitro is set to receive $50 million as an upfront payment, and it will be eligible to receive an additional $20 million in near term operational milestones.

We believe that machine learning and data generated by novel experimental platforms offer the opportunity to rethink how we discover and design novel medicines, said Richard Hargreaves, Ph.D., senior vice president, head of neuroscience TRC research and early development, Bristol Myers Squibb. There is an unmet medical need for therapies to treat ALS and FTD and we are excited by the prospect of working with Insitros team towards our shared goal of identifying transformative treatments for patients with these devastating diseases.

Insitro recently strengthened its machine learning-based drug discovery capabilities through the acquisition of Haystack Sciences back on Oct. 22. Haystack focuses on synthesizing, breeding and analyzing large, diverse combinatorial chemical libraries encoded by unique DNA sequences called DNA-encoded libraries (DELs). Insitro intends on leveraging the DEL technology to collect massive small molecule data.

We are thrilled to have the Haystack team join Insitro, Koller said at the time of the announcement. For the past two years, Insitro has been building a company focused on the creation of predictive cell-based models of disease in order to enable the discovery of novel targets and evaluate the benefits of new or existing molecules in genetically defined patient segments. This acquisition enables us to expand our capabilities to the area of therapeutic design and advances us towards our goal of leveraging machine learning across the entire process of designing and developing better medicines for patients.

Haystacks platform combines several elements, including the capability to synthesize small molecule collections. With these advantages, Insitro will be better equipped to develop multi-dimensional predictive models for small molecule design.

I am excited by the opportunity to join a company with such a uniquely open and collaborative culture and to work with and learn from colleagues in data science, machine learning, automation and cell biology, said Richard E. Watts, co-founder and chief executive officer of Haystack Sciences. The capabilities enabled by joining our efforts are considerably greater than the sum of the parts, and I look forward to helping build core drug discovery efforts at Insitro.

Visit link:
Insitro and BMS Team Up to Pave the Way for New ALS and FTD Treatments - BioSpace

Yale Daily News

Advocating for the transition of medicine away from race-based practices and toward a more race-conscious approach, Yale Medical School MD-PhD student Jessica Cerdea GRD 21, Yale Emergency Medicine physician Jennifer Tsai and Howard University PhD student Marie Plaisime recently co-authored an editorial for The Lancet, a peer-reviewed medical journal, this month about reforming medical education for future doctors.

The editorial characterizes the current practice of medicine as race-based, stating that physicians often infer that race has inherent biological significance, whereas in actuality race is merely a social construct. The authors say the future of medicine should move from this race-based approach to a race-conscious approach, with the end goal being a reduction in health inequities across racial lines. They advocated for emphasizing institutional inequities in healthcare during medical education, which they said would raise the cultural competency of future physicians.

Race-based medicine uses and treats race as an essential biological variable that has utility in medical education and clinical practice, Cerdea said. Race-conscious medicine understands that race is a social and power construct that changes for political utility over time, and that it is a poor proxy for human genetic variation. Instead, the more salient variable when it comes to differences in human groups that have been socially categorized in this way is the experience of racism and racialization This idea that there are biological differences between racial groups comes from colonization. This is how white supremacy operates.

The editorial was published in The Lancet after the prominent medical journal released a statement supporting the Black Lives Matter movement and its continuing commitment to advancing racial equality. This editorial was also published following a summer of racial unrest and protests around the country that advocated for putting an end to police brutality against Black Americans. The timing of the publication was significant to the authors.

Certainly we were motivated by the very apparent murders of George Floyd, Ahmaud Arbery and Breonna Taylor, among others, Tsai said. But also because this is a very long-standing problem that I think all three of us have been working on, thinking about and advocating against beforehand.

The article presented a wide range of examples in which race heavily influences physicians medical assessment of patients, such as the Atherosclerotic Cardiovascular Disease risk calculator equation. This online tool determines a given patients risk of having a cardiovascular event within ten years, Cerdea said. These calculations involve categorizing the patient as either Black or not Black. If the patient is Black, the predicted risk is significantly increased, and the patient is more likely to start taking a certain medication earlier than patients of other racial groups.

The prescription dosage for certain drugs can also vary based on racial groups. According to Cerdea, medical practitioners consider East Asian people to have different metabolisms, which means that a drug like Eltrombopag, a bone marrow stimulant, is started at half the normal dose for these people. This type of race-based medicine is condemned in the article.

You cant know someones pharmacokinetics, or the way that they metabolize a drug, by looking at them, or by their race, Cerdea said. Thats the problem with race-based medicine.

The Lancet piece includes different policy recommendations for researchers, clinicians and practitioners. According to Plaisime, It was crafted with care towards its intended audience of physicians, picking and choosing words that would be most accessible. The most important step in moving forward, Tsai said, is to change the curriculum of medical schools to be more race-conscious.

The authors also wrote this editorial from the perspective of their own experiences as women of color within the American healthcare system. Cerdea is Italian and Chilean with Indigenous Mapuche ancestry, Plaisime is Haitian American and Tsai is Taiwanese American.

As a Black woman, for sure there have definitely been times where Ive been treated differently based on how I appeared in the clinical room, how I was spoken to, Plaisime said. Also being the daughter of Haitian immigrants, I know first-hand what its like to have your accent judged. Not just one isolated event that kind of sparked this, its my story, and I want to make sure that all people receive equitable care.

The authors also emphasized that even research studies are subjected to racialization, despite undergoing objective screening processes instituted by peer-reviewed journals. Although race has no inherent biological significance, countless epidemiological studies include race as a critical variable when mapping out the prevalence of certain diseases.

In their article, the authors urged clinical research journals to include instructions in their publication guidelines that denounce the use of race as a proxy for biological variables such as genetics, pharmacokinetics and metabolism.

Prestigious publications continue to allow research that [uses] problematic versions of race in their research, Tsai said. They still allow that to be published, which means this kind of data and this kind of thinking is continually generated and perpetuated.

Plaisime, who is a medical sociologist studying the impacts of race and racism in clinical decision-making processes, explained that biologizing race is harmful. Prior to this collaboration, she had published a piece about the implications of using race in medicine.

She emphasized the need for using evidence-based treatments that do not rely solely on race as a factor of consideration, as this can often be detrimental to members of racial minority groups.

The different biomarkers and tools they use arent necessarily based on science, but more on racist assumptions, Plaisime said. My work was based on how that kind of training impacts later on how patients receive care, and how medical students are trained.

Cerdea and Plaisime are both Robert Wood Johnson Foundation Health Policy Research Scholars, and Tsai is completing her residency at the Yale New Haven Hospital.

Anjali Mangla | anjali.mangla@yale.edu

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Members of medical community call for shift from race-based to race-conscious medicine - Yale Daily News

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

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

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

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

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

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

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

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

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

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

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

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

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

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

View original post here:
New screening tool could turn up genes tied to developmental disorders - STAT

Angelika Amon, professor of biology and a member of the Koch Institute for Integrative Cancer Research, died on Oct. 29 at age 53, following a two-and-a-half-year battle with ovarian cancer.

"Known for her piercing scientific insight and infectious enthusiasm for the deepest questions of science, Professor Amon built an extraordinary career and in the process, a devoted community of colleagues, students and friends," MIT President L. Rafael Reif wrote in a letter to the MIT community.

Angelika was a force of nature and a highly valued member of our community, reflects Tyler Jacks, the David H. Koch Professor of Biology at MIT and director of the Koch Institute. Her intellect and wit were equally sharp, and she brought unmatched passion to everything she did. Through her groundbreaking research, her mentorship of so many, her teaching, and a host of other contributions, Angelika has made an incredible impact on the world one that will last long into the future.

A pioneer in cell biology

From the earliest stages of her career, Amon made profound contributions to our understanding of the fundamental biology of the cell, deciphering the regulatory networks that govern cell division and proliferation in yeast, mice, and mammalian organoids, and shedding light on the causes of chromosome mis-segregation and its consequences for human diseases.

Human cells have 23 pairs of chromosomes, but as they divide they can make errors that lead to too many or too few chromosomes, resulting in aneuploidy. Amons meticulous and rigorous experiments, first in yeast and then in mammalian cells, helped to uncover the biological consequences of having too many chromosomes. Her studies determined that extra chromosomes significantly impact the composition of the cell, causing stress in important processes such as protein folding and metabolism, and leading to additional mistakes that could drive cancer. Although stress resulting from aneuploidy affects cells ability to survive and proliferate, cancer cells which are nearly universally aneuploid can grow uncontrollably. Amon showed that aneuploidy disrupts cells usual error-repair systems, allowing genetic mutations to quickly accumulate.

Aneuploidy is usually fatal, but in some instances extra copies of specific chromosomes can lead to conditions such as Down syndrome and developmental disorders including those known as Patau and Edwards syndromes. This led Amon to work to understand how these negative effects result in some of the health problems associated specifically with Down syndrome, such as acute lymphoblastic leukemia. Her expertise in this area led her to be named co-director of the recently established Alana Down Syndrome Center at MIT.

Angelikas intellect and research were as astonishing as her bravery and her spirit. Her labs fundamental work on aneuploidy was integral to our establishment of the center, say Li-Huei Tsai, the Picower Professor of Neuroscience and co-director of the Alana Down Syndrome Center. Her exploration of the myriad consequences of aneuploidy for human health was vitally important and will continue to guide scientific and medical research.

Another major focus of research in the Amon lab has been on the relationship between how cells grow, divide, and age. Among other insights, this work has revealed that once cells reach a certain large size, they lose the ability to proliferate and are unable to reenter the cell cycle. Further, this growth contributes to senescence, an irreversible cell cycle arrest, and tissue aging. In related work, Amon has investigated the relationships between stem cell size, stem cell function, and tissue age. Her labs studies have found that in hematopoetic stem cells, small size is important to cells ability to function and proliferate in fact, she posted recent findings on bioRxiv earlier this week and have been examining the same questions in epithelial cells as well.

Amon lab experiments delved deep into the mechanics of the biology, trying to understand the mechanisms behind their observations. To support this work, she established research collaborations to leverage approaches and technologies developed by her colleagues at the Koch Institute, including sophisticated intestinal organoid and mouse models developed by the Yilmaz Laboratory, and a microfluidic device developed by the Manalis Laboratory for measuring physical characteristics of single cells.

The thrill of discovery

Born in 1967, Amon grew up in Vienna, Austria, in a family of six. Playing outside all day with her three younger siblings, she developed an early love of biology and animals. She could not remember a time when she was not interested in biology, initially wanting to become a zoologist. But in high school, she saw an old black-and-white film from the 1950s about chromosome segregation, and found the moment that the sister chromatids split apart breathtaking. She knew then that she wanted to study the inner workings of the cell and decided to focus on genetics at the University of Vienna in Austria.

After receiving her BS, Amon continued her doctoral work there under Professor Kim Nasmyth at the Research Institute of Molecular Pathology, earning her PhD in 1993. From the outset, she made important contributions to the field of cell cycle dynamics. Her work on yeast genetics in the Nasmyth laboratory led to major discoveries about how one stage of the cell cycle sets up for the next, revealing that cyclins, proteins that accumulate within cells as they enter mitosis, must be broken down before cells pass from mitosis to G1, a period of cell growth.

Towards the end of her doctorate, Amon became interested in fruitfly genetics and read the work of Ruth Lehmann, then a faculty member at MIT and a member of the Whitehead Institute. Impressed by the elegance of Lehmanns genetic approach, she applied and was accepted to her lab. In 1994, Amon arrived in the United States, not knowing that it would become her permanent home or that she would eventually become a professor.

While Amons love affair with fruitfly genetics would prove short, her promise was immediately apparent to Lehmann, now director of the Whitehead Institute. I will never forget picking Angelika up from the airport when she was flying in from Vienna to join my lab. Despite the long trip, she was just so full of energy, ready to talk science, says Lehmann. She had read all the papers in the new field and cut through the results to hit equally on the main points.

But as Amon frequently was fond of saying, yeast will spoil you. Lehmann explains that because they grow so fast and there are so many tools, your brain is the only limitation. I tried to convince her of the beauty and advantages of my slower-growing favorite organism. But in the end, yeast won and Angelika went on to establish a remarkable body of work, starting with her many contributions to how cells divide and more recently to discover a cellular aneuploidy program.

In 1996, after Lehmann had left for New York Universitys Skirball Institute, Amon was invited to become a Whitehead Fellow, a prestigious program that offers recent PhDs resources and mentorship to undertake their own investigations. Her work on the question of how yeast cells progress through the cell cycle and partition their chromosomes would be instrumental in establishing her as one of the worlds leading geneticists. While at Whitehead, her lab made key findings centered around the role of an enzyme called Cdc14 in prompting cells to exit mitosis, including that the enzyme is sequestered in a cellular compartment called the nucleolus and must be released before the cell can exit.

I was one of those blessed to share with her a eureka moment, as she would call it, says Rosella Visintin, a postdoc in Amons lab at the time of the discovery and now an assistant professor at the European School of Molecular Medicine in Milan. She had so many. Most of us are lucky to get just one, and I was one of the lucky ones. Ill never forget her smile and scream neither will the entire Whitehead Institute when she saw for the first time Cdc14 localization: You did it, you did it, you figured it out! Passion, excitement, joy everything was in that scream.

In 1999, Amons work as a Whitehead Fellow earned her a faculty position in the MIT Department of Biology and the MIT Center for Cancer Research, the predecessor to the Koch Institute. A full professor since 2007, she also became the Kathleen and Curtis Marble Professor in Cancer Research, associate director of the Paul F. Glenn Center for Biology of Aging Research at MIT, a member of the Ludwig Center for Molecular Oncology at MIT, and an investigator of the Howard Hughes Medical Institute.

Her pathbreaking research was recognized by several awards and honors, including the 2003 National Science Foundation Alan T. Waterman Award, the 2007 Paul Marks Prize for Cancer Research, the 2008 National Academy of Sciences (NAS) Award in Molecular Biology, and the 2013 Ernst Jung Prize for Medicine. In 2019, she won the Breakthrough Prize in Life Sciences and the Vilcek Prize in Biomedical Science, and was named to the Carnegie Corporation of New Yorks annual list of Great Immigrants, Great Americans. This year, she was given the Human Frontier Science Program Nakasone Award. She was also a member of the NAS and the American Academy of Arts and Sciences.

Lighting the way forward

Amons perseverance, deep curiosity, and enthusiasm for discovery served her well in her roles as teacher, mentor, and colleague. She has worked with many labs across the world and developed a deep network of scientific collaboration and friendships. She was a sought-after speaker for seminars and the many conferences she attended. In over 20 years as a professor at MIT, she has mentored more than 80 postdocs, graduate students, and undergraduates, and received the School of Sciences undergraduate teaching prize.

Angelika was an amazing, energetic, passionate, and creative scientist, an outstanding mentor to many, and an excellent teacher, says Alan Grossman, the Praecis Professor of Biology and head of MITs Department of Biology. Her impact and legacy will live on and be perpetuated by all those she touched.

Angelika existed in a league of her own, explains Kristin Knouse, one of Amons former graduate students and a current Whitehead Fellow. She had the energy and excitement of someone who picked up a pipette for the first time, but the brilliance and wisdom of someone who had been doing it for decades. Her infectious energy and brilliant mind were matched by a boundless heart and tenacious grit. She could glance at any data and immediately deliver a sharp insight that would never have crossed any other mind. Her positive attributes were infectious, and any interaction with her, no matter how transient, assuredly left you feeling better about yourself and your science.

Taking great delight in helping young scientists find their own eureka moments, Amon was a fearless advocate for science and the rights of women and minorities and inspired others to fight as well. She was not afraid to speak out in support of the research and causes she believed strongly in. She was a role model for young female scientists and spent countless hours mentoring and guiding them in a male-dominated field. While she graciously accepted awards for women in science, including the Vanderbilt Prize and the Women in Cell Biology Senior Award, she questioned the value of prizes focused on women as women, rather than on their scientific contributions.

Angelika Amon was an inspiring leader, notes Lehmann, not only by her trailblazing science but also by her fearlessness to call out sexism and other -isms in our community. Her captivating laugh and unwavering mentorship and guidance will be missed by students and faculty alike. MIT and the science community have lost an exemplary leader, mentor, friend, and mensch.

Amons wide-ranging curiosity led her to consider new ideas beyond her own field. In recent years, she has developed a love for dinosaurs and fossils, and often mentioned that she would like to study terraforming, which she considered essential for a human success to life on other planets.

It was always amazing to talk with Angelika about science, because her interests were so deep and so broad, her intellect so sharp, and her enthusiasm so infectious, remembers Vivian Siegel, a lecturer in the Department of Biology and friend since Amons postdoctoral days. Beyond her own work in the lab, she was fascinated by so many things, including dinosaurs dreaming of taking her daughters on a dig lichen, and even life on Mars.

Angelika was brilliant; she illuminated science and scientists, says Frank Solomon, professor of biology and member of the Koch Institute. And she was intense; she warmed the people around her, and expanded what it means to be a friend.

Amon is survived by her husband Johannes Weis, and her daughters Theresa and Clara Weis, and her three siblings and their families.

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Angelika Amon, cell biologist who pioneered research on chromosome imbalance, dies at 53 - MIT News

The Alexander Grass Humanities Institute (AGHI), in conjunction with Great Talk, Inc., hosted a panel of scientists to speak about the ethical considerations and implications of stem cell research on Oct. 21.

The event was moderated by Director of AGHI William Egginton. The four panelists included two experts in genomics research, a journalist who specializes in the role of technology in biomedical research and an expert in medical law.

Dr. Anthony Wynshaw-Boris, chair of the Department of Genetics and Genome Sciences at Case Western Reserve University School of Medicine, discussed how cell lines were cultivated as tools in the past for scientists to use to grow cell cultures to study diseases or develop vaccines. However, there wasnt as much debate about the development of these tools in the past as there is now.

These are scientific tools that we use. The political and social aspects... are arising today because of our polarization, Wynshaw-Boris said.

The panel had an in-depth conversation regarding the ethics of the use of scientific tools such as stem cell lines derived from fetal tissue, embryonic cells, abortion-derived cell lines and cells acquired without consent.

Dr. Eric Green, director of the National Human Genome Research Institute at the National Institutes of Health, argued that the investment that has been made in these cell lines to calibrate them for use in biomedical research cannot be ignored.

Should there be a halt on the use of that mature tool because of its origins that were created in a time when there was a different view? Green asked.

Antonio Regalado, senior editor for biomedicine at MIT Technology Review who writes about the impact of technology on medicine and biomedical research, responded to Greens query.

Regalado brought up the fact that makeup companies have been facing a lot of backlash recently for testing their products on animals. Regalado pointed out that makeup companies could then use a similar argument by saying that since they have already invested money in animal testing procedures, they should not have to find new, less harmful methods of testing.

I don't know that we should rule out the possibility of alternatives if the scientific community decides to put their minds to it. Perhaps an equivalent cell line could be developed, Regalado said.

Diane Hoffman, director of the Law and Health Care Program at the University of Maryland Francis King Carey School of Law, described various perspectives in debate over the ethical concerns of stem cell research.

The challenge, according to Hoffman, is striking a balance between implementing a blanket policy through the government and informing consumers to allow them to make ethical decisions.

Industry wanting innovation, and government wanting safety and efficacy, and consumers wanting access. Those three things are... how we consider these ethical issues, Hoffmann said.

The conversation then shifted to eugenics, the practice of editing human DNA to achieve specific, desirable characteristics, such as eliminating diseases, changing eye color or editing IQ.

Green described an initiative funded by the Human Genome Project, the Ethical, Legal and Social Implications Research Program (ELSI), which focuses on the ethical, legal and social implications of biomedical research.

We can meld together what is scientifically possible to what is the body of evidence of what has come out when we have looked at these ELSI issues and then have conversations... and try to come to consensus on what the guardrails should look like, Green said.

Hoffmann echoed Green, describing the need of the scientific community to also consider allocation of these resources.

Weve got a ways to go in terms of thinking about... how we can be more just in our allocation of medical resources and the benefits of the research were doing, Hoffmann said.

She brought up the idea of giving priority in receiving benefits to vulnerable populations that have been previously harmed by the health-care system.

Wynshaw-Boris added that each study that is conducted needs to address the ELSI considerations mentioned by Green.

Studies have to be done... in partnership with diverse populations, and we have to be committed to that, Wynshaw-Boris said. We have to make progress on it all the time, and that's what we have to be committed to.

The discussion concluded with a consensus among the panelists that the scientific community needs to address social and health inequities as advancements in genetics and genomic techniques continue to occur.

We have to bring more trust to science than exists now, Green said.

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Panelists debate the implications and ethics of stem cell research - Johns Hopkins News-Letter

Newswise The inflammasomea protein signaling network that is activated to rid the body of virus or bacteria-infected cellsmay play an important role in triggering an immune response to cancer and causing an existing class of drugs to work better against cancers.

A collaborative research study led by experts at the Johns Hopkins Kimmel Cancer Center and University of Maryland Marlene and Stewart Greenebaum Cancer Center, supported by Stand Up To Cancer and the Adelson Medical Research Foundation, found that the inflammasome imparts a DNA repair defect-like state in cancer cells. In laboratory and animal models of ovarian and breast cancer cells, it induced an immune activating signal that directly made the cells susceptible to treatment with drugs called PARP inhibitors, drugs that disable the cancer cells ability to repair DNA damage caused by anticancer therapies. As a result, the cancer cell dies.

The findings published online May 26 in the Proceedings of the National Academy of Sciences, appear to apply across multiple tumor types and create the potential for a wider use of PARP inhibitors.

Newswise In laboratory models, the researchers used the epigenetic drug 5-azacytidine to induce transcriptional BRCAness in two-thirds and one-third of ovarian and triple negative breast cancer cell lines tested. These BRCAness data were correlated with inflammasome activation in two cell lines, which demonstrated the most marked induction of BRCAness, explains Michael Topper, Ph.D., co-corresponding author on the study, Evelyn Grollman Glick Scholar and instructor in oncology at the Johns Hopkins Kimmel Cancer Center. Epigenetics refers to chemical alterations to the DNA of cells that can change gene behavior without mutating the DNA. The drug 5-azacityidine is classified as a demethylating agent because it blocks a chemical process known as DNA methylation and can restore function to some cancer suppressor genes. Ongoing research also studies the ability of this drug, and other epigenetic drugs, to prime cancer cells for a better response to immunotherapies.

We believe we have uncovered a novel relationship in which the drug not only primes the immune response but also causes the breast and ovarian cancer cells to act as if they have a BRCA mutation. We think this reveals a new mechanism that has not previously been linked to immune therapy response, says Topper.

Turning the inflammasome on with epigenetic therapy, makes cancer cells targets of the immune system and responsive to drugs known as PARP inhibitors, the researchers say. Specifically, it makes tumor cells that do not have BRCA mutations act like they do, says Feyruz Rassool, Ph.D., the senior corresponding author, professor of radiation oncology and co-director of Experimental Therapeutics Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

BRCA mutations alter the bodys ability to repair DNA, putting those affected at higher risk of developing breast, ovarian, pancreas and other cancers. However, cancersparticularly breast and ovarian cancersthat contain BRCA mutations often respond to treatment with PARP inhibitors, which disable the cancer cells ability to repair damage caused by anticancer drugs and radiation therapy.

This mutation is present in only a small percentage of patients with breast and ovarian cancers, and this is the only setting where PARP inhibitors have demonstrable clinical efficacy, says co-author Stephen Baylin, M.D., Virginia and D.K. Ludwig Professor for Cancer Research.

Using 5-azacytidine to make cancer cells, which do not have BRCA mutations act like they have the mutationsa situation the researchers refer to as BRCAnesssensitizes cancer cells to treatment with PARP inhibitors and may expand the benefit of the drug to more patients.

The relationships between the inflammasome in the tumor cells and diminished ability of the cells to repair DNA damage may apply to multiple common tumor types, says Baylin. In data obtained from The Cancer Genome Atlas, Topper showed the possibility that activating the inflammasome with 5-azacytidine could produce BRCAness in many common tumor types. Treating with drugs like 5-azacytidine could extend treatment to patients with a broad range of cancers. A clinical trial combining an inhibitor of DNA methylation and a PARP inhibitor in patients with breast cancers, which do not have BRCA mutations, has begun through Stand up to Cancer.

The researchers also explain that a pathway called STING (stimulator of interferon genes) is a key regulator of the inflammasome. STING, shown to convert cold tumors, or tumors that do not attract the attention of the immune system, into hot tumors, ones that are most likely to respond to immunotherapies. STING causes CD8+ T cells to traffic to tumors and, in animal models, made breast cancer cells more responsive to immune checkpoint inhibitors.

In a surprising twist, the work of the investigators could potentially shed light on a severe and deadly inflammatory process, called cytokine storm syndrome (CSS), occurring in SARS-CoV-2 infection, the researchers say. They hypothesize that overactivation of the inflammasome may be a key regulator of CSS, the most severe complication of COVID-19 infection. Topper, Rassool and Baylin are collaborating with an international consortium called COV-IRT (COVID-19 International Research Team), aimed at using an open science model to rapidly advance COVID-19 research and therapies. They hope to use their inflammasome discovery to study and develop a serum test to predict early which patients will develop the most severe COVID-19 infections and to look for existing drugs that could inhibit the inflammasome and stop CSS.

In addition to Topper, Rassool and Baylin, other investigators participating in the research included Lena McLaughlin, Lora Stojanovic, Aksinija Kogan, Julia Rutherford, Eun Yong Choi, Ying Zou and Rena Lapidus, from University of Maryland, and Ray-Whay Chiu Yen, and Limin Xia from the Johns Hopkins Kimmel Cancer Center.

The research was funded by the Van Andel InstituteStand up to Cancer, the Adelson Medical Research Foundation, Evelyn Grollman Glick Scholar, The Hodson Trust, the Leukemia Lymphoma Society, the Maryland Cigarette Restitution Fund Program, the National Cancer InstituteCancer Center Support Grant P30 CA134274 University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, the Molecular Medicine Graduate Program, University of Maryland, the Biochemistry Graduate Program, University of Maryland and the Human Genetics Graduate Program, University of Maryland, the Commonwealth Foundation, the Defense Health Program through the Department of Defense Ovarian Cancer Research Program, and Teal Innovator Award OC130454/ W81XWH-14-1-0385.

Excerpt from:
Activating Inflammasome May Improve Cancer's Response To Immunotherapy And Parp Inhibitors - Newswise

More than a century ago, in 1910, President William Howard Taft made what then seemed a bold but reasonable prediction: Within five years, he said, cancer will have been removed from the list of fatal maladies.

So, what happened?

Despite what seem like endless decades of hope, exhaustive research and unyielding effort by the worlds smartest scientists, we still have yet to find a cure or long-term treatments for cancer. But finally, we appear to be edging closer to the finish line, and immunotherapy might prove key.

For decades, the cancer treatment of choice has been chemotherapy. But, while chemotherapy can be incredibly effective at treating cancer, it takes a steep toll on human body. The side-effects of most chemotherapy treatments can be quite severe, and while the end result does often get rid of malignant cells, it also destroys plenty of healthy cells in the process.

Cancer is immensely complicated. Its not just one disease it can actually take over a hundred forms, and attack different parts of our body. Whats worse, what starts as one disease can mutate into something entirely different. Many tumors also contain more than one type of cancer cell.

Another challenge of treating cancer lies in the fact that there are great differences in patients physiologies, lifestyles, attitudes towards treatment, responses to treatment, genetic makeup and even epigenetic factors.

Cancer is as individual as the person who has it, explainsJoyce Ohm, PhD, at the Department of Cancer Genetics and Genomics at Roswell Park Cancer Institute in Buffalo, New York.

Lets say there are identical twin sisters, both with breast cancer. They may have been born with exactly the same genetic mutations, but one responds to therapy and one doesnt. One may live and one may die.

Its exceptionally difficult to find something that will work on everyone. Immunotherapy seeks to resolve this issue by personalizing treatments for each patient.

Immunotherapy isnt a new treatment by any means; scientists have been researching it for many years, and theyve invested a lot of time creating the right procedures and improving chances for all cancer patients.

The talk of immunotherapy started way back in 1890s, when William Coley, a physician, started researching how our immune system responds to viral infections. He hypothesized that scientists could jumpstart our natural immune response to cancer by provoking it with a controlled virus infection. But for years, little practical progress was made, and immunotherapy was viewed as having limited potential.

As crude as this method sounds, its basics eventually led scientists to explore how our own immune system responds to cancer and what can be done to target it without damaging other somatic cells. It also works on many types of cancers, even some that do not respond to chemotherapy or radiation.

Although immunotherapy is not yet as widely used assurgery,chemotherapy, orradiation therapy, immunotherapy drugs have been approved to treat many types of cancer. The one the doctor decides to use depends on the type of cancer they are tackling.

The main aim of immunotherapy today is to help activate dormant T-cells and help the immune system better recognize cancerous cells and get rid of them safely. T-cell transfer therapy basically attempts to re-engineer our immune response. Its a complicated process but so far it has shown great success. Other cancer immunotherapy treatments include immune checkpoint inhibitors that block certain chemicals in our body from stopping immune response to cancer cells; the use of cytokines, laboratory-made versions of a type of natural protein that boosts our immune response; lab-made monoclonal antibodies that bind to specific targets on cancer cells; and treatment vaccines.

The key in developing immunotherapies is finding the right cancer targets. Chow Kwan Ting, a researcher from City University of Hong Kong (CityU), who has won the famous Croucher Innovation Award in recognition of her scientific achievements, focuses on the role of plasmacytoid dendritic cells (pDCs) in cancer treatment.

These cells havent been researched thoroughly before, but theyre known to play an important part of immune systems response to viral infections. Dr. Chows studies have shown that pDCs play a role in other types of infections as well, and that they could potentially do more than simply fight off an infection: they might actually play a role in cancer immunity.

Other scientists are advancing a range of promising immunotherapies that researchers hope will lead to breakthrough cures. A team of researchers at the German Cancer Research Center and the Berlin Institute of Health are targeting the metabolic enzyme IL4I1 (Interleukin-4-Induced-1). The survival probability of patients with gliomas, a type of malignant brain tumor, decreased when the enzyme was present in higher concentrations in these tumors.

In 2004, Sophie Lucas, a researcher at the University of Louvain de Duve Institute, began studying the blocking of immune defenses in tumors in order to understand the functioning of cells that are said to be immunosuppressive (they block the bodys immune responses). The goal was to identify and remove them, thus stimulating antibodies to act against the tumor.Last August, Nature Communications published the results of the first tests carried out by Dr. Lucas and her team on a tool using what are called anti-GARP antibodies that prevent the bodys natural immune response from being blocked. It worked on mice; human studies are next.

Of course, more research is needed to turn immunotherapy research into potential cures, but the very fact that scientists keep learning new things about cancer treatment is encouraging. Scientists are looking into liver and breast cancer as they are more prevalent in Hong Kong than other types of cancer.

Immunotherapy can sometimes have similar side-effects as chemotherapy, such as nausea, vomiting and hair loss, but they are usually less severe. It can also be used in combination with radiation therapy or surgery.

Along with gene therapy and tumor DNA sequencing, immunotherapy is providing new options and helping us edge closer to promises made more than a century ago.

Claire Adams is a content creator and external associate of the City University of Hong Kong. Her goal is to promote CityU young scholars research papers that are closely related to the healthcare industry. She wishes to emphasise the importance of the research paper on rare cells and the innovative immunotherapeutic strategy, which truly brings hope to new cancer immunotherapy and vaccine. By promoting this work among the scientific and healthcare community, Claire is hoping to raise awareness of the City University of Hong Kongs contribution to society. Follow her on Twitter@adamsnclaire

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How immunotherapy is revolutionizing cancer care - Genetic Literacy Project