Category Archives: Human Genetics

Cyclica harnesses AI and machine learning, along with a vast library of global human genome discovery, to model potential protein interactions and drastically speed up the drug discovery process.

Peter Power/The Globe and Mail

It can take, on average, more than a decade and about $1-billion for a new pharmaceutical drug to make its way from the lab to the prescription pad.

Just five in 5,000 drugs that enter preclinical testing advance to human clinical trials. From there, only about one in five of those drugs is approved for human use, according to a review by the California Biomedical Research Association.

There are many reasons why it takes so long and costs so much money, says Naheed Kurji, president and chief executive officer of Toronto-based Cyclica Inc., an artificial intelligence (AI)-driven biotech drug discovery platform. When you take a drug, and you place it into a complex biological system like a human or an animal, its interacting with upwards of 300 proteins. And those other proteins are not known, initially. Theyre oftentimes undesirable and they can lead to side effects.

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These side effects are one of the main reasons only one in 5,000 potential drugs ever makes it to a medicine cabinet.

Cyclica harnesses AI and machine learning, along with a vast library of global human genome discovery, to model potential protein interactions and drastically speed up the drug discovery process.

We are building the biotech pipeline of the future, Mr. Kurji says.

The seed of Cyclica was planted in 2011 at an MBA business case competition at the University of Torontos Rotman School of Management, presented by company co-founder Jason Mitakidis.

The proposal won the competition hands down, says Mr. Kurji, who was in the audience that day. Cyclica launched in 2013. Mr. Kurji joined shortly after as co-founder and chief financial officer and became president and CEO when Mr. Mitakidis left the company in 2016.

From humble beginnings in a basement office with a small team of co-op students, today Cyclica has more than 70 employees and advisers at its headquarters in Toronto, a team in the U.S. and another in the United Kingdom. The company has consultants all over the world and partnerships with biotech players in Brazil, Singapore, Korea, China, the U.S., Europe, the U.K., India and Australia, among others.

Disease is most often a malfunctioning of a biological protein in the human body. Computational techniques have been used for decades to pinpoint these biological drivers of disease, the malfunctioning proteins, and then find a molecular key that could be turned into medicine to address the malfunction. But those earlier efforts were limited.

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The techniques that they were using were too slow, they were too expensive and the quality of the predictions just were not that high, Mr. Kurji says.

Then three things happened that drastically changed the landscape, he says: First, the Human Genome Project produced reams of data on genetics and the genome. Second, the cloud made available unprecedented computational horsepower. And third, AI and machine learning began to take hold.

A field of about 15 companies in the space when Cyclica launched has grown to more than 400 worldwide today.

Cyclica has two platforms powered by the Google Cloud: Ligand Design and Ligand Express.

The underlying technology of these platforms is an AI-driven database of all publicly available known protein structures, as well as third-party proprietary data that Cyclica has acquired. Recently, the company integrated Google Deep Minds Alpha Fold 2 protein structure database, as well.

After pinpointing the malfunctioning protein that is the root cause of disease, the next step in drug development is to identify a molecule that will bind with that protein to address the malfunction.

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Cyclicas platforms can investigate molecules by matching them against all the proteins in the human body, explains Andreas Windemuth, the companys chief scientific officer.

Traditionally, this research takes a target-based approach, examining the molecule for the one function it is hoped to affect.

What our platform does is really provides a panoramic view of the molecule, he says.

Cyclicas database makes available approximately 85 per cent of the human proteome collection of all human proteins as well as other species.

Were sort of packaging all the knowledge about the drug-protein binding into our AI model and that can then be applied for discovering drugs, Dr. Windemuth says.

The AI system keeps getting better over time as more data are added, adds Stephen MacKinnon, Cyclicas vice-president of research and development, and it operates much faster than other forms of prediction.

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Thats what allows us to extrapolate those predictions to many, many more proteins not just predict for that one target protein in the tunnel, but for all the proteins in the cell, Dr. MacKinnon explains.

Cyclica co-founder and CEO Naheed Kurji in his home office in Toronto on Sept. 30.

Peter Power/The Globe and Mail

In short, Cyclicas Ai-driven platforms can test thousands of proteins and millions of molecules in a fraction of the time.

Dr. Windemuth says the hope is that by speeding up and streamlining the drug discovery process, development costs will decrease and, ultimately, the cost of drugs to consumers will go down as well.

Every month [in development] is worth many millions of dollars and the failure rate is enormous, he says. We can make it faster, and we can reduce the failure rate.

Cyclica has switched gears from its initial focus of licensing its technology to the pharmaceutical industry. The company now sometimes partners with early-stage biotech companies working on a specific disease, becoming investors and using their technology to advance drug development, or with academic groups looking to commercialize their research.

But the primary focus is their own drug discovery pipeline.

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We recognized that to capture the value that our platform was creating, we wouldnt do that through just revenue-generating deals with Big Pharma. We had to ideate, create and invent our own drug discovery pipeline, Mr. Kurji says.

The company recently collaborated with researchers at the university formerly known as Ryerson, the University of Toronto and the Vector Institute to explore existing drugs that might be repurposed to treat symptoms of COVID-19. The results, which identified a drug currently used to treat lung cancer, are currently being submitted for peer review.

Over the past three years, Cyclica has created about eight companies and has more than 80 programs in its portfolio. None is in the clinical phase yet, Mr. Kurji says.

Theres no AI and drug discovery company that has a drug that has gone through the clinical [phase] to market approval. Its still too soon, he says. In a space thats only eight years old but theres been a substantial amount of progress across the industry.

CDKL5 Deficiency Disorder (CDD) is a rare genetic condition that affects one in every 40,000 to 60,000 children born.

A genetic form of epilepsy, CDD affects mostly girls and it can have devastating symptoms that include the onset of severe seizures as early as a week after birth.

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It is honestly devastating for the child because it stops all the developmental process, says Cleber Trujillo, the lead senior neuroscientist at Stemonix, a subsidiary of Vyant Bio Inc., a biotech drug discovery company based in New Jersey. They can be really frequent, several times per day, these seizures.

The disorder is caused by a mutation in the CDKL5, or cyclin-dependent kinase-like 5, which is the gene responsible for creating a protein necessary for normal brain development and function. The exact reason for the mutation is unknown and there is no treatment or cure.

Cyclica and Vyant Bio recently announced a strategic collaboration to use Cyclicas AI-driven platform to identify potential pathways to the treatment of the disorder.

Vyant has exceptionally good models for the disease activity, Dr. MacKinnon says. And Cyclica has an AI-driven database of global human genome information that helps researchers such as Vyant Bio to identify and model potential target proteins that can be used to build a drug to treat the disorder.

This really exemplifies partnership, as the researchers coming to us have a good sense of the biology, have these good models for how a disease exists in a cell and we work together to come up with drugs or drug candidates, that will likely have these effects on the systems that theyre looking to achieve for therapeutic outcomes, Dr. MacKinnon says.

The aim is to find target molecules, Dr. Trujillo explains, and then search or screen for compounds that can interact with the target to improve the cells biology.

Cyclicas biotech pipeline means researchers dont start from scratch when looking for proteomes that could potentially work, he says.

Its really hard to find a drug from billions of different possibilities, Dr. Trujillo says. They can create a list that we think are the top candidates.

If we can, in collaboration [with Cyclica], narrow down and join efforts on the biology side or the modelling side, with their expertise, I feel that we can accelerate and make better models and find better compounds.

CDD is a rare disorder but one that is becoming more prevalent, owing largely to a better understanding of the disorder and better screening, he says.

The disorder significantly shortens the lives of sufferers, Dr. Trujillo says, whether from the disease itself or the severe seizures that can cause massive neurological damage.

Its devastating for the family and caregivers, also, he says.

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How this company is using data-driven drug discovery to fight disease - The Globe and Mail

image:A representation of cell diversity in the brain. Individual nuclei are colored in the bright hues of t-SNE plots used in epigenomics analysis to distinguish individual brain cell types. Layers of background color suggest extrinsic factors that influence cell function. view more

Credit: Michael Nunn, Salk Institute

LA JOLLA(October 6, 2021) It takes billions of cells to make a human brain, and scientists have long struggled to map this complex network of neurons. Now, dozens of research teams around the country, led in part by Salk scientists, have made inroads into creating an atlas of the mouse brain as a first step toward a human brain atlas.

The researchers, collaborating as part of the National Institute of Healths BRAIN Initiative Cell Census Network (BICCN), report the new data today in a special issue of the journal Nature. The results describe how different cell types are organized and connected throughout the mouse brain.

Our first goal is to use the mouse brain as a model to really understand the diversity of cells in the brain and how theyre regulated, says Salk Professor and Howard Hughes Medical Institute InvestigatorJoseph Ecker, co-director of the BICCN. Once weve established tools to do this, we can move to working on primate and human brains.

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is a large-scale effort that seeks to deepen understanding of the inner workings of the human mind and to improve how we treat, prevent and cure disorders of the brain. Since its initial funding in 2014, the BRAIN Initiative has awarded more than $1.8 billion in research awards.

The BICCN, one subset of the BRAIN Initiative, specifically focuses on creating brain atlases that describe the full plethora of cellsas characterized by many different techniquesin mammalian brains. Salk is one of three institutions that were given U19 awards to act as central players in generating data for the BICCN.

This is not just a phone book for the brain, says Margarita Behrens, a Salk associate research professor who helped lead the new BICCN papers. In the long run, to treat brain diseases, we need to be able to hone in on exactly which cell types are having trouble.

The special issue of Nature has 17 total BICCN articles, including five co-authored by Salk researchers that describe approaches to studying brain cells and new characterizations of subtypes of brain cells in mice. Some highlights include:

While other papers in the special issue relate to the function or structure of mouse brain cells, the work led by Ecker, Behrens and their colleagues largely focuses on the epigenomics of brain cells in mice. Every cell in a mouse brain contains the same sequence of DNA, but variations in how this DNA is regulatedits so-called epigenomegive cells their unique identity. The arrangement of methyl chemical groups on the cytosine base in DNA (known as cytosine methylation), which specifies when genes are to be turned on or off, are one form of epigenomic regulation that may highly influence disease and health in the brain.

In one of the new papers, the Salk team analyzed 103,982 mouse brain cells using single-cell DNA methylation sequencing. This approach, developed in the Ecker lab, lets researchers study the pattern of methyl chemical groups on each strand of DNA in brain cells.

When they applied the technique to the thousands of cells collected from 45 different regions of the mouse brain, they were able to identify 161 clusters of cell types, each distinguished by their pattern of methylation.

Before now, there have been a handful of ways to describe brain cells based on their location or their electrical activity, says Hanqing Liu, a graduate student in the Ecker lab and co-first author of the paper. Weve really extended the definition of cell type here and used epigenomics to define hundreds of potential cell types.

The team went on to show that the methylation patterns could be used to predict where in the brain any given cell came fromnot just within broad regions but down to specific layers of cells within a region. This means that eventually, drugs could be developed that act only on small groups of cells, by targeting their unique epigenomics.

In another paper, co-authored by Ecker and Salk Professor Edward Callaway, researchers studied the association between DNA methylation and neural connections. The team developed a new way of isolating cells that connect regions of the brain, then studying their methylation. They used the approach on 11,827 individual mouse neurons, all extending outward from the mouse cortex. The patterns of methylation in the cells, they discovered, correlated with cells projection (destination) patterns. Neurons that led from the motor cortex to the striatum, for instance, had distinct epigenomics from neurons that connected the primary visual cortex and the thalamus.

Neurons dont function in isolation, they function by communicating with each other, so understanding how these connections are established and how they work is really fundamental to understanding the brain, says Zhuzhu Zhang, a Salk postdoctoral fellow and a co-first author of the paper with graduate student Jingtian Zhou, both members of Eckers laboratory.

The researchers say that the new data on the mouse brain cells is merely the first step in creating a complete atlas of the mouse brainlet alone the human brain. But understanding what differentiates cell types is critical to future research and future brain therapeutics.

In these foundational studies, were describing the parts list for the brain, says Callaway. Having this parts list is revolutionary, and will open up a whole new set of opportunities for studying the brain.

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Hanqing Liu and Jingtian Zhou, both of Salk, were co-first authors on the DNA methylation atlas paper; Zhuzhu Zhang and Jingtian Zhou, also both of Salk, were co-first authors on the cortical projection paper. The methylation atlas work was supported by the National Institutes of Mental Health (U19MH11483), the National Human Genome Research Institute (R01HG010634) and the Howard Hughes Medical Institute. The cortical projection paper was supported by the National Institute of Mental Health (U19MH114831and R01MH063912), the National Eye Institute (R01EY022577 and F31 EY028853) and the Howard Hughes Medical Institute.

For More Information:

Nature

Title: DNA Methylation Atlas of the Mouse Brain at Single-Cell Resolution

Link: https://www.nature.com/articles/s41586-020-03182-8

Nature

Title: Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain

Link: https://www.nature.com/articles/s41586-021-03223-w

Nature

Title: A multimodal cell census and atlas of the mammalian primary motor cortex

Link: https://www.nature.com/articles/s41586-021-03950-0

About the Salk Institute for Biological Studies:

Every cure has a starting point. The Salk Institute embodies Jonas Salks mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimers, aging or diabetes, Salk is where cures begin. Learn more at: salk.edu.

Experimental study

Animals

6-Oct-2021

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Salk teams advance efforts to treat, prevent and cure brain disorders, via NIH brain atlas - EurekAlert

Genetic Variation Projects

Improved human knowledge of genetic variation is key to our understanding the causes of many diseases. The study of variation in the genome centered historically on PCR amplification of short genomic regions. More recently, new high-throughput technologies have made it viable to use whole genome sequencing for detection of variation.

There are a number of techniques used to select and amplify genomic regions of interest including whole genome or chromosome sampling by random shotgun sequencing, PCR amplification covering contiguous stretches of targeted genomic regions, PCR amplification of targeted gene coding regions and array-based hybridization to immobilized probes covering genomic regions, targeted exonic sequences or the entire exome. Each of these efforts has benefited from the close and historical affiliation with the Department of Molecular and Human Genetics (MHG), as well as other departments and institutions in the Texas Medical Center. The in-depth knowledge generated from these efforts is paving the way toward a new era of genetic research and the promise of genomically-driven personalized medicine.

The BCM-HGSC pioneered the concept of sequencing directed PCR amplification across the exons and splice junctions of potential disease genes. These techniques have been refined into a robust laboratory and informatics pipeline for Sanger sequencing of directed PCR (Medical Re-sequencing) The BCM-HGSC is currently investigating the replacement of PCR amplification with capture chip technology; sequencing for variant discovery is moving to second generation platforms such as Roche/454, AB SOLiD, and Illumina/Solexa.

As part of the 1000 Genomes Project, the BCM-HGSC is playing a defining role in Pilot 3, the targeted sequencing of more than 1000 genes across 1000 individuals. The Center has worked closely with Roche/Nimblegen to develop and design array-based capture chips targeting either the entire human exome or subsets of genes. These sub-regions of the genome are then eluted and used to construct Roche/454 sequencing libraries; sequencing libraries prepared for the other second generation platforms are under development.

The BCM-HGSC has pursued two paths for discovery of sequence and structural variants across defined regions of the human genome. As a part of the International HapMap Project, the BCM-HGSC generated sequence from a pool of 16 human DNAs to identify common single base variants that could then be used to generate subsequent deep genotyping across the initial four ethnic populations. A similar project was carried out using material from individual flow-sorted chromosomes. These data were used to develop our SNP computational identification methods.

The efficiency of this general approach led its application in other species. For example, within the bovine Hereford genome project, we have sampled more than 300,000 sequence reads from six additional bovine breeds. Using the methods that we developed in characterizing human data, we found an average of one SNP every 1.2kb with a remarkably high conversion rate of nearly 95% when tested independently. A similar approach in the honeybee genome project was used to generate variant data from a strain of Africanized bees. Ten thousand markers discovered there are now being used to map the genes responsible for traits associated with aggression.

The second path involved the generation of overlapping PCR amplicons across ten defined 500 kb regions (as defined by the first phase of the ENCODE project from 48 individuals to ascertain all variants across these intervals. This large project allowed the development of many of the protocols and informatics tools that we are using today.

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Human Genetics | BCM-HGSC

The department of Human Genetics considers its teaching responsibilities top priority. Good education in genetics is essential for medical students, medical specialists, general practitioners, and future scientists. We have a clear responsibility to society, as a personal DNA profile will become as ordinary as a determination of your hemoglobin levels. Since the interpretation of this huge amount of complex genetic data will ultimately be done by (medical) specialists and should be understandable for (family) doctors in primary care, our goal is to provide high-quality education of basic genetics for all healthcare professionals.

The department participates in the curricula of Medical Sciences, Biomedical Sciences,Biology, Dentistry, as well as in the Masters program Molecular Mechanisms of Disease. Specific courses that are organized include Medical Genomics, Human Genetics, Genomics and Statistics andGenetic and Metabolic Diseases. In total, more than 50 lecturers contribute their expertise to more than 25 courses, accentuating the central position that the field of genetics holds in life sciences.

For more information, you can contact dr. Arjan de Brouwer, teaching coordinator of the department of Human Genetics.

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Human Genetics - Radboudumc

DetailsLast Updated: Monday, 20 September 2021 09:52

The mission of the Department of Genetics is to promote excellence in education and research in the areas of model organism genetics, human genetics, computational genetics, bioinformatics, and genomics. The Department is situated on the Busch Campus of Rutgers University in Piscataway, NJ. There are more than 30 faculty members in the Department, with laboratories located in the Nelson Biological Laboratories, the Life Sciences Building, and the Waksman Institute.

The Department oversees an undergraduate major in genetics within the Division of Life Science (DLS) and the Schools of Arts and Sciences (SAS), and the Genetic Counseling Master's Program.

The Department is affiliated with the Human Genetics Institute of New Jersey (HGINJ), which houses core microscopy and imaging facilities and offers state-of-the-art custom genomic solutions through its association with Infinity BiologiX (IBX). IBX provides comprehensive services in bioprocessing, genomics, sample analytics and biostorage to the global scientific community.

Considering Med School or Dental School? Genetics is a great major for either career. The Rutgers HPO provides the recent admission statistics by department here.

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Welcome to the Department of Genetics

Sep 30, 2021 10:00 AM

A nationwide team of researchers, led by scientists at University of Utah Health and The Rockefeller University, has determined how a genetic mutation found in mice and monkeys interferes with viruses such as HIV and Ebola. They say the finding could eventually lead to the development of medical interventions in humans

The gene, called retroCHMP3, encodes an altered protein that disrupts the ability of certain viruses to exit an infected cell and prevents it from going on to infect other cells.

Normally, some viruses encase themselves in cell membranes and then make an exit by budding off from the host cell. RetroCHMP3 delays that process long enough that the virus can no longer escape.

This was an unexpected discovery, says Nels Elde, Ph.D., senior author of the study and an evolutionary geneticist in the Department of Human Genetics at U of U Health. We were surprised that slowing down our cell biology just a little bit throws virus replication off its game.

The study appears online Sept. 30 in advance of the Oct. 14 issue of Cell.

RetroCHMP3 originated as a duplicated copy of a gene called charged multivesicular body protein 3, or CHMP3. While some monkeys, mice, and other animals have retroCHMP3 or other variants, humans only have the original CHMP3.

In humans and other creatures, CHMP3 is well known for playing a key part of a role in cellular processes that are vital for maintaining cellular membrane integrity, intercellular signaling, and cell division.

HIV and certain other viruses hijack this pathway to bud off from the cellular membrane and infect other cells. Based on their research, Elde and his colleagues suspected that the duplications of CHMP3 they discovered in primates and mice blocked this from happening as protection against viruses like HIV and other viral diseases.

Building on this notion, Elde and other scientists began exploring whether variants of retroCHMP3 might work as an antiviral. In laboratory experiments conducted elsewhere, a shorter, altered version of human CHMP3 successfully prevented HIV from budding off cells. But there was a glitch: the modified protein also disrupted important cellular functions, causing the cells to die.

Unlike the other researchers, Elde and his colleagues at U of U Health had naturally occurring variants of CHMP3 from other animals in hand. So, working in collaboration with researchers Sanford Simon at The Rockefeller University, along with Phuong Tieu Schmitt and Anthony Schmitt at Pennsylvania State University, they tried a different approach.

Using genetic tools, they coaxed human cells to produce the version of retroCHMP3 found in squirrel monkeys. Then, they infected the cells with HIV and found that the virus had difficulty budding off from the cells, essentially stopping them in their tracks. And this occurred without disrupting metabolic signaling or related cellular functions that can cause cell death.

Were excited about the work because we showed some time ago that many different enveloped viruses use this pathway, called the ESCRT pathway, to escape cells, says Wes Sundquist, Ph.D., a co-corresponding author of the study and chair of the Department of Biochemistry at the University of Utah. We always thought that this might be a point at which cells could defend themselves against such viruses, but we didnt see how that could happen without interfering with other very important cellular functions.

From an evolutionary perspective, Elde believes this represents a new type of immunity that can arise quickly to protect against short-lived threats.

We thought the ESCRT pathway was an Achilles heel that viruses like HIV and Ebola could always exploit as they bud off and infect new cells, Elde says. RetroCHMP3 flipped the script, making the viruses vulnerable. Moving forward, we hope to learn from this lesson and use it to counter viral diseases.

More specifically, that lesson raises the possibility that an intervention that slows down the process may be inconsequential for the host, but provide us with a new anti-retroviral, says Sanford Simon, Ph.D, a study co-author and a professor of Cellular Biophysics at The Rockefeller University.

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In addition to Drs. Elde and Sundquist, University of Utah and University of Utah Health scientists Lara Rheinemann, Diane Miller Downhour, Gaelle Mercenne, Kristen Davenport, Christina Necessary, and John McCullough contributed to this study.

The study, RetroCHMP3 Blocks Budding of Enveloped Viruses Without Blocking Cytokinesis, appears in the October 14, 2021 issue of Cell. This research was supported by the National Institutes of Health, United States Department of Agriculture, the Burroughs Wellcome Fund, and a Pew Charitable Trusts Innovation Fund Award.

Research News Human Genetics Infectious Diseases HIV Ebola

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Gene Found in Monkeys and Mice Could Work as a New Type of Antiviral to Block HIV, Ebola, and Other Deadly Viruses in Humans - University of Utah...

DR. WALLACE: Im a 16-year-old girl and I met this guy online recently who I found interesting. He showed me a picture of himself and hes really cute. But my friends have been warning me that he might not be the guy in the picture. How can I be sure that its really him? He keeps telling me only the minimum about himself and wont tell me what school he goes to or what city he lives in. I dont get why hes so evasive about such basic questions.

Should I continue to trust him so that we can have a successful online friendship? To be even safer, I could make a promise to myself that Ill never go anywhere to meet him in person. What do you think? I find him interesting, via email

I FIND HIM INTERESTING: No matter how long you have been talking to this guy or how friendly he has been, he is still a stranger and, as you pointed out, he might very well not be the boy in the picture.

It can be extremely dangerous if you decide to continue to engage regularly with this person. This could be a 50-year-old man with untoward intentions for all you know.

I implore you to stop this communication immediately as nothing good will come from it, and there could well be many serious risks to your safety involved. Some warning signs from this guy have already been divulged, as youve outlined via his elusive communications.

Stop communicating with him immediately and focus your attention on boys who are definitely your own age at your school or in your social circles in the real world not the virtual one.

DR. WALLACE: Im 12 years old and I have red hair, brown eyes and pale skin with some freckles sprinkled all around. I am the only boy in our family and I have three older sisters.

Whats weird is that I dont look like any of my sisters or my parents at all! They all have blue eyes, blonde hair and olive-colored skin. Im convinced that at some point I was adopted, but I have no proof other than my looks. How can I find out where I really came from? Likely adopted, via email

LIKELY ADOPTED: Have you asked your parents if you were adopted? It would be acceptable for you to ask this question at an appropriate time when youre alone with them. But dont be surprised if youre not adopted.

Human genetics are set up so that recessive genes are involved, and certain individuals have traits that relatives and ancestors a few generations back may have had, too. Not everyone looks like their parents or siblings even though their DNA confirms the family connection to a 100% certainty.

Have you seen your birth certificate or asked to see a copy of it? Please start first with your parents to hear their full story about how you came into their lives. I trust they will be open and honest with you.

As you get older, you can also consider options that can help you verify your ancestry with a DNA test and various genealogy studies as well.

Dr. Robert Wallace welcomes questions from readers. Although he is unable to reply to all of them individually, he will answer as many as possible in this column. Email him at rwallace@thegreatestgift.com.

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Teen should stop online chat with new guy - Cumberland Times-News

Bringing science to the practice of psychiatry has been the personal goal of Sheldon H. Preskorn, MDthe Educator of the Year.

Psychiatric TimesTM was honored and delighted to present Sheldon H. Preskorn, MD, as Educator of the Year at this years Annual Psychiatric TimesTM World CME Conference. An academic psychiatrist, a researcher, an educator, and a mentorPreskorn is, as John J. Miller, MD, described a pioneer in the field of psychopharmacology.

Preskorn shared with attendees the unexpected beginning of his more than 40-years-and-running career in psychiatry. On his TV, he watched a video of Jose Delgado being able to stop a ball, charging in his tracks. To Preskorn, that meant that the brain was related to behaviorand he wanted to learn more.

Amongst his many honors and awards, Preskorn is known for spending the 1980s establishing the value of the therapeutic drug monitoring of tricyclic antidepressants and understanding toxicity. Additionally, in the 1990s, he helped explain the liver cytochrome P450 enzyme system.

My personal goal has been, and remains, bringing science to the practice of psychiatry, Preskorn shared.

During the session, he pointed out the overlap between diagnoses and science in signs and symptoms of borderline personality, bipolar disorder, major depression. He claimed it is not the symptoms that distinguish these disorders, but rather the stability of the symptoms themselves.1

Psychiatry has been mainly stuck at the level of syndromic diagnoses, but we are making inroads and have over the last 50 years into pathophysiology and etiology, he stated.

Additionally, Preskorn thinks of his therapeutic drug monitoring focus as toxicity-centric rather than efficacy-centric. The reason? We've had a better signal to noise ratio in trying to understand toxicity of the drugs and the avoidance of that than we did with antidepressant efficacy. As a matter of fact, in another article that I published, I showed that it's really almost impossible given the signal to noise problem in clinical trials of antidepressants to show any relationship between our blood levels and clinical benefit.

Preskorn also shared an equation of his creation. According to him, 3 variables determine clinical response: sites of action (affinity, intrinsic activity); drug concentration and its site(s) of action (absorption, distribution, metabolism, elimination); and underlying biology of the patient (genetics, age, disease, environment).2

We are born different, said Preskorn. Age, how we vary over our lifespan, disease (which is acquired through pathophysiological processes), and then the environment here referring to the internal environment. That is what underlies drug-drug interactions, where a drug enters the environment of the body and interacts with another drug, either pharmacodynamically, which is the first variable, or pharmacokinetically, which is the second variable in this equation.

Preskorn closed his speech, smiling, with a promise for the future: Its been a great pleasure for me to have shared these few minutes with you and to talk about the developments over the last 40 years. But as I would say: You aint seen nothing yet.

References

1. Preskorn SH, Baker B. The overlap of DSM-IV syndromes: potential implications for the practice of polypsychopharmacology, psychiatric drug development and the human genome project. J Psychiatr Pract. 2002;8(3):170-177.

2. Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors. Professional Communications, Inc; 1996.

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Pioneering Psychopharmacology: Educator of the Year Award - Psychiatric Times

By Allison Proffitt

September 28, 2021 | At the beginning of September, the National Institutes of Health launched the Impact of Genomic Variation on Function (IGVF) consortium, a new initiative of NIHs National Human Genome Research Institute (NHGRI). Now, NHGRI has named the first 25 awards across 30 U.S. research sites totaling approximately $185 million over five years.

Researchers have identified millions of human genomic variants that differ across the world, including thousands of disease-associated ones. The IGVF consortium plans to identify which variants in the genome are relevant for health and disease by integrating experimental methods with advanced computer models.

The programs goals are systematic perturbation of the genome to assess the impact of genomic variation on genome function and phenotype, high-resolution identification of where and when genes and regulatory elements function, advancement of network-level understanding of the influence of genetic variation and genome function on phenotype, development and testing of innovative predictive models of the impact of genomic variation on genome function, generation of a resource centered on a catalog of variant impacts and including data, tools, and models that will be shared with the broader research community, and enabling others to perform related studies using these approaches.

Biomedical researchers have recently made remarkable advances in the experimental and computational methods available for elucidating genome function, said Carolyn Hutter, Ph.D., director of the NHGRI Division of Genome Sciences, in a press release. The IGVF consortium will include world leaders in these areas, and together they will leverage these advances to tackle an incredibly challenging and important series of questions related to how genomic variation influences biological function.

The current IGVF consortium includes labs in five areas: Functional Characterization Centers, Regulatory Network Projects, Mapping Centers, Data and Administrative Coordinating Centers, and Predictive Modeling Projects.

The 30 U.S. sites that make up those areas include UC San Francisco; University of Washington; Stanford University; Dana-Farber Cancer Institute; University of Texas Southwestern Medical Center; University of North Carolina, Chapel Hill; Childrens Hospital Boston; Massachusetts General Hospital; Brigham and Womens Hospital; Duke University; Broad Institute; UC Irvine; California Institute of Technology; University of Michigan; Harvard School of Public Health; Northeastern University; University of Wisconsin; University of Massachusetts Medical School; University of Texas MD Anderson Cancer Center; University of Pennsylvania; University of Pittsburgh; Johns Hopkins University School of Medicine; Sloan Kettering Institute for Cancer Research; UC San Diego; UC Los Angeles; Yale University; Washington University, Saint Louis; and Northwestern University.

For the full breakdown of which groups are working in which areas, see the list online.

In an interview with ASHG News, Stephanie Morris, a Program Director in NHGRIs Division of Genome Sciences, outlined how the consortiums results will be integrated into healthcare and research going forward. Today, clinicians rely on statistical correlations that link genomic variation to disease, which have proven valuable. However, of the tens of thousands of disease-associated variants, researchers have only specifically identified a small number of these variants. The consortium will study and characterize thousands of genomic variants and determine which of these directly impact health and disease, which will greatly expand the evidence available to clinicians, Morris told ASHG News.

First Projects Kick Off

Some groups have already publicized their intended research projects. The University of California San Diego School of Medicine researchers will receive $6.4 million in grant funding to study how external signals and genetic variations influence the behavior of one cell type in particular: insulin-producing beta cells in the pancreas.

We plan to develop a roadmap of genetic variations, relevant in beta cells, to predict changes in insulin outputimportant information that may better enable us to prevent and treat diabetes, said team lead Maike Sander, MD, professor and director of the Pediatric Diabetes Research Center at UC San Diego School of Medicine, in a press release.

Washington University School of Medicine in St. Louis has received a $7 million grant as part of the consortium and will serve as the data and administrative coordinating center for the multicenter project.

All information generated by the consortium will be made freely available to the research community via a web portal that will be built from the WashU Epigenome Browser, a tool developed by Ting Wangs team that allows researchers around the world to search and browse genomic data. Because there are thousands of genomic variants associated with disease, and it is not possible to manipulate each variant individually and in each biological setting, consortium researchers also will develop computational modeling approaches to predict the impact of variants on genome function.

Duke University is the recipient of two grants totaling nearly $12 million as part of the consortium. An $8.6 million award will fund the Duke Characterization Center, led by Charlie Gersbach, Greg Crawford and Tim Reddy. The goal of the Duke IGVF Functional Characterization Center is to systematically perturb large numbers of regulatory elements and study their function across different biological contexts. Its a critical next step to more fully understand how the genome works, Crawford told Duke Cancer Institute News.

A second $3.2 million award will fund the Duke Predictive Modeling Center, led by Andrew Allen, David Page, and Sayan Mukherjee. They will take the raw data generated in the Functional Characterization Centers and transform it into consumable information that predicts the effect of variation on function. This work will be focused into three parts. First, they will simulate the data being developed in the Functional Characterization Centers and develop a simulation framework that can replicate the data. The team will also develop new graphical, model-based machine learning approaches that predict the functional effect of noncoding variation on function in diverse cell types. And finally, the team will use population genetics to look for genetic elements in the population that affect function.

Originally posted here:
NIH Distributes $185M for Impact of Genomic Variation on Function (IGVF) Consortium - Bio-IT World

Edinburgh and Cambridge, UK, 1 October 2021 - Macomics Ltd, an immuno-oncology company with world-leading expertise in macrophage biology, announces today that it has made five new appointments to its scientific team, to support and accelerate its R&D.

Moritz Haneklaus PhD joins as Senior Scientist, Carmen Rodriguez Seoane PhD as Scientist, with Chantell Payton PhD and Conor Poland PhD joining as Associate Scientists, and Sadie Kemp BSc as Senior Research Technician. Moritz will be based in Cambridge and will utilise his deep immunology expertise to support progression of the company's discovery portfolio and development of novel cell-based assays. He brings 10 years molecular immunology experience to the company with international experience gained in the UK, Ireland, Sweden and Germany.

Carmen, Conor, and Sadie will be based at Macomics Edinburgh site and Chantell at the Cambridge site. Together they bring over 40 years combined research experience to the company, with specialisms including complex cellular models, cellular and molecular biology, functional genomics, and cancer biomarker discovery.

This expansion follows Macomics follow-on financing of 4.24 million announced in July. It is developing precision medicines to modulate macrophages for the treatment of cancer. The company is progressing a diversified portfolio of therapies targeting disease specific tumour associated macrophages (TAMs) towards the clinic. Its target discovery platform enables identification and validation of novel macrophage therapeutic targets and is based on its deep understanding of macrophage biology.

Commenting on the expansion Dr Luca Cassetta, VP Immunology and co-founder who joined the company full time from his academic role said:

I welcome our new colleagues to the team. Each brings valuable experience as we progress our early-stage antibody programs towards the clinic, expand our portfolio and further invest in our target discovery technology.

Macomics now employs 13 across its sites on the Cambridge Science Park and within Edinburgh University and will expand further in the coming months.

Dr Steve Myatt, CEO of Macomics added:

Our vision is to become a leading immuno-oncology company pioneering macrophage-based therapies for the treatment of cancer. These new appointments reflect our strategy to build a world-class team across all functions and support us in the delivery of this vision.

-Ends-

About Macomics http://www.macomics.com

Macomics Ltd is an immuno-oncology company with world-leading expertise in macrophage biology, developing precision medicines to modulate macrophages for the treatment of cancer. The company is progressing a diversified portfolio of therapies targeting disease specific tumour associated macrophages (TAMs) towards the clinic. Its target discovery platform enables identification and validation of novel macrophage therapeutic targets and is based on its deep understanding of macrophage biology.

Macomics was co-founded in 2019 by Prof. Jeffrey Pollard and Dr. Luca Cassetta, University of Edinburgh, internationally recognised leaders in macrophage biology. It has R&D and office facilities in Edinburgh and Cambridge, UK and is backed by Epidarex Capital, Scottish Enterprise, and Caribou Property Limited.

Follow us on LinkedIn and https://twitter.com/MacomicsL

About the new appointments

Moritz Haneklaus, PhD - Senior Scientist

Moritz is a molecular immunologist with over 10 years experience studying human myeloid biology. He has extensive expertise in applying molecular techniques and genomics to complex immunological questions.

He joins from an academic career, most recently as a Research Fellow at the Institute of Child Health, University College London studying brain tumour single cell analysis. Prior to that he was a Postdoctoral Fellow at the Wellcome Sanger Institute, Cambridge as part of the Open Targets consortium as investigating neuroinflammation in the context of Alzheimers disease.

Moritz obtained his PhD in Immunology at Trinity College Dublin studying inflammatory signalling in macrophages. He has a MSc in BioMedicine from the Karolinska Institute, Stockholm, Sweden and a BSc in Biology from University of Heidelberg, Germany.

Carmen Rodriguez-Seoane, PhD Scientist

Carmen has over 10 years of research experience with expertise in the use of human and embryonic/induced pluripotent stem cell models and a wide range of molecular biology techniques.

Carmen joins from the University of Edinburgh where she was a post-doctoral Research Fellow at the Centre for Inflammation Research, having started as a Research Assistant. She moved to the UK after obtaining her PhD from the Brain Protein Malfunction Lab at the Universidade de Santiago de Compostela, Spain. She has a M.Sc. in Biomedical Research and a B.Sc. in Biology.

Chantell Payton, PhD - Associate Scientist

Chantell has extensive experience in tissue culture, cell line development and characterisation, confocal microscopy, and in vitro assay development.

Chantell joins Macomics from the world-leading Roslin Institute at the University of Edinburgh, where she undertook a PhD investigating the acquisition and potential biomarkers of cancer chemotherapy and radiotherapy resistance. She has a BSc (Hons) from the University of Lincoln where she undertook several research placements investigating protein expression in several cancer signalling pathways

Conor Poland, PhD - Associate Scientist

Conor has experience in academic and industrial settings. He is a cell biologist experienced in working with induced pluripotent stem cells, immortalised cells, primary cell cultures and fibroblasts from human skin samples.

He joins from Cignpost Diagnostics, a private Covid testing facility, where he established and ran its qPCR laboratories for COVID-19 testing during the recent pandemic. Prior to this he completed his PhD at the University of Dundee at the Jacqui Wood Cancer centre, where he gained extensive experience with induced pluripotent stem cells and CRISPR-Cas9 gene editing among other molecular techniques. Prior to this he gained experience at Wellcome Trust Centre for Human Genetics, Oxford and in the microbiology lab at Geneius Lab Ltd. He has a BSc (Hons) Human Genetics from Newcastle University.

Sadie Kemp - Senior Research Technician

Sadie brings over 15 years of experience, gained in both commercial and academic laboratories. With a background in cell culture and cell infection assays, her expertise includes confocal microscopy, immunohistochemistry, ELISA and molecular biology techniques.

Sadie joins from seven years at Napier University where she held technical roles of increasing responsibility. Prior to that gained significant experience at the University of Edinburgh and Moredun Scientific. During these roles she has contributed to projects across a range of therapeutic areas including immunology, bacteriology and cancer.

She has a BSC (Hons) in Natural Sciences from the Open University and is an Associate Fellow of the Higher Education Academy.

Media enquiries (for Macomics)

Sue Charles, Charles Consultants

T: +44 (0)7968 726585

E: sue@charles-consultants.com

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Macomics Announces New Hires that Expands its Macrophage-based Drug Discovery R&D Team - BioSpace