Daily Archives: October 7, 2021

The first look at a threatened rattlesnake species recent genetic history suggests that inbreeding necessitated by limited habitat may not be as detrimental as theory would predict it to be.

In fact, scientists speculate that Eastern massasauga rattlesnakes may have pre-adapted to living in small, isolated populations where the most dangerous genetic mutations that arose could be easily exposed and purged.

Researchers sequenced the genomes of 90 Eastern massasauga rattlesnakes, which were listed as threatened under the Endangered Species Act in 2016 because of loss and fragmentation of their wetland habitat. For comparison, the researchers also sequenced 10 genomes of a close relative, the Western massasauga rattlesnake, a common species with no limitations on breeding opportunities and large populations.

The Ohio State University team found that the most potentially damaging gene mutations were less abundant in the Eastern than the Western species. This finding suggests the breeding limitations of small, isolated populations might be accompanied by an evolutionary advantage of being able to elbow out genetic variants that get in the way of survival, saidH. Lisle Gibbs, professor of evolution, ecology and organismal biology at Ohio State and senior author of the study.

This is something that has been reported very recently in other endangered species, but its the first time its been shown in a reptile, Gibbs said. We always worry about genetics and the loss of variation and what it means to be in a small population in which theres lots of inbreeding. At least in this species, maybe its not such a big deal.

From a conservation perspective, perhaps we can downplay genetics and say ecology such as habitat restoration is more important.

Gibbs completed the study with Alexander Ochoa, a former postdoctoral researcher at Ohio State who is now a postdoctoral scholar at the University of Central Florida. The research is published in the journal Molecular Ecology.

Eastern massasauga rattlesnakes live in isolated spaces in midwestern and eastern North America, and evolutionary theory posits that the inevitable inbreeding in such populations threatens species with extinction as genetic mutations accumulate. The smallest populations might reach 30 snakes, but Ohios Killdeer Plains Wildlife Area is home to one of the most genetically diverse and largest populations in the country, numbering in the thousands.

Gibbs has studied Eastern massasaugas for over two decades and, as director of the Ohio Biodiversity Conservation Partnership, advises the Ohio Department of Natural Resources on management of the species.

Through years and years of study, we know that most populations are isolated, like little natural zoos scattered throughout the landscape, Gibbs said. Due to habitat degradation, weve known they show little variation but weve never actually looked at variation in genes that code for things that matter to a rattlesnake.

Only recently has it been possible to apply the research techniques perfected with the human genome to work with this species. Gibbs and Ochoa zeroed in on identifying mutations in genes that may affect survival and reproduction to gauge how hazardous inbreeding might be to Eastern massasaugas.

Though a higher overall number of potentially deleterious mutations were found in the common Western massasaugas, that didnt translate to more threats to their survival because most troublesome gene copies were offset by protective copies. That can happen only in heterozygotes, which have two different copies, or alleles, of a particular gene one inherited from each parent. Because of generations of inbreeding, Eastern massasaugas are much more likely to have two copies of the same allele.

Thats why inbreeding has impacts because thats when you get two bad alleles showing up together, with no good allele to compensate, so there is a negative effect, Gibbs said. Theres more inbreeding, so overall you get more mostly bad mutations together, but the really bad ones, because theyre exposed, are also eliminated at a much greater rate.

Through another analytical technique comparing the narrowing of the Eastern and Western massasauga genetic makeup over several hundred years, Gibbs and Ochoa confirmed the impact human activity has had on the Eastern massasaugas swampy habitat. Unlike the Eastern species, Western massasaugas live in grassy and woodland regions of the south-central United States that are less densely populated by humans.

We looked at what has happened in these snakes and their population sizes over the last 300 years, which is when humans have been tromping all over North America, impacting the landscape, Gibbs said. The impacts in terms of reducing population sizes are greater in Eastern than in Western massasaugas over this period.

The findings could influence management decisions. A common conservation practice would involve introducing snakes from a more genetically diverse population into a highly isolated group to counter the effects of inbreeding. But it turns out the Eastern massasauga might benefit more from preservation of its habitat while the genetics takes care of itself.

This counterintuitive result makes us rethink what living in a small population is, and whether genetic problems are as important as we think they are, Gibbs said. This is certainly not to say living in a small population isnt bad it just may be that the genetic effects are not as bad as we thought.

This work was supported by the State Wildlife Grants Program administered jointly by the U.S. Fish and Wildlife Service and the Ohio Division of Wildlife, with funds provided by the Ohio Biodiversity Conservation Partnership between Ohio State and the Ohio Division of Wildlife, as well as the National Science Foundation.

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Threatened rattlesnakes' inbreeding makes species more resistant to bad mutations - The Ohio State University News

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Experts in movement disorders highlighted advances in the field from 20 years ago to now, including improvements in deep brain stimulation, earlier treatment with levodopa, and a focus on nonmotor symptoms.

While neurologists still hope for elusive cures for movement disorders, they appreciate the major scientific advances that have led to a greater understanding and management of Parkinson's disease (PD), dystonia, and essential tremor.

Deep brain stimulation (DBS) is a major case in point. When DBS first received approval from the Food and Drug Administration in 1997, it was indicated for stimulating the ventral intermediate nucleus of the thalamus to treat tremor resulting from PD or essential tremor. In 2002, the FDA approved DBS of the subthalamic nucleus or internal portion of the globus pallidus internus to treat PD symptoms that were no longer adequately controlled with medications. The following year, DBS was approved for dystonia.

As a result, many clinicians and patients held it out as a last resort, said David Charles, MD, FAAN, a DBS researcher who is professor and vice chair of neurology at Vanderbilt University Medical Center in Nashville.

Then a European study became the catalyst for a paradigm shift in the United States when the FDA approved DBS in 2016 for mid-stage PD. The approval paved the way for the use of DBS as adjunct therapy when disease duration is at least four years and motor complications persist for four months or longer. Dr. Charles hailed that development as one of the biggest advances in DBS.

A number of studies have demonstrated that DBS often continues to be effective over the long haul. The data are very clear that DBS plus medicine is superior to medicine alone in controlling symptoms and improving quality of life in mid- and advanced-stage disease, he said. Furthermore, providing the therapy in mid-stage means that the person with Parkinson's gets many years of benefit.

DBS implantation techniques have become more targeted, greatly reducing the incidence of complications. It's actually safer to do the operation on people with mid-stage disease, because they are often younger and have fewer comorbidities, Dr. Charles said, explaining that the older the patient is, the higher the risk of an adverse event occurring.

The selection of DBS equipment also has expanded. Initially, only one manufacturer produced equipment approved for use in the United States, he said. Now, three companies are vying for market share.

The technology has also improved from the standpoint that electrodes, or leads, implanted in a patient's brain will now allow the physician to steer the current, Dr. Charles told Neurology Today. By directing the energy more precisely toward the optimal location in the brain, the physician can decrease the possibility of side effects. In addition, one of the devices can be programmed and adjusted remotely via telehealth.

While DBS remains an invasive procedure and the risks are never nil, it can be extremely effective, said Michele Tagliati, MD, FAAN, professor and vice chairman of neurology and director of the movement disorders division at Cedars-Sinai Medical Center in Los Angeles.

Dr. Tagliati noted that the last 20 years have seen the explosion, for lack of a better term, of deep brain stimulation for movement disorders. FDA approval for PD came again in 2002 and in 2003 for dystonia, following the approval for essential tremor in 1997.

With properly selected patients and in good handsin terms of surgery and programming the deviceDBS can be life-changing in advanced Parkinson's, untreatable dystonia, and medication-refractory essential tremor, he said, adding that the incidence of complications is much lower under a seasoned surgeon's wing.

Recent progress in human genetics also has led to significant strides in the understanding of PD and related disorders. For instance, in the last two decades, scientists have discovered many more contributing genes. Mutations in the glucocerebrosidase gene, which encodes the lysosomal enzyme that is impaired in Gaucher's disease, are relatively common risk factors for movement disorders.

Although genetic cause is thought to be a small proportion of Parkinson's, this is an important discovery for therapeutics, said Cheryl H. Waters, MD, FAAN, FRCPC, the Albert and Judith Glickman Professor of Neurology in the division of movement disorders at Columbia University Medical Center in New York. Identifying the genes helps establish new drug targets that may help some, if not, all patients.

During this time framein the early 2000sanother discovery led to an association between PD and mutations in the leucine-rich repeat kinase-2 gene.

One of the big changes in the last 20 years, from my perspective, is the recognition of genetic mutations that can increase risk of Parkinson's, said Andrew S. Feigin, MD, professor of neurology at NYU Langone Health and director of the Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders.

This holds a lot of promise, Dr. Feigin said. Future clinical trials will likely target therapies at mechanisms related to these genetic mutations.

More recently, deep phenotypingthe use of big data to arrive at full clinical and biomarker characterizationis a strategy that has the potential to change the prognostic landscape for movement disorders, said Christopher G. Goetz, MD, FAAN, professor of neurological sciences and pharmacology at Rush University Medical Center in Chicago.

To this end, neurologists are playing a pivotal role in the epidemiological research arena by collecting repositories on patients, documenting behaviors such as hallucinations and dyskinesias, duration of their PD since onset, and the presence or absence of a genetic link to their disorder. The repositories could be useful to compare patients with similar profiles miles apart, even in different countries, said Dr. Goetz, a senior neurologist in the movement disorders program at Rush.

In the past, when we were trying to understand how a patient would respond or have a prognosis, we looked at the meanthe averageresponse across the population, and now we are thinking that's not the strategy, he said. Instead, we should be phenotypingdeeply understanding each patient's profile.

The idea that we could learn from all the big data of an individual essentially represents a whole new way of thinking, Dr. Goetz added. In advancing this notion a step further, he suggested that theoretically, we could predict also who would respond better to a given medication. It's a new concept that we didn't have 20 years ago.

On the medication front, neurologists have come to a consensus that they should consider prescribing levodopa sooner rather than later. There has been a significant change in Parkinson's disease management, with the pendulum swinging towards more use of levodopa and less use of dopamine agonists, even early in the disease, said Melissa J. Nirenberg, MD, PhD, FAAN, professor of neurology at the Icahn School of Medicine at Mount Sinai in New York.

We have learned that dopamine agonists can cause impulse control disorders, Dr. Nirenberg added, noting that some patients may develop severe withdrawal symptoms. Known as dopamine agonist withdrawal syndrome, this complication can make it difficult to taper treatment.

Neurologists previously were reluctant to use levodopa early in PD due to unfounded fears that it might be toxic to the brain or worsen long-term outcomes. It is now clear that levodopa is not neurotoxic and does not worsen outcomes, said Dr. Nirenberg, a member of Neurology Today's editorial board. Levodopa is the most effective treatment for Parkinson's disease, and it should be used as needed to treat symptoms.

Dr. Waters agreed with that assessment, stating that whereas 20 years ago we might have used dopamine agonists, we now recognize a high risk of impulsive and compulsive behaviors with dopamine agonists, she said. So, we do not delay levodopa, as it was shown not to cause the disease to progress more rapidly or lose its efficacy over time.

Many adjunctive agents, such as infusion and rescue therapy, have been helpful as complements to levodopa therapy. Rescue therapies, which can reduce the burden of the off experience for patients, include injections of apomorphine, sublingual apomorphine, and inhaled levodopa, she added.

Dr. Waters pointed out, too, that there are now three vesicular monoamine transporter type 2 inhibitors for the treatment of tardive dyskinesia and possibly the tics associated with Tourette syndrome. Side effects include drug-induced or secondary parkinsonism and depression. Not all have been approved for these indications in the United States.

Another major change in our understanding and treatment of Parkinson's disease has been the increased recognition of nonmotor symptoms, Dr. Nirenberg said, citing the need to diagnose and treat these symptoms. This is a very active area of study and very important in the clinic, she said.

These concerning signs run the gamut from sleep disorders to cognitive decline, depression, urinary problems and constipation, as well as hallucinations, anxiety, depression, orthostatic hypotension, or a combination of such disturbances, neurologists noted.

Rapid eye movement sleep behavior disorder is one of the most indicative nonmotor manifestations of PD and can be particularly disruptive, Dr. Feigin said, because patients may end up punching their bed partner, falling on the floor, or even sleepwalking as they literally act out their dreams.

Neurologists interviewed for the article highlighted orthostatic hypotension as yet another nonmotor symptom of PD. However, they noted, more treatments are also more available for various nonmotor complications than there were 20 years ago, as is the case with the impact of depression on PD. This increasing awareness has led to better management of depression, including more frequent use of antidepressants, helping patients feel and function better, they said.

Neurologists also have become more adept at differentiating typical PD from atypical forms of the disorder, such as multiple system atrophy and progressive supranuclear palsy. Clinical characteristics complemented by magnetic resonance imaging can make a significant difference in these assessments, allowing clinicians to determine the treatment course, progression, and prognosis, Dr. Waters said.

Advancing technology has brought other benefits as well. Applications catering to remote office visits have been useful for monitoring patients and for engaging them in physical activities, particularly during the pandemic, she said, adding that the only thing that we've learned for certain to protect [against the progression of] Parkinson's is exercise.

Dr. Feigin concurred that there has been more widespread use of nonmedical interventions to improve the quality of life for patients with PD. Among the plethora of options are physical therapy, boxing programs, and dance and art initiatives. While they may not slow disease progression, these approaches have been helpful to people, he said. And there is some evidence that these types of therapies may improve long-term functioning and general well-being.

The importance of multifaceted care cannot be understated. In one day, Dr. Tagliati noted, patients with movement disorders can consult with several specialists under one rooffor instance, a neurologist, neurosurgeon, psychologist, and physical therapist. The convenience represents an evolution toward multidisciplinary care clinics in premier academic medical centers that serve as a one-stop shop for meeting patients' multiple needs.

Patients love this opportunity to share their different problems with different specialists in one single day, in one single morning, Dr. Tagliati said. That's one of the trends he has observed in his specialty when he compares it with two decades ago. The changes are particularly notable for PD, which he calls the bread and butter of movement disorders due to its frequency.

Training of neurology residents and fellowship trainees has adapted to these myriad changes. Residents are taught to identify various movement disorders, while fellows learn much more than previous cohorts of trainees, Dr. Waters said.

Fellows must recognize all the illnesses within the subspecialty, determine when to order genetic testing, and how to perform botulinum toxin injections and conduct DBS programming. They also need to be well-versed in all the different medications and know how to interpret imaging studies. In addition, she said, they may become involved in administering advanced treatments such as intestinal gel or subcutaneous infusions or rescue therapies.

Patients are also better educated and now seek input from neurologists at earlier stages of their disease trajectory than they did 20 years ago. This affords neurologists the opportunity to treat them with lower doses of medications, reducing the rate of side effects, said Dr. Goetz.

But at times, it is still disconcerting that curative treatments haven't emerged. Our disappointment is that we don't know precisely what causes Parkinson's, and multiple clinical trials for neuroprotection have failed, Dr. Waters said, adding that we have failed in finding treatments for freezing of gait, dementia, and fatigue.

Dr. Nirenberg remains enthusiastic about active clinical trials investigating drugs that specifically target genetic subtypes. She is also excited about the study of biomarkers, including blood, tissue, and spinal fluid markers and imaging studies that can facilitate early diagnosis and make a difference in bringing about breakthrough discoveries.

The holy grail is to find disease-modifying treatment for Parkinson's, she said. I hope that we will be able to offer patients such treatments way before the next anniversary issue [of Neurology Today]. That's what we're working on right now.

Dr. Goetz's contends that the inevitably progressive nature of neurodegenerative diseases doesn't mean the field of movement disorders isn't brimming with optimism. In addition to his interest in deep phenotyping, he said alpha-synuclein, which damages the dopamine cell, could be a target for antibody therapy in the future.

Especially in the context of the COVID era, we're excited about the prospects, he said. Could we develop a vaccine against the abnormal synuclein, just like the way we did with the vaccine against a virus?

Another scientific area of possibilities stems from research into gut bacteria and their impact on the brain, suggesting that dietary changes could have a positive effect on patients with movement disorders.

We all wish that we could have cracked the disease in these past 20 years and that we found the single chemical equation for the causation of the diseasethe very first chemical reaction that takes a normal dopamine cell and starts to make it into a pathologic cell, Dr. Goetz said. We have failed to crack that today, but that doesn't mean that we won't crack it tomorrow.

Until then, if you can change a patient's quality of life, you have changed him and his family, and that is an enormous scientific contribution.

Rush University Medical has received funding for research by Dr. Goetz from the NIH, Department of Defense, and Michael J. Fox Foundation. Dr. Goetz has received a faculty stipend from the International Parkinson and Movement Disorder Society; guest professorship honorarium provided by the University of Chicago and Illinois State Neurological Society, a volume editor stipend from Elsevier Publishers, and royalties from Elsevier and Wolters Kluwer. Dr. Waters received research support from Neuraly, Biogen, Roche, and Sanofi; consulting fees from Kyowa, Sunovion, and Acadia; and speakers' honoraria from Adamas, Amneal, Kyowa, Neurocrine, and Acorda. Dr. Feigin has received honorarium from Kyowa-Kirin. Dr. Charles has received education grants paid to Vanderbilt from Aeon, Abbott, AbbVie, Boston Scientific, Impax, Intec, Ipsen, Lundbeck, Medtronic, Merz, Novartis, Pharma Two B, Supernus. He has received consulting fees from Merz, Supernus, Alliance for Patient Access, Newronika, Revance, and is a nonpaid member of the data safety and monitoring board for the trial, STN DBS in PD Sleep Dysfunction.

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Then and Now: 20 Years of Monumental Strides in Movement... : Neurology Today - LWW Journals

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

See the rest here:
Salk teams advance efforts to treat, prevent and cure brain disorders, via NIH brain atlas - EurekAlert