Category Archives: Transhuman News

Drew Endy, PhD, a Stanford bioengineer, is the kind of brilliant that makes your head spin. His ideas come at a mile a minute, each one a potential mini revolution of standard biology, and his excitement for his work is palpable. But, to me, the best part about Endy is his drive to see a mega-mission through: to use bioengineering to change the world for the better, making contentious efforts to innovate with an eye toward solving social, humanitarian and environmental challenges.

In one of my latest Stanford Medicine magazine stories, "How synthetic biology could save us," I speak to Endy about his lofty vision and the research he's conducting to see it through.

If you ask Endy, synthetic biology is a field that aims to "make the making of things" easier. It's a type of science that expands beyond the natural world, creating tools and techniques to support the development of new biology-based innovations -- like new forms of medicine, or an altered crop that can fight pests on its own.

"We tend to think of biology as something that happens to us," Endy said in the story. "But more and more, we are happening to biology. We're in an era, scientifically, where we can express our intentions into the very kernel of life to allow for possibilities that are simply never going to exist otherwise."

One of Endy's big projects is something he calls "the cleanome," a concept rooted in genetics, but with a twist: In a cleanome, all of an organism's non-crucial genetic elements are removed. (Every living thing contains fundamental genes that support its life, in addition to stretches of DNA that are, essentially, garbage.) The goal is to remove genetic fluff, leaving only the core components that allow an organism to survive.

As Endy said in the story:

If you want to build an organism, you want to definitively know what you're working with, and right now part of what bioengineers are working with is ambiguity."

What bioengineering really needs, according to Endy, is certainty as to which genes are needed for a particular organism to survive along with what each gene is doing. ... Establishing a cleanome for key organisms would allow bioengineers to build and create with more certainty and safety, he said.

Endy and the researchers in his lab have other big ideas percolating too, one of which he's dubbed a "fail-safe" -- basically a built-in self destruct button for an engineered organism. Say, for instance, a scientist creates a type of cancer-fighting cell that runs around the body and gobbles up tumor cells. If that cell started to evolve new cell-gobbling abilities, that would be dangerous. A fail-safe construct built into the cell would notice such a change and kill the rogue cell before it kills its healthy neighbors.

During our interviews, I reflected on the enormity of his proposal: A civilization that not only coexists with bioengineering but also depends on it, harnesses it, continually develops it -- even loves it.

"You'd almost have to be some sort of benevolent dictator to truly see it through," I'd joked to him. He sees it a little differently. "Perhaps more like reluctant philosopher king."

Image by David Plunkert

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Saving the world with synthetic biology - Scope - Scope

PARIS--(BUSINESS WIRE)--Regulatory News:

GenSight Biologics (Euronext: SIGHT, ISIN: FR0013183985, PEA-PME eligible), a biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders, today announced that clinical data of LUMEVOQ and GS030 gene therapies will be presented at the 125th Annual Meeting of the American Academy of Ophthalmology (AAO) in New Orleans, Louisiana (November 12-15, 2021).

Retina Subspecialty Day @ American Academy of Ophthalmology (AAO)November 12, 2021Morial Convention Center, New Orleans

Jos-Alain Sahel, MD, Co-founder of GenSight Biologics and of the Institut de la Vision (Sorbonne-Universit/Inserm/CNRS), Paris, France, and Distinguished Professor and Chairman of the Department of Ophthalmology at University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, will discuss the reported signs of efficacy from a second patient affected by Retinitis Pigmentosa and treated with GS030 in the Phase I/IIa trial PIONEER. A first case report was published in Nature Medicine in May 2021.

Optogenetics in the Clinic: Safety and Efficacy Updates on the Phase I/II Clinical Trial PIONEER

American Academy of Ophthalmology (AAO)November 12-15, 2021Morial Convention Center, New Orleans

Nancy J. Newman, MD, LeoDelle Jolley Professor of Ophthalmology and Neurology at the Emory University School of Medicine in Atlanta, GA, USA, and the International Coordinating Investigator of the REFLECT Phase III trial of LUMEVOQ, will discuss the findings from the REFLECT trial in the context of Leber Hereditary Optic Neuropathy (LHON) natural history and the two other clinical trials RESCUE and REVERSE.

The Phase 3 REFLECT Trial: Efficacy and Safety of Bilateral Gene Therapy for LHON

Sean P. Donahue, MD, PhD, Coleman Professor and Vice Chair for Clinical Affairs, and Chief, Pediatric Ophthalmology Department at the Vanderbilt Childrens Hospital in Nashville, TN, USA, and an International Principal Investigator in the REFLECT Phase III trial of LUMEVOQ, will discuss the findings from 6 patients affected by ND4 LHON and bilaterally treated with LUMEVOQ in an FDA-approved compassionate use protocol.

Initial Results From Bilateral Gene Therapy for LHON 11778 Mutation in a Compassionate Use Protocol

About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on developing and commercializing innovative gene therapies for retinal neurodegenerative diseases and central nervous system disorders. GenSight Biologics pipeline leverages two core technology platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help preserve or restore vision in patients suffering from blinding retinal diseases. GenSight Biologics lead product candidate, LUMEVOQ (GS010; lenadogene nolparvovec), has been submitted for marketing approval in Europe for the treatment of Leber Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease affecting primarily teens and young adults that leads to irreversible blindness. Using its gene therapy-based approach, GenSight Biologics product candidates are designed to be administered in a single treatment to each eye by intravitreal injection to offer patients a sustainable functional visual recovery.

Link:
GenSight Biologics to Present New Clinical Data of LUMEVOQ and GS030 Gene Therapies at the American Academy of Ophthalmology 2021 Meeting - Business...

An assessment of gene therapy ADVM-022 for the treatment of diabetic macular edema (DME) identified dose-dependent safety factors that may influence direction of investigation into the promising therapy in patients with retina diseases.

Findings from the phase 2 INFINITY trial, presented at the American Academy of Ophthalmology (AAO) 2021 Meeting this week by David S. Boyer, MD, Adjunct Clinical Professor of Ophthalmology at USC Keck School of Medicine, contribute to the growing portfolio of ADVM-022 in diabetic ophthalmic disease specifically.

It has already been said that ADVM-022 is a novel biofactory approach to gene therapy, Boyer said. There is a strong, ubiquitous promoter that is designed for robust protein expression, liberating aflibercept from ourselves.

The prior OPTIC study has shown that patients with nAMD previously required frequent injection therapy to maintain vision. Whats more, investigators observed a 97% reduction in mean annualized number of anti-VEGF injections among the 15 patients with nAMD administered 6E11 vg/eye ADVM-022while mean best corrected visual acuity (BCVA) and central subfield thickness (CST) levels were maintained.

OPTIC also showed no patients treated with ADVM-022 reported treatment-related non-ocular adverse events. All treatment-related ocular adverse events were either mild (83%) or moderate (17%) in severity. Ocular inflammation at the 2x1011 vg/eye dose regimen was minimal, and generally resolved with steroid eye drops.

The robust findings of this trial led to the phase 2 INFINITY, in which Boyer and colleagues sought the durability, safety and efficacy of intravitreal ADVM-022 injection in 34 patients with DME. Investigators compared high dose (6x1011 vg/eye), low dose (2x1011), and control for time to worsening of DME disease in the study eye at 24 weeks.

Patients were screened and randomized, then received a loading dose injection of either sham or aflibercept 2 mg. Investigational gene therapy injections were given at day 8.

Over 24 weeks, just 3 (25%) and 5 (39%) patients on high-dose and low-dose ADVM-022 required a supplemental aflibercept injection to address worsening DME at week 24, versus 8 (89%) patients administered aflibercept.

Whats more, nearly half of patients (46%) in each ADVM-022 treatment arm reported a 2 step improvement in diabetic retinopathy severity scale (DRSS) scores at week 12. Another 18% and 36%, respectively, achieved a 3 step improvement by week 24.

That said, more gene therapy-treated patients in the phase 2 trial reported intraocular inflammation: 83% and 92% of the high- and low-dose group, respectively, reported any inflammation, versus just 33% of aflibercept patients. ADVM-022-related adverse events were 57% mild, 41% moderate, and 2% severe.

Across OPTIC and INFINITY, investigators observed dose- and disease state-dependent factors on ADVM-022 efficacy and safety in patients with either nAMD or DME. Boyer stated future development plans for the gene therapy will focus on the treatment of nAMD, and a lower doses.

The difference between the safety seen in OPTIC and INFITIY is being studied, but is unknown, Boyer concluded.

The study, Results From a Phase 2 Study of ADVM-022 Intravitreal Gene Therapy for Diabetic Macula Edema: The INFINITY Trial, was presented at AAO 2021.

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Gene Therapy ADVM-022 Provides Mixed Efficacy, Safety in Treating DME - MD Magazine

Indiana University School of Medicine researchers investigated how the immune cells in the brain -- microglia -- relate to a gene mutation recently found in Alzheimer's disease patients. The findings of the study were published in the journal 'Science Advances'.

The study, led by Hande Karahan, PhD, a postdoctoral fellow in medical and molecular genetics, and Jungsu Kim, PhD, the P. Michael Conneally Professor of Medical and Molecular Genetics, found that deleting the gene -- called ABI3 -- significantly increased amyloid-beta plaque accumulation in the brain and decreased the amount of microglia around the plaques. "This study can provide further insight into understanding the key functions of microglia contributing to the disease and help identify new therapeutic targets," Karahan said.

Karahan based her research on a human genetics study of more than 85,000 people -- fewer than half were Alzheimer's patients -- that identified the mutation in the ABI3 gene. Researchers concluded this mutation increased the risk of late-onset Alzheimer's. "However, there was no investigation into the function of the ABI3 gene in the brain or about how this gene affects microglia function," Karahan said, a fact that led to her research. The team deleted the ABI3 gene from an Alzheimer's disease mouse model and tested the functions of the gene in microglia in cell cultures.

In the mouse model, they saw increased levels of plaques and inflammation in the brain and signs of synaptic dysfunction -- characteristics associated with learning and memory deficits of the disease. Additionally, Karahan said the deletion of the gene impaired the movement of microglia. The immune cells cannot move closer to plaques to try to clear up the proteins.

Amyloid plaques are commonly found in the brains of patients with Alzheimer's; amyloid-beta proteins clump together and form plaques, which destroy nerve cell connections. "Our study provides the first in vivo functional evidence that the loss of ABI3 function may increase the risk of developing Alzheimer's disease by affecting amyloid beta accumulation and neuroinflammation," Karahan said.

Over the past few years, Karahan has been building upon her Alzheimer's disease research. In 2019, Karahan received the Sarah Roush Memorial Fellowship in Alzheimer's Disease Research, established by the Indiana Alzheimer's Disease Research Center and funded through a generous donation from James and Nancy Carpenter and a matching contribution from Stark Neurosciences Research Institute, where Karahan conducts her research. Karahan and Kim received three separate grants supporting this research from the National Institute on Aging, the National Institutes of Health (NIH) branch for Alzheimer's research, resulting in USD 7.8 million over the next five years.

"One grant will fund the creation of a mouse model that will allow us to delete the ABI3 gene in any cell types in the body, such as brain microglia and peripheral immune cells," Kim said. "Once we validate this new model, we will make it available to others in the research community to use this model for their own investigations," Kim added.

The other grants will fund additional mouse and cell models for the team to further investigate how the ABI3 gene in microglia affects Alzheimer's disease pathologies as well as fund state-of-the-art techniques, including brain imaging using the Bruker BioSpec 9.4T PET-MRI scanner, located in the Roberts Translational Imaging Facility at Stark Neurosciences Research Institute. Each of these projects has an end goal of identifying druggable targets for the treatment of the disease, Karahan and Kim said. The team will collaborate with the IU School of Medicine-Purdue TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center. (ANI)

(This story has not been edited by Devdiscourse staff and is auto-generated from a syndicated feed.)

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Role of gene associated with Alzheimer's disease in brain's immune cells investigated by scientists - Devdiscourse

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Attitudes among parents of persons with autism spectrum disorder towards information about genetic risk and future health | European Journal of Human...

GENEVA andCASTRES, France, Nov. 15, 2021 /PRNewswire/ --The EspeRare Foundation and the Pierre Fabre group announced today the start of the EDELIFE clinical trial aimed at confirming the safety and efficacy of ER004, a prenatal treatment for XLHED (X-linked Hypohidrotic Ectodermal Dysplasia), a rare and debilitating congenital disease. If positive, the study could lead to the first approved treatment for XLHED by 2026.

XLHED is a rare disease which affects approximately 4/100,000 live male births every year. This genetic disorder is a dermatologic-related condition which leads to abnormal development of the skin, sweat glands, sebaceous glands, hair, oral cavity and respiratory mucosal glands resulting in serious clinical manifestations such as hyperthermia, craniofacial anomalies and recurrent respiratory infections.

"Starting patient enrolment in the EDELIFE clinical trial is a huge milestone for the Hypohidrotic Ectodermal Dysplasia community," said Caroline Kant, the Co-founder and CEO of the EspeRare Foundation, the primary sponsor of the study. "Administered during the second and third trimesters of pregnancy, ER004 has the potential to become a 'single-course treatment,' which significantly improves the symptoms of this debilitating disease throughout the lives of patients. If successful, ER004 could fundamentally change the lives of these patients and may also pave the way for other prenatal therapies to correct genetic diseases before birth."

The EDELIFE clinical trial will investigate the efficacy and safety of intra-amniotic ER004 as a prenatal treatment for male foetuses who have been confirmed to have XLHED. In the main study phase, efficacy and safety of approximately 15 treated children will be assessed up to 6 months of age and safety of the mothers will be assessed up to 1 month after delivery. In the long-term follow-up phase, efficacy and safety of the treated children will be assessed up to 5 years of age. Treated children's sweating ability will be compared to that of an untreated affected relative, when available, or to that of a genotype-matched control subject coming from disease natural history data. The main phase of the clinical study is expected to last until 2025.

The study starts first in Germany, at the University Hospital of Erlangen, with Pr Schneider as the study coordinating investigator. Additional study centers will be progressively opened in France, Italy, Spain, United Kingdom and the USA.

"The EDELIFE study truly exemplifies Pierre Fabre's commitment to supporting those with rare dermatologic diseases as we have already done in infantile hemangiomas," said Eric Ducournau, CEO of the Pierre Fabre Group. "Our priority is to enrol 20 pregnant women with a confirmed diagnosis of XLHED in the foetus. As this is a very rare condition, together with the patient community, we are doing everything we can to support these women participate in the study, including helping them travel to a nearby country if there is no open investigational site in their own country."

The treatment ER004 has received the "breakthrough therapy" designation in 2020 by the US Federal Drug Administration (FDA). Its clinical development also benefits from the European Medical Agency's (EMA) PRIME (PRIority MEdicines) program.

A dedicated web site (www.EDELIFEclinicaltrial.com) is being made available for interested families, providing details on the clinical trial and the conditions for enrolment. Details are also available on http://www.clinicaltrial.gov.

About XLHED

XLHED is a severegenetic disorder that affects the structure of the ectoderm, the most exterior part of the three primary germ layers formed during early embryonic life, from which the skin and its appendages are derived. XLHED is caused by mutations in EDA, a gene that encodes an important developmental signaling protein, EDA1. The absence of functional EDA1 in the ectoderm results in abnormal development of the skin, sweat glands, sebaceous glands, hair, oral cavity, and respiratory mucosal glands.

About ER004

ER004 is a pioneering in-utero therapy designed to replace the function of endogenous Ectodysplasin A1 (EDA1), a protein key to the normal development of ectodermal structures in the foetus. ER-004 is a recombinant, soluble, and humanized form of EDA1 that is given as a single course treatment and delivered through intra-amniotic injections during the late stage of pregnancy. This approach has already demonstrated a significant potential in humans where it normalized sweat gland function in three patients treated in this fashion by Prof. Holm Schneider at the University Hospital Erlangen in Germany. First results were published in the New England Journal of Medicine[1] and in the British Journal of Clinical Pharmacology[2] as well as featured in Nature Medicine's Research Highlights[3].

For more information on the EspeRare Foundation, please visit http://www.esperare.org.

For more information on the Pierre Fabre Group, please visit http://www.pierre-fabre.com.

References

1.Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia.Schneider H, Faschingbauer F, Schuepbach-Mallepell S, Krber I, Wohlfart S, Dick A, Wahlbuhl M, Kowalczyk-Quintas C, Vigolo M, Kirby N, Tannert C, Rompel O, Rascher W, Beckmann MW, Schneider P. N Engl J Med 2018; 378: 1604-1610.2.Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects.Krber I, Klein OD, Morhart P, Faschingbauer F, Grange DK, Clarke A, Bodemer C, Maitz S, Huttner K, Kirby N, Durand C, Schneider H. Br J Clin Pharmacol. 2020;86(10):2063-2069.3. In utero correction of a genetic disorder.Stower H.Nature Medicine 2018; 24: 702.

Contacts:

EspeRare Foundation[emailprotected]

Pierre Fabre[emailprotected]

SOURCE Pierre Fabre; EspeRare foundation

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Pierre Fabre and the EspeRare Foundation start the EDELIFE clinical trial of a prenatal treatment for a rare genetic disease, XLHED - PRNewswire

X-rays show dog lungs examined in the Valley fever veterinary vaccine trials. On the left is a fully vaccinated dog, in the center is a partially vaccinated dog, on the right is an unvaccinated dog.

When veterinarian Scott Hoffmanattended veterinary school in Ohio, heread about Valley fever, but never expected he'd encounter it. That changed when he began working in Phoenix.

At our clinic, I probably would say we see anywhere from two to 20 cases a month," Hoffman said of his central Phoenix practice, North Kenilworth Veterinary Care. "If youd interview other veterinarians they may even give you a higher number."

For dogs, Valley fever can mean coughing, weight loss, skin lesions, and even seizures. Hoffman warns clients the diagnosis typically precedes months of suffering for the dogs and months of veterinary bills for owners. Arizona dog owners spend about $60 million on the disease each year, according to the University of Arizona College of Medicine Valley Fever Center for Excellence. And Hoffman said theres really no way to avoid the disease.

Unfortunately, the No. 1 way you can prevent it is not live here in Arizona," Hoffman said.

That may soon change.For the first time, University of Arizona researchers say theyve found a vaccine that can prevent the illness in pets. Theyre hopeful it will protect humans someday, too.

Valley fever, or coccidioidomycosis,comes from a fungus that grows in desert soils. When dogs or humans inhale airborne fungal spores, the fungus can infect the lungs and other parts of the body. It can be a grueling disease, and its more common in Arizona than anywhere else.

Valley fever is considered an orphan disease because nationally, its a very small problem," said Dr.John Galgiani, director of theUniversity of Arizona College of Medicine Valley Fever Center for Excellence anddirector of the Banner Health Valley Fever Center. "But if you talk to people who have lived [in Arizona], everyone usually knows somebody who's had Valley fever. And it's often their dog."

Katherine Davis-Young/KJZZ

Dr. John Galgiani is a professor with the University of Arizona College of Medicine and director of the Banner Health Valley Fever Center.

Galgiani and other researchers have spent decades trying to find a vaccine to prevent Valley fever. But that goal has always been a long-shot. Not only does Valley fever not get the national attention and research funding that other diseases get, but there's never been a vaccine for a fungal illness in the history of medicine.

But Galgiani and his team say theyre onto something.

Lisa Shubitz, a veterinarian and research scientist with theValley Fever Center for Excellence, is the lead author ona new paper on a Valley fever vaccine trial in dogs. She said the findings came about in a stroke of serendipity.

Galgiani and Shubitz's team worked with Marc Orbach on the research. Orbach is aplant pathologist in the University of Arizona College of Agriculture and Life Sciencesnot the kind of scientist who might typically work on vaccine development. But in this case, Orbach's expertise was exactly what Valley fever researchers needed.

We were interested in, what are the genes in fungi that make them pathogens? So, what allows them to cause disease in hosts?" Orbach said.

Orbach and his lab isolated the gene they thought made the Valley fever fungus infectious and removed the gene. To test their theory, they exposed lab mice to their edited version of the fungus.Without that gene, the fungus didnt make the mice sick.

So the next question was, it doesnt make them sick; does it vaccinate them? Shubitz said.

Noelle Haro-Gomez/University of Arizona Health Sciences

Veterinarian Lisa Shubitz with the University of Arizona Valley Fever Center for Excellence is lead author on new research on a Valley fever vaccine for dogs.

After more trials in mice, researchers used the edited fungus to vaccinate a group of dogs. After vaccination, they exposed the dogs to real Valley fever spores.When they looked at those dogs lungs, in most cases, there were no detectable signs of infection. Only a few of the dogs had developed very mild lung infiltrates.

None of the dogs were sick, in other words, no one would have taken that dog to the vet," Shubitz said.

The dogs tolerated the vaccines well, and with two doses, Orbach said the vaccine was even more effective than researchers thought possible.

It was really exciting when we got the first results, pretty much beyond anything that we could expect because it was better than anything that had been tried," Orbach said.

The first-of-its-kind fungal vaccine is harder to preserve than traditional, viral vaccines. So now, researchers are looking for a way to give the vaccine doses a longer shelf-life. But theyre optimistic they could have their vaccine in veterinary offices by 2023 if they can get USDA approval.

It would be a huge step toward protecting Arizona dogs. But Galgiani said its exciting for another reason.

Sky Schaudt/KJZZ

It just looks like this vaccine works really, really well. And for me, as a physician, it adds that much more pretty powerful evidence that we should be able to do the same thing for humans," Galgiani said.

At least 9,500 Arizonans have been infected with Valley fever this year, according to the Arizona Department of Health Services. As with dogs, the human disease can last months. Galgiani said one of the most common symptoms is fatigue debilitating enough that it keeps people from being able to work. The illness has a $1.5 billion annual impact on Arizona and California's economies, according to the Valley Fever Center for Excellence.

A human vaccine wouldnt be very different from the veterinary vaccine, Galgiani said, but one major difference would be its development cost.

The veterinary vaccine is probably fully funded," Galgiani said. "But we dont have yet the funding for the human campaign.

He said development of the veterinary vaccine cost about $15 million. He expects years-long clinical trials for humans could cost ten times that.

Arizona Congressmen Tom OHalleran and David Schweikert recently signed ontoa bipartisan billalong with representatives from California to fund fungal vaccine research. Galgiani hopes the bill gets traction in Congress. And, even though Valley fever is most common to the Southwest, he hopes otherlawmakers will see the value of the investment.

This is a biohazard that we live in. Its a very small part of the country, but its ours, Galgiani said.

Challenges remain, but Galgiani is optimistic.Even if a human vaccine is still years away, he said, its more within reach now than ever before.

Katherine Davis-Young/KJZZ

Banner University Medicine in Phoenix

Katherine Davis-Young/KJZZ

The Banner University Lung Institute

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Arizona researchers have a Valley fever vaccine for dogs and that's good news for humans - KJZZ

For three decades, a mysterious cluster of proteins found on the cell body of neurons in the hippocampus has puzzled scientists. Highly conserved features are relatively unchanged through evolutionary timescales, suggesting they have an essential functional property in these very different types of animals.

A new study has finally revealed what these clusters are. The UC Davis School of Medicine study has shown that these mysterious clusters of proteins are calcium-signaling hotspots that activate gene transcription.

Transcription allows portions of the neurons DNA to be transcribed into strands of RNA that are then used to create the proteins needed by the cell.

Scientists knew that these clusters are formed by a protein that passes potassium ions through membranes. Whats more, these clusters have a particular type of calcium channel that allows calcium to penetrate cells. Inside the cells, the calcium triggers various physiological responses based on cell type.

Disturbance to these clusters can cause severe neurological disorders. But the reason behind it remains unclear.

To determine the function of the neuronal clusters, scientists came up with a new approach that allowed them to uncouple the calcium channel from the potassium channel clusters in neurons.

Nicholas C. Vierra, a lead author for the study, said,A key finding was that this treatment blocked calcium-triggered gene expression. This suggests that the calcium channel-potassium channel partnership at these clusters is important for neuronal function.

Scientists tricked the calcium channels at these clusters for their experiment by flooding the neurons with decoy potassium channel fragments. They fell away from the clusters when the calcium channels grabbed onto the decoys instead of the real potassium channels. As a result, the process known as excitation-transcription coupling, which links changes in neuronal electrical activity to changes in gene expression, was inactivated.

Trimmer said,There are a lot of different calcium channels, but the particular type of calcium channel found at these clusters is necessary for converting changes in electrical activity to changes in gene expression. We found that if you interfere with the calcium-signaling proteins located at these unusual clusters, you eliminate excitation-transcription coupling, which is critical for learning, memory, and other forms of neuronal plasticity.

The study is expected to open up new avenues of research.

Vierra said,A lot of research has focused on calcium signaling in dendrites the sites where neurons receive signals from other neurons. Calcium signaling in the cell body of neurons has received less attention. Now we understand much more about the significance of signaling at these specific sites on the cell body of the neuron.

Trimmer said,We are only at the beginning of understanding the significance of this signaling, but these new results may provide information that could shape new research into its role in brain function, and perhaps eventually into the development of new classes of therapeutics.

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Study revealed the function of mysterious structure found on neurons - Tech Explorist

Which genes control the defining features that make us look as we do? And how do they make it happen?

In 1990, University of California San Diego biologist William McGinnis conducted a seminal experiment that helped scientists unravel how high-level control genes called Hox genes shape our appearance features. The McGinnis experiment helped pave the way for understanding the role of Hox genes in determining the uniform appearances of species, from humans to chimpanzees to flies.

Drosophila mimica, a rare fruit fly collected from Hawaii Volcanoes National Park.

McGinnis, a professor emeritus of Cell and Developmental Biology and former dean of the Division of Biological Sciences, helped discover a defining DNA region that he termed the homeobox, a sequence within genes that directs anatomical development. Since the now-famous McGinnis experiment, evolutionary and developmental biologists have pondered how these highly influential Hox genes determine the identities of different body regions.

More than three decades later, a study published Nov. 10 as the featured cover in Science Advances and led by Ankush Auradkar, a UC San Diego postdoctoral scholar mentored by coauthor McGinnis and study senior author Ethan Bier, helps answer questions about how Hox genes function.

The now-textbook McGinnis experiment tested whether the proteins produced by a human or mouse Hox gene could function in flies. Following in these footsteps, the new study leveraged modern CRISPR gene editing to investigate whether all aspects of Hox gene function, which consists of both protein coding and control regions, could be replaced in a common laboratory fruit fly (Drosophila melanogaster) with its counterpart from a rarer Hawaiian cousin (Drosophila mimica), which has a very different face.

The gene in question, proboscipedia, would plainly reveal itself since it directs the formation of strikingly different mouth partssmooth and spongy in D. mel but more grill-like (resembling the face of the alien in Predator science fiction films) in D. mim.

Study coauthor Emily Bulger first collected the notoriously difficult-to-breed D. mim samples from Hawaii Volcanoes National Park, along with the only native fruit (Sapindus saponaria - Hawaiian soapberry) that the insects are known to eat, in order to establish a temporary colony in Biers laboratory. Auradkar then collaborated with coauthor Sushil Devkota to decipher the genome sequence of the D. mim proboscipedia gene, which was nearly 44,000 bases long. The researchers then deleted the D. mel proboscipedia gene and replaced it with the D. mim version of the same.

Electron microscopy images contrast the smooth and spongy features of the common Drosophila melanogaster fruit fly (left) and the grill-like features of its rarer cousin, the Hawaiian Drosophila mimica.

As McGinnis had predicted, the new results revealed that the graceful facial structure of D. mel emerged as the winner over the rough features of D. mim. One trait of D. mim, however, did surface during the experiment: Sensory organs called maxillary palps that stick out from the face in D. mel instead ran parallel to feeding mouthparts as they do in D. mim. Auradkar used sophisticated genetic tools to determine the basis for this difference and tracked it down to a change in the pattern by which the proboscipedia gene is activated (control region changes).

The experiments results help answer longstanding questions about whether Hox genes function as master regulatory genes that dictate different body parts in organisms. Or, as McGinnis proposed, whether Hox genes instead provide abstract positional codes and serve as scaffolds for downstream genes that best benefit the organism. Other than the maxillary palps, the new results demonstrated that McGinnis scaffolding idea proved to be the case.

William McGinnis, professor emeritus of Cell and Developmental Biology.

McGinnis says that beyond the implications for evolutionary biology, the results could help explain developmental issues rooted in fundamental human genetic processes.

These fly studies provide a window into deep evolutionary time and inform us about the mechanisms by which body plans change during evolution, said Bier. These insights may lead to a better of understanding of processes tied to congenital birth defects in humans. With the advent of powerful new CRISPR-based genome editing systems for human therapy on the horizon, new strategies might be formulated to mitigate some of the effects of these often debilitating conditions.

According to Bier, these investigations also provide an example of the intimate connection between the support of basic science and human welfare. The research described in the Science Advances paper was supported by a Paul G. Allen Frontiers Group Distinguished Investigators Award, National Institutes of Health grant R01 GM117321 and a gift from the Tata Trusts in India to the Tata Institute for Genetics and SocietyUniversity of California San Diego (TIGS-UC San Diego). The paper was authored by Ankush Auradkar, Emily Bulger, Sushil Devkota, William McGinnis and Ethan Bier.

Competing interest note: Bier has equity interest in two companies he co-founded: Synbal Inc. and Agragene, Inc., which may potentially benefit from the research results. He also serves on Synbals board of directors and the scientific advisory board for both companies.

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New Research Helps Explain the Genetic Basis of Why We Look the Way We Do - UC San Diego Health