SAN FRANCISCO, Dec. 17, 2019 /PRNewswire/ -- The genome of human cells looks a lot like a tangled ball of yarn, with tightly wound clumps from which myriad loose strands escape and loop out. But there is order to this tangleand growing evidence that the genome's 3D architecture influences the activity of its genes. Understanding the rules that control gene activity has been the object of a long collaboration between Gladstone investigators Deepak Srivastava, Benoit Bruneau, Katherine Pollard, Bruce Conklin, and Nevan Krogan, and their UC San Francisco (UCSF) partner Brian Black. Together, they have already found many key regulators of gene activity in the heart.

Now, their collaboration has received a strong shot in the arm from the National Institute of Health with the recent award of a Program Project Grant totaling $13 million between the labs for the next five years.

With this new support, the researchers will carry out a comprehensive probe into gene activity in heart cells and its intersection with the genome's 3D organization during heart formation.

"It is truly gratifying to see our long collaboration supported in this way by the National Institute of Health,"says Srivastava, president of Gladstone Institutes and project leader on this multi-investigator grant. "This funding will allow us to dig deep into processes that are fundamental to heart cell biology, but that will also directly inform our efforts to design therapies for congenital heart disease, heart failure, and other heart diseases."

Heart failure is the most common cause of death in adults, and congenital heart defects the most common form of birth defects. These defects have been traced to mutations in a number of proteins that regulate gene activity in heart cells, including the proteins at the core of the researchers' new proposal.

"However, the investigation of the 3D organization of the genome is a relatively new area, particularly in the heart," says Srivastava, who is also a pediatric cardiologist and has devoted much of his career to understanding heart formation and congenital heart defects.

The work outlined in this grant is therefore expected to yield novel insight into heart disease and spur the design of new therapies. It will also help the researchers improve their ability to coax human cells into becoming various types of heart cells. This technology could eventually be used to regenerate failing heart tissue.

Gladstone Senior InvestigatorBruce Conklinwill lend his expertise in cardiac stem cell biology and CRISPR gene-editing technology to the project.

The researchers' plan is to correlate gene activity and genome organization at the whole-genome scale and during multiple stages of heart formation. This will require enormous technological power. It will also require massive computing power and statistical analysis to store and sift through the large data sets the group will generate.

But the team is well-positioned to take on this challenge.

"Our studies are facilitated by extraordinary new technology,"says Bruneau, also a cardiovascular development specialist and the director of the Gladstone Institute of Cardiovascular Disease.

The $13 million proposal will leverage Srivastava, Bruneau, and Black's deep understanding of heart development and disease, and enlist the state-of-the-art technologies and analytic tools that Pollard and Krogan have developed to collect and analyze information about biological networks on a grand scale.

"Our team combines a remarkable array of expertise and technologies," says Srivastava, who is also director of the Roddenberry Stem Cell Center at Gladstone. "It would be impossible for any one or two labs in isolation to pursue the complex goals we set out to achieve with this project."

Dynamic Protein Networks

The project focuses on a small set of proteins the team has previously shown to be crucial for the formation of a functional heart. These proteins, known as transcription factors, activate or silence genes by binding to specific DNA sequences in the genes' vicinity.

The scientists have shown that cardiac transcription factors can associate with each other and with other proteins. "Depending on the associations they form, they turn genes on, off, or somewhere in between, and different types of heart cells may form," says Black.

But for a transcription factor to turn a gene on or off, it needs to access the gene's DNA sequence. That's not as easy as it sounds, as much of the genome is wound up in tight coils that give no foothold to transcription factors.

Bruneau's team studies proteins that modulate the accessibility of DNA sequences along the genome, a process known as chromatin remodeling. These proteins unspool segments of the genome from the tightly wound coils, opening up stretches of DNA that transcription factors can bind.

Like transcription factors, chromatin remodeling proteins associate with each other and with other proteins, forming associations that vary depending on the cell type or the stage of heart formation.

Interestingly, Srivastava's group recently discovered that cardiac transcription factors may have long-range effects on the 3D organization of the genome. The genome is housed in a separate compartment of the cell, a spherical structure called the nucleus. Srivastava's team found that cardiac transcription factors may pull genome loops all the way to proteins lining the edges of the nucleus.

The picture that emerges from these findings is that of a vast network of proteins that coordinate gene activity and genome architecture, and change as the heart forms.

Now the researchers want to know how these networks form, how many proteins they entail, and what genes they affect.

Dynamic Lab Partnerships

To answer these questions, the team will analyze the associations between cardiac transcription factors, chromatin remodeling proteins, and their various partners during heart development. They will pair this analysis with a genome-wide survey of the genes these proteins target and of these genes' activity.

"Our overarching goal is to understand all the levels of gene regulation in developing hearts, from genes and transcription factors to chromatin remodeling and to genome organization within the nucleus," says Bruneau, who is also a professor of pediatrics at UCSF.

The researchers will use a battery of sophisticated techniques to capture the complexes that proteins form with each other or with DNA sequences and to record which genes are active or inactive in different types of heart cells.

They will leverage various models of heart development, including human induced pluripotent stem cells (hiPS cells) that can give rise to heart tissue in the dish, or cells from the developing heart of mouse embryos. They will also use CRISPR technology and other genetic tools to insert mutations in heart cells and evaluate the impact of these mutations on the protein-genome networks.

Their success will depend on high-throughput data collection and analysis, and powerful statistics to guarantee the validity of the findings. That's where Krogan and Pollard come in.

Krogan's labwill contribute technology his lab developed to determine how proteins interact with one another in the celland how those interactions affect the interaction of proteins with DNA.

Pollard's groupwill devise statistical methods to rigorously analyze the protein networks and gene activity profiles the researchers uncover through the lens of genetic causes of heart disease.

"The biggest challenge will be to develop novel computational methods, including artificial intelligence tools," says Pollard, who directs the Gladstone Institute for Data Science and Biotechnology. "This is the first time that scientists will integrate such diverse kinds of data to understand a disease."

Together, these tools will allow the researchers to reliably identify connections between protein networks and gene activity at all stages of heart formation, in the context of disease or healthy heart formation.

"This project crystallizes a more than a decade-long collaboration across our labs, with a laser focus on fundamental concepts of gene regulation," says Bruneau.

"We will learn how these concepts apply to the heart and to heart diseases," he adds, "but we think they will also be relevant to other organs and sets of diseases."

Media Contact:Megan McDevittmegan.mcdevitt@Gladstone.ucsf.edu

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team-of-researchers-who-received.jpg Team of Researchers who Received the Grant New funding from the NIH fuels collaboration between UCSF's Brian Black and Gladstone's Deepak Srivastava, Benoit Bruneau (front row, left to right), Katie Pollard, Bruce Conklin (back row, left to right), and Nevan Krogan (not shown).

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This story was originally published by Mother Jones and appears here as part of the Climate Desk collaboration

Do you love burgersbut not the animal cruelty and environmental degradation that go into making them? I come bearing good news: Someday, you might be able to get your meat fix, without all that bad stuff. Scientists can now grow animal flesh, without raisingor in most cases killingan animal. This food, called lab-grown meat, cell-based meat, cultured meat, cultivated meat, clean meat, or as comedian Stephen Colbert jokingly called it in 2009, shmeat, has set off a flurry of media attention in recent years. Dozens of lab-grown meat companies have materialized, most aiming to solve the problems associated with large-scale beef, pork, poultry, and seafood production.

Finless Foods, a 12-person food-tech startup founded in 2017 and based in Emeryville, California, claims to be the first company to focus on lab-grown fish, although a handful of other startups have since joined them. In October, 28-year-old Finless Foods co-founder Mike Selden gave me a tour of their facility, and I dished about it on the latest episode of the Mother Jones food politics podcast Bite:

Selden and his co-founder Brian Wyrwas, both products of an agricultural biochemistry program at UMass Amherst, started the company, he says, to make something good.

We started off with zebrafish and goldfish, which already had a lot of cell biology research behind them, Selden explains. From there, we did our first prototypes, which were carp. The company grew tilapia, bass, rainbow trout, salmon, Mahi Mahi, lobster, and Fugu (poisonous pufferfish) meat before settling on Bluefin tuna, whose stocks have dropped sharply in the last few decades.

The idea behind lab-grown fish, Selden says, is multi-pronged. The technology, they hope, will prevent the killing of animals for food, cut down on overfishing, and eliminate mercury and microplastic contamination in seafood. We see this as creating a clean food supply on land: no mercury, no plastic, no animals involved, and it can still meet peoples needs.

Selden doesnt like the term lab-grown. Industry insiders argue it makes their products sound artificial and unappetizing. He instead prefers to call it cell-based. He argues that the process of growing fish in a lab is actually very similar to how fish grow and develop in the wild.

It begins with a sampleabout the size of a grain of riceof real meat from a real fish. (The tuna doesnt have to die during this process, but often does. In the companys two-and-a-half-year history, theyve killed fewer than 20 tuna.) Those cells are put in a liquid feed, like a nutritious soup, which gives them the energy to grow and divide, just like they would in a real, growing fish.

Despite the obvious advantages of lab-grown fish, there arent any products on the market. For Finless Foods, the cost of making one serving of their fish is still too high for consumers. I wont say exactly what number it is, Selden tells me, but youre not going to buy it. This is true across the industry: lab-grown beef, at one point costing as much as $280,000 to produce a hamburger, is also still prohibitively expensive, though its price is expected to drop to a mere $10 in two years.

Hitting the right price is one of the industrys biggest hurdles, if not the biggest one, according to Liz Specht, associate director of science and technology at the Good Food Institute, a nonprofit which lobbies for plant-based and cell-based alternatives to meat, dairy, and eggs. The industry, she says, has the science down. What does need to happenand I dont want to downplay or trivialize how challenging this will beis getting it to the scale and the price point that will ultimately be necessary.

On top of that, Finless Foods is still working out the kinks on the flavor. The first iteration of its fish, carp served as a croquette and prepared by a local chef, which it unveiled in 2017, didnt taste like much, Selden concedes. At the time, journalist Amy Fleming described it in a story for The Guardian as delicious and disappointing. When I called Fleming in November to get more detail about the taste, she said she recalls it being crispy on the outside and smooth and delicate on the inside. It had a subtle flavor of the sea, as the chef described it to Fleming, like water in an oyster shell. They were really lovely, she says, But did taste of fish? It was hard to say. You couldnt see any fish in there and you can discern any fleshy fish sort of texture.

Now, after two more years of taste-tests Selden claims the flavor of his Bluefin is really good. I think it tastes fantastic, he says. And I think that it really speaks for itself. (Ill have to take Seldens word for it; at the time of my visit, they didnt have any fish available for tasting.)

Finless Foods lab-grown carp, in a frying pan. Finless Foods

The companys success could depend on finding the right flavor. When I ask Selden why people would choose his product over other alternatives, like sustainably caught or farm-raised fish, he says, They wont. He elaborated: Were specifically shooting for people who really dont care about sustainability. To appeal to seafood connoisseurs, he says, his company plans to first sell to upscale restaurants rather than grocery stores. Fine dining, he believes, is an easier way to get public perception on your sideespecially when were specifically searching for foodies rather than for a sustainably-minded consumer.

Funders seem to agreethey have already invested millions of dollars into Finless Foods. Early supporters include an aquaculture investment firm based out of Norway called Hatch, an Italian food science company, Hi-Food, a Japanese tuna company, Dainichi Corporation, and Draper Associates, a venture capital firm founded by Silicon Valley investor Tim Draper. Animal welfare organizations including PETA and Mercy for Animals have voiced support for lab-grown meat as a whole. And according to a 2018 survey conducted by Faunalytics, a non-profit animal advocacy research organization, 66 percent of consumers were willing to try clean meat.

There is one group of people that likely isnt so enthusiastic about lab-grown seafood: fishermen. I think that we need essentially a Green New Deal but for agriculture, says Selden. He believes a jobs guarantee might alleviate some of the growing pains associated with transitioning to a partial lab-grown meat food system. I think that the people who are doing that fishing, are doing that farming, we need to provide something for them so that they can still survive, even if we transition out of their industry as a method of food production.

It is yet to be seen whether Finless Foods sashimi will win over die-hard seafood fanatics. Then again, they might not have a choice: As climate change worsens, and the ocean becomes too hot, too acidic, too polluted, and over-fished, its possible that one day some types of seafood may come only in a lab-grown variety. As Specht told me, I think cultivated meat may truly be our only option for preserving the diversity of aquatic species we eat.

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We Destroyed the Oceans. Now Scientists Are Growing Seafood in Labs. - National Observer

Vancouver, British Columbia-based Novoheart signed an exclusive licensing deal with Harvard Universitys Office of Technology Development.

The deal allows Novoheart to merge its MyHeart Platform with Harvards tissue-engineered scale model of the heart ventricle and bioreactor technology. Novoheart invented and commercialized the first and only human heart-in-a-jar model for drug discovery and development.

Harvards valved bioreactor technology was engineered in Kevin Kit Parkers laboratory. He is the Tarr Family Professor of Bioengineering and Applied Physics at Harvard A. Paulson School of Engineering and Applied Sciences.

The two institutions expect that the merged technology will result in a next-generation human heart-in-a-jar that will be a superior human heart model for disease modeling, drug discovery and development with unmatched biofidelity as well as significantly enhanced predictive accuracy, capacity and versatility.

In addition to developing various bioengineered human heart constructs, Novoheart wants to develop the technology into transplantable grafts for cell-based regenerative heart therapies. The companys various products include Human Ventricular Cardiomyocytes (hvCM), Cardiac Anisotropic Sheet (hvCAS), Cardiac Tissue Strip (hvCTS), and Cardiac Organoid Chamber (hvCOC). It also offers consultation and screening and phenotyping services using its 2D or 3D tissue assays.

On November 26, Novoheart announced a collaboration with AstraZeneca to develop the worlds first human-specific in vitro, functional model of heart failure with preserved ejection fraction (HFpEF). Working with AstraZenecas Cardiovascular, Renal and Metabolism team, they will initially establish a new in vitro model using Novohearts proprietary 3D human ventricular cardiac organoid chamber (hvCOC), also known as the human heart-in-a-jar.

Of the Harvard licensing deal, Kevin Costa, co-founder and chief scientific officer of Novoheart, said, By integrating Harvards valved bioreactor technology with our own proprietary human heart-in-a-jar, Novoheart will advance its disease modeling capabilities to an unprecedented level of biofidelity for in vitro human cardiac assays. It will lead to the development of next-generation heart models that would be impossible in the absence of functional valves, including for highly prevalent heart diseases such as dilated cardiomyopathy and hypertrophic cardiomyopathy. The models can be directly applied to the discovery of new therapeutics targeting such diseases.

The work run in the Parker lab was led by Luke MacQueen, a research associate.

Parker said, My lab develops engineered cardiovascular tissue in order to better understand the physiology of the system, better identify the causes and mechanisms of disease, and develop regenerative solutions for patients in need. While we continue that work at Harvard, it is gratifying to see our innovations adopted into a platform with immediate relevance to the discovery and development of new therapeutics.

Parkers overall work is on cardiac cell biology and tissue engineering, traumatic brain injury, and biological applications of microtechnology and nanotechnology. He is involved in a broad range of projects working to develop nanofabrics for tissue regeneration for organs-on-chips to treat pediatric diseases like asthma, muscular dystrophy, diabetes, brain injury and congenital heart disease. He was previously a member of the Defense Science Research Council, an advisory activity of the Department of Defenses Defense Advanced Research Projects Agency (DARPA).

The heart-in-a-jar concept is at least one step up from using laboratory animals and cell cultures for research and drug development.

Novohearts human heart-in-a-jar is already in use by our various pharma and biotech clients, said Ronald Li, Novohearts co-founder and chief executive officer. We anticipate that incorporating Harvards technology will broaden our commercial applications and offerings for facilitated drug discovery and development.

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Novoheart and Harvard Partner on Heart-in-a-Jar Technology to Advance Cardiac Drug Development - BioSpace

Gene therapy is fighting to enter mainstream medicine. With sickle cell disease, the fight is heating up.

Roughly two years ago, the FDA made the historic decision to approve the first gene therapy in the US, finally realizing the therapeutic potential of hacking our biological base code after decades of cycles of hope and despair. Other approvals soon followed, including Luxturna to target inherited blindness and Zolgensma, a single injection that could save children with a degenerative disease from their muscles wasting away and dying before the age of two.

Yet despite their transformative potential, gene therapy has only targeted relatively rareand often fataldisorders. Thats about to change.

This year, a handful of companies deployed gene therapy against sickle-cell anemia, a condition that affects over 20 million people worldwide and 100,000 Americans. With over a dozen therapies in the run, sickle-cell disease could be the indication that allows gene therapy to enter the mainstream. Yet because of its unique nature, sickle-cell could also be the indication that shines an unflinching spotlight on challenges to the nascent breakthrough, both ethically and technologically.

You see, sickle-cell anemia, while being one of the worlds best-known genetic diseases, and one of the best understood, also predominantly affects third-world countries and marginalized people of color in the US. So far, gene therapy has come with a hefty bill exceeding millions; few people afflicted by the condition can carry that amount. The potential treatments are enormously complex, further upping costs to include lengthy hospital stays, and increasing potential side effects. To muddy the waters even more, the disorder, though causing tremendous pain and risk of stroke, already has approved pharmaceutical treatments and isnt necessarily considered life-threatening.

How we handle gene therapies for sickle-cell could inform many other similar therapies to come. With nearly 400 clinical trials in the making and two dozen nearing approval, theres no doubt that hacking our genes will become one of the most transformative medical wonders of the new decade. The question is: will it ever be available for everyone in need?

Even those uninterested in biology have likely heard of the disorder. Sickle-cell anemia holds the crown as the first genetic disorder to be traced to its molecular roots nearly a hundred years ago.

The root of the disorder is a single genetic mutation that drastically changes the structure of the oxygen-carrying protein, beta-globin, in red blood cells. The result is that the cells, rather than forming their usual slick disc-shape, turn into jagged, sickle-shaped daggers that damage blood vessels or block them altogether. The symptoms arent always uniform; rather, they come in crisis episodes during which the pain becomes nearly intolerable.

Kids with sickle-cell disorder usually die before the age of five; those who survive suffer a lifetime of debilitating pain and increased risk of stroke and infection. The symptoms can be managed to a degree with a cocktail of drugsantibiotics, painkillers, and a drug that reduces crisis episodes but ups infection risksand frequent blood transfusions or bone marrow transplants. More recently, the FDA approved a drug that helps prevent sickled-shaped cells from forming clumps in the vessels to further combat the disorder.

To Dr. David Williams at Boston Childrens Hospital in Massachusetts, the availability of these treatmentshowever inadequatesuggests that gene therapy remains too risky for sickle-cell disease. Its not an immediately lethal diseaseit wouldnt be ethical to treat those patients with a highly risky experimental approach, he said to Nature.

Others disagree. Freeing patients from a lifetime of risks and pain seems worthy, regardless of the price tag. Inspired by recent FDA approvals, companies have jumped onto three different treatments in a bitter fight to be the first to win approval.

The complexity of sickle-cell disease also opens the door to competing ideas about how to best treat it.

The most direct approach, backed by Bluebird Bio in Cambridge, Massachusetts, uses a virus to insert a functional copy of the broken beta-globin gene into blood cells. This approach seems to be on track for winning the first FDA approval for the disorder.

The second idea is to add a beneficial oxygen-carrying protein, rather than fixing the broken one. Here, viruses carry gamma-globin, which is a variant mostly present in fetal blood cells, but shuts off production soon after birth. Gamma-globin acts as a repellent that prevents clotting, a main trigger for strokes and other dangerous vascular diseases.

Yet another idea also focuses on gamma-globin, the good guy oxygen-carrier. Here, rather than inserting genes to produce the protein, the key is to remove the breaks that halt its production after birth. Both Bluebird Bio and Sangamo Therapeutics, based in Richmond, California, are pursing this approach. The rise of CRISPR-oriented companies is especially giving the idea new promise, in which CRISPR can theoretically shut off the break without too many side effects.

But there are complications. All three approaches also tap into cell therapy: blood-producing cells are removed from the body through chemotherapy, genetically edited, and re-infused into the bone marrow to reconstruct the entire blood system.

Its a risky, costly, and lengthy solution. Nevertheless, there have already been signs of success in the US. One person in a Bluebird Bio trial remained symptom-free for a year; another, using a CRISPR-based approach, hasnt experienced a crisis in four months since leaving the hospital. For about a year, Bluebird Bio has monitored a dozen treated patients. So far, according to the company, none has reported episodes of severe pain.

Despite these early successes, advocates worry about the actual impact of a genetic approach to sickle-cell disease.

Similar to other gene therapies, the treatment is considered a last-line, hail Mary solution for the most difficult cases of sickle cell disease because of its inherent risks and costly nature. Yet end-of-the-line patients often suffer from kidney, liver, and heart damages that make chemotherapy far too dangerous.

Then theres the problem of global access. Some developing countries, where sickle-cell disease is more prevalent, dont even have consistent access to safe blood transfusions, not to mention the laboratory equipment needed for altering blood-producing stem cells. Recent efforts in education, early screening, and prevention have also allowed people to live longer and reduce the stigma of the disorder.

Is a $1 million price tag ever attainable? To combat exhorbitant costs, Bluebird Bio is offering an installment payment plan for five years, which can be terminated anytime the treatment stops working. Yet for patients in South Africa, India, or Cambodia, the costs far exceed the $3 per month price tag for standard treatment. Even hydroxyurea, the newly-approved FDA drug to reduce crisis pain episodes, is just a fraction of the price tag that comes with gene therapy.

As gene therapy technologies are further refined and their base cost reduced, its possible that overall costs will drop. Yet whether these treatments will be affordable in the long run remains questionable. Even as scientists focus on efficacy rather than price tag, NIH director Dr. Francis Collins believes not thinking about global access is almost unethical. There are historical examples for optimism: vaccines, once rather fringe, now touch almost every corner of our world with the help of scientific knowledge, advocacy groups, andfundamentallyproven efficacy.

With the rise of gene therapy, were now in an age of personalized medicine beyond imagination. Its true that perhaps sickle-cell disease genetic therapies arent quite there yet in terms of safety and efficacy; but without tackling access issues, the therapy will be stymied in its impact for global good. As genetic editing tools become more powerful, gene therapy has the potential to save even more livesif its made accessible to those who need it most.

Image Credit: Image by Narupon Promvichai from Pixabay

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Gene Therapy for Sickle-Cell Anemia Looks Promisingbut It's Riddled With Controversy - Singularity Hub

New research has shed light on the origins of spinocerebellar ataxia type 7 (SCA7) and demonstrates effective new therapeutic pathways for SCA7 and the more than 40 other types of spinocerebellar ataxia. The study, which appears online Monday on the website of the journal Neuron, implicates metabolic dysregulation leading to altered calcium homeostasis in neurons as the underlying cause of cerebellar ataxias.

This study not only tells us about how SCA7 begins at a basic mechanistic level,but it also provides a variety of therapeutic opportunities to treat SCA7 and other ataxias."

Al La Spada, MD, PhD, professor of Neurology, Neurobiology, and Cell Biology, at the Duke School of Medicine, and the study's senior author

SCA7 is an inherited neurodegenerative disorder that causes progressive problems with vision, movement, and balance. Individuals with SCA7 have CAG-polyglutamine repeat expansions in one of their genes; these expansions lead to progressive neuronal death in the cerebellum. SCA7 has no cure or disease-modifying therapies.

La Spada and colleagues performed transcriptome analysis on mice living with SCA7. These mice displayed down-regulation of genes that controlled calcium flux and abnormal calcium-dependent membrane excitability in neurons in their cerebellum.

La Spada's team also linked dysfunction of the protein Sirtuin 1 (Sirt1) in the development of cerebellar ataxia. Sirt1 is a "master regulator" protein associated both with improved neuronal health and with reduced overall neurodegenerative effects associated with aging. La Spada's team observed reduced activity of Sirt1 in SCA7 mice; this reduced activity was associated with depletion of NAD+, a molecule important for metabolic functions and for catalyzing the activity of numerous enzymes, including Sirt1.

When the team crossed mouse models of SCA7 with Sirt1 transgenic mice, they found improvements in cerebellar degeneration, calcium flux defects, and membrane excitability. They also found that NAD+ repletion rescued SCA7 disease phenotypes in both mouse models and human stem cell-derived neurons from patients.

These findings elucidate Sirt1's role in neuroprotection by promoting calcium regulation and describe changes in NAD+ metabolism that reduce the activity of Sirt1 in neurodegenerative disease.

"Sirt1 has been known to be neuroprotective, but it's a little unclear as to why," said Colleen Stoyas, PhD, first author of the study, and a postdoctoral fellow at the Genomics Institute of the Novartis Research Foundation in San Diego. "Tying NAD+ metabolism and Sirt1 activity to a crucial neuronal functional pathway offers a handful of ways to intervene that could be potentially useful and practical to patients."

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Study sheds light on the origins of spinocerebellar ataxia type 7 - News-Medical.net

Written by AZoNanoDec 17 2019

Despite the rising popularity of nanotechnology, the risk assessment for nanoparticles is an arduous process that poses considerable difficulties to the German Federal Institute for Risk Assessment (BfR).

Image Credit: Siarhei_AdobeStock.

To determine more efficient test techniques, a research team, including scientists from BfR and the Helmholtz Centre for Environmental Research (UFZ), closely examined the biological impacts of nanomaterials. The results of the study have been published in the Particle and Fibre Toxicology journal.

Nanomaterials are used in many applications, ranging from construction materials to dyes, and from medicine to electronics and cosmetic products. They can be found in various different applications, but the nature of these materials is not known.

Nanomaterials are defined purely by their size. Materials between one and 100 nanometres in size are referred to as a nanomaterial.

Dr Kristin Schubert, Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research

To help visualize the tiny size of nanomaterials, 1 nm is only one-millionth of a millimeter. As nanomaterials are very tiny, they can easily penetrate the bodyfor instance, via the gastrointestinal tract, skin, and lungs where they can lead to adverse impacts.

Similar to traditional chemicals, nanomaterials should also be tested for possible health hazards before they are produced, used, and commercialized at the industrial level.

Each nanomaterial is now being tested individually. Moreover, individual tests are required for each nanomaterial variant because even the tiniest changesfor instance, in surface or size propertiescan impact toxicity.

Risk assessment for nanomaterials is sometimes difficult and very time-consuming. And the list of substances to be tested is getting longer every day, because nanotechnology is growing to become a key technology with wide-ranging applications. We therefore urgently need to find solutions for more efficient risk assessment.

Dr Andrea Haase, German Federal Institute for Risk Assessment

But how to suitably classify the nanomaterials into groups? Do their effects have similarities? And what properties of materials are related to these effects? In the new study, the BfR and UFZ researchers, as well as industry representatives, collaborated to answer these questions.

We focused on the biological effects and examined which molecules and signalling pathways in the cell are influenced by which types of nanomaterials, added Schubert.

The researchers performed in vitro experiments, where they exposed the epithelial cells found in rats lungs to different types of nanomaterials and then observed for changes inside the cells. To accomplish this task, the researchers utilized the so-called multi-omics techniquesthey first detected various amino acids and lipids as well as several thousand cell proteins, and analyzed significant signaling pathways inside the cell.

Then, with the help of an innovative bioinformatic analysis method, they assessed large amounts of data and reached some fascinating results.

We were able to show that nanomaterials with toxic effects initially trigger oxidative stress and that in the process certain proteins are up- or down-regulated in the cell. In future, these key molecules could serve as biomarkers to detect and provide evidence of potential toxic effects of nanomaterials quickly and effectively.

Dr Kristin Schubert, Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research

If the nanomaterial has high levels of toxicity, it results in increased oxidative stress. This is followed by the development of inflammatory processes, and the cell dies after a specific point.

We now have a better understanding of how nanomaterials affect the cell, added Haase. And with the help of biomarkers we can now also detect much lower toxic effects than previously possible.

In addition, the scientists detected distinct links between changes in the cellular metabolism and specific properties of nanomaterials.

For example, we were able to show that nanomaterials with a large surface area affect the cell quite differently from those with a small surface area, added Schubert.

It will be very useful to know the type of parameters that play a major role in toxic effects. It implies that nanomaterials can be improved at the time of the manufacturing process, for instance, via small changes, thereby reducing the harmful effects.

Our study has taken us several large steps forward, stated Schubert. For the first time, we have extensively analysed the biological mechanisms underlying the toxic effects, classified nanomaterials into groups based on their biological effects and identified key biomarkers for novel test methods.

Andrea Haase from BfR is more than happy: The results are important for future work. They will contribute to new concepts for the efficient, reliable risk assessment of nanomaterials and set the direction in which we need to go.

Source: https://www.ufz.de/

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Researchers Explore the Biological Effects of Nanomaterials - AZoNano

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism,could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

"Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, 'Hey, I'm under attack, you better protect yourself,'" says Gerald Shadel, a professor in Salk's Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science.

Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds--or even thousands--of mitochondria.

Shadel's lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus--by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell's interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.

To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage--and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

"Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress," says Shadel.

Most of the time, he points out, it's probably a good thing that the mtDNA is more prone to damage--it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin--by damaging mtDNA first and setting off molecular alarm bells--can be less effective at damaging the nuclear DNA of cancer cells.

"It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance," Shadel says.

His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell's nucleus to ward off damage.

Reference:Wu, Z., Oeck, S., West, A. P., Mangalhara, K. C., Sainz, A. G., Newman, L. E., Shadel, G. S. (2019). Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism. https://doi.org/10.1038/s42255-019-0150-8

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Mitochondria Are the Canary in the Coal Mine for Cellular Stress - Technology Networks

Mitochondria, tiny structures present in most cells, are known for their energy-generating machinery. Now, Salk researchers have discovered a new function of mitochondria: they set off molecular alarms when cells are exposed to stress or chemicals that can damage DNA, such as chemotherapy. The results, published online in Nature Metabolism on December 9, 2019, could lead to new cancer treatments that prevent tumors from becoming resistant to chemotherapy.

Mitochondria are acting as a first line of defense in sensing DNA stress. The mitochondria tell the rest of the cell, 'Hey, I'm under attack, you better protect yourself.'"

Gerald Shadel, professor in Salk's Molecular and Cell Biology Laboratory and the Audrey Geisel Chair in Biomedical Science

Most of the DNA that a cell needs to function is found inside the cell's nucleus, packaged in chromosomes and inherited from both parents. But mitochondria each contain their own small circles of DNA (called mitochondrial DNA or mtDNA), passed only from a mother to her offspring. And most cells contain hundreds--or even thousands--of mitochondria.

Shadel's lab group previously showed that cells respond to improperly packaged mtDNA similarly to how they would react to an invading virus--by releasing it from mitochondria and launching an immune response that beefs up the cell's defenses.

In the new study, Shadel and his colleagues set out to look in more detail at what molecular pathways are activated by the release of damaged mtDNA into the cell's interior. They homed in on a subset of genes known as interferon-stimulated genes, or ISGs, that are typically activated by the presence of viruses. But in this case, the team realized, the genes were a particular subset of ISGs turned on by viruses. And this same subset of ISGs is often found to be activated in cancer cells that have developed resistance to chemotherapy with DNA-damaging agents like doxyrubicin.

To destroy cancer, doxyrubicin targets the nuclear DNA. But the new study found that the drug also causes the damage and release of mtDNA, which in turn activates ISGs. This subset of ISGs, the group discovered, helps protect nuclear DNA from damage--and, thus, causes increased resistance to the chemotherapy drug. When Shadel and his colleagues induced mitochondrial stress in melanoma cancer cells, the cells became more resistant to doxyrubicin when grown in culture dishes and even in mice, as higher levels of the ISGs were protecting the cell's DNA.

"Perhaps the fact that mitochondrial DNA is present in so many copies in each cell, and has fewer of its own DNA repair pathways, makes it a very effective sensor of DNA stress," says Shadel.

Most of the time, he points out, it's probably a good thing that the mtDNA is more prone to damage--it acts like a canary in a coal mine to protect healthy cells. But in cancer cells, it means that doxyrubicin--by damaging mtDNA first and setting off molecular alarm bells--can be less effective at damaging the nuclear DNA of cancer cells.

"It says to me that if you can prevent damage to mitochondrial DNA or its release during cancer treatment, you might prevent this form of chemotherapy resistance," Shadel says.

His group is planning future studies on exactly how mtDNA is damaged and released and which DNA repair pathways are activated by the ISGs in the cell's nucleus to ward off damage.

Source:

Journal reference:

Wu, Z., et al. (2019) Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism. doi.org/10.1038/s42255-019-0150-8.

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Salk researchers uncover new function of mitochondria - News-Medical.net

NANJING, China, Dec. 16, 2019 /PRNewswire/ -- GenScript Biotech Corp., one of the leadingbiotechnology companies inChina, today announcedits inaugural GenScript Biotech Global Forum on Jan. 14 in San Francisco, coinciding with the JP Morgan Healthcare Conference week. The Forum, exploring the theme "Cell and Gene Therapy and the Booming China Market," will feature gene and cell therapy leaders in industry, academia and the investment community and is expected to draw several hundred attendees.

"Advancements in cell and gene therapy have attracted global attention in recent years, as the promise of bringing life-changing treatments to cancer patients and others comes closer to reality," said Frank Zhang, PhD., founder and CEO of GenScript. "GenScript's Global Forum aims to foster closer collaborations among scientists, regulators, and industry, not just in the booming China market but around the globe. We hope that by working together we can advance the industry and accelerate drug development."

GenScript's Global Forum, will take place from 1:30 p.m. to 5:30 p.m. at the Grand Hyatt San Francisco. Highlights of the agenda include:

For more information about the Forum and to register for the event please visit hereor https://www.genscript.com/biotech-global-forum-2020.html.

About GenScript Biotechnology

GenScript Biotech Corporation (Stock Code: 1548.HK) is a global biotechnology group. GenScript's businesses encompass four major categories based on its leading gene synthesis technology, including operation as a Life Science CRO, enzyme and synthetic biology products, biologics development and manufacturing, as well as cell therapy.

Founded in 2002 and listed on the Hong Kong Stock Exchange in 2015, GenScript has an established global presence across Greater China, North America, the EU, and Asia Pacific. Today, over 300,000 customers from over 160 countries and regions around the world have used GenScript's premier, convenient, and reliable products and services.

GenScript currently has more than 2900 employees globally, 34% of whom hold master's and/or Ph.D. degrees. In addition, GenScript has a number of leading commercial technologies, including more than 100 patents and over 270 patent applications. As of June 2019, GenScript's products and services have been cited by 40,300 scientific papers worldwide.

GenScript is committed to striving towards its vision of being the most reliable biotech company in the world to make humans and nature healthier through biotechnology.

For more information, please visit https://www.genscript.com/

Contact:

Corporate:Fiona CheCorporate Communication Manager, GenScript+86 -025-58897288-6321Fiona.che@genscript.com

MediaSusan ThomasPrincipal, Endpoint Communications(619) 540-9195susan@endpointcommunications.net

View original content to download multimedia:http://www.prnewswire.com/news-releases/genscript-biotech-to-host-global-forum-on-cell-and-gene-therapy-and-the-booming-china-market-during-jpm-week-300975054.html

SOURCE GenScript Biotech Corp.

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GenScript Biotech to Host Global Forum on Cell and Gene Therapy and the Booming China Market During JPM Week - BioSpace

One out of eight couples has trouble conceiving, with nearly a quarter of those cases caused by unexplained male infertility. For the past decade, research has linked that infertility to defective sperm that fail to "evict" proteins called histones from DNA during development. However, the mechanisms behind that eviction and where this is happening in the sperm DNA has remained both controversial and unclear.

Now, researchers at Penn Medicine show, using newer genome-wide DNA sequencing tools, the precise genetic locations of those retained histones, as well as a key gene regulating it. The findings were published in Developmental Cell.

Taking it a step further, the researchers created a new mouse model with a mutated version of the gene, Gcn5, which allows investigators to closely track the defects in sperm from the early stages of sperm development through fertilization and on. This is an important step forward as it could lead to a better understanding of not only infertility in men -- and ways to potentially reverse it -- but also the suspected epigenetic mutations being passed onto the embryo from males either naturally or through in vitro fertilization.

Epigenetics, the factors influencing an organism's genetics that are not encoded in the DNA, play a strong role in sperm and egg formation.

For men who have unexplained infertility, everything may look normal at the doctors: normal semen counts, normal motility. Yet they can still have problems conceiving. One explanation for persistent problems is histones being in the wrong location, which may affect sperm and then early development. Now, we have a really good model to study what happens when you don't get rid of the histones appropriately in the sperm and what that may look like in the embryo."

Lacey J. Luense, PhD, first author, research associate in the lab of study senior author, Shelley L. Berger, PhD, the Daniel S. Och University Professor in the departments of Cell and Developmental Biology and Biology, and director of the Penn Epigenetics Institute

Healthy sperm lose 90 to 95 percent of histones, the main proteins in chromatin that package DNA and turn genes on and off, and replace them with protamines, which are smaller proteins able to properly pack the DNA into tiny sperm. Given the role of retained histones in infertility and embryonic development, there is great interest in determining the genomic locations so they could potentially be utilized for further study and ultimately treatment.

Past studies have produced conflicting results on the whereabouts of histones. A technology known as MNase-sequencing that uses an enzymatic reaction to pinpoint location has placed the retained histones on important gene promotors. Other studies with the same approach found histones at DNA repeats and placed in so-called "gene deserts," where they play less of a role in regulation.

"There has been controversy in the field trying to understand these discrepant data," Luense said. "In this new study, we found that both of these previously described models are correct. We find histones on genes that appear to be important for embryo development, but we also find them at repetitive elements, places that do need to be turned off and to prevent expression of these regions in the embryo."

The researchers applied a technology known as ATAC-sequencing, a more precise and faster approach, to track waves of histones at unique sites across the genome during the early and late stages of sperm development in mice. ATAC-seq can identify parts of the genome open and closed -- in this case, regions that retain the sperm histones -- and then make a cut and tag the DNA, which can then be sequenced.

In the mouse models created with the mutated Gcn5 gene, the researchers found these mice to have very low fertility. The researchers also showed that retained histones in normal mice sperm correlated with histone positions in very early embryos, supporting the hypothesis that paternal histones transfer epigenetic information to the next generation.

Having this type of mutant model gives scientists a tool to closely study the mechanisms underlying the mutated sperm's trajectory and understand what effect it may have on the embryo and in development. It also opens an opportunity to study potential therapeutic targets.

"Right now, the burden of IVF and other assisted-reproductive technologies fall on women. Even it's the male factor, it's still women who have to go through hormone injections and procedures," Berger said. "Now imagine being able to apply epigenetic therapeutics to change the levels of histones and protamines in males before embryogenesis? That's one of the questions we want to explore and this model will allow us to move toward that direction."

There are numerous available epigenetic drugs used to treat cancer and other diseases. Given their mechanisms, treating sperm with drugs to increase histone eviction is one potential route to explore.

Limitations with human embryos in science have led to a lack of overall research on infertility and the role of the father's epigenome on embryo development, which underscores the importance of studies such as this, the researchers said.

"There are a lot different factors that can alter the sperm epigenome: diet, drugs, alcohol, for example," Luense said. "We are just now starting to understand how that can affect the child and affect development. These initial, basic studies that we are doing are critical, so we can better understand what's driving these epigenetic mutations."

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Penn researchers track defective sperm epigenome linked to male infertility - News-Medical.net