USDA Hands Out Funding for National Institute for Cellular Agriculture

The US Department of Agriculture will award Tufts University $10 million over five years to establish the National Institute for Cellular Agriculture: a flagship American cultivated protein research centre of excellence.

USDA awarded the grant as a part of a $146 million investment in sustainable agricultural research projects announced by USDA Secretary Tom Vilsack on 6 October. This investment is being made by USDA-NIFA’s Agriculture and Food Research Initiative’s (AFRI) Sustainable Agricultural Systems program — the nation’s largest competitive grants program for agricultural sciences.

Tufts University Professor David Kaplan, a cultivated meat expert, will lead the initiative and will be joined by investigators from Virginia Tech, Virginia State, University of California-Davis, MIT, and University of Massachusetts-Boston. The new institute will “develop outreach, extension, and education for the next generation of professionals” in cellular agriculture and lead research that will help to expand the menu of climate-friendly protein options and improve food system resilience.

“USDA’s historic funding for a National Institute for Cellular Agriculture is an important advancement for cultivated meat research and science. I am pleased that USDA’s leadership continues to recognise the important role these technologies can play in combating climate change and adding much needed resiliency to our food system,” said Appropriations Committee Chair Rep. Rosa DeLauro (D-CT).

Cultivated meat production is emerging as a feasible solution to help address the growing global demand for meat. By developing sustainable agri-food systems to meet this growing demand, the Good Food Institute says this investment in cultivated meat will support critical research necessary to rapidly scale cultivated meat production, expand menu options, and contribute to a robust, resilient, climate-smart food and agricultural system.

“This is a major step forward in our work to tackle climate change, infuse resiliency into our food systems, and build a stronger, more sustainable future. I am thrilled that this historic grant will be housed in the 5th District at Tufts University, a true leader in cultivated meat research, and am eager to see this transformative research brought to life,” said Rep. Katherine Clark, whose district includes the Tufts School of Engineering, where this research will primarily take place.

Source: New Food Magazine

What Are Researchers Doing to Stop Dementia?

Laura Williamson wrote . . . . . . . . .

They are words nobody wants to hear: Alzheimer’s disease and dementia. As the population ages, a growing number of older adults gradually lose cherished memories and the ability to think and, ultimately, to perform even the most basic functions of daily living.

Researchers say dementias are so varied and complex, there remain more questions than answers when it comes to how to thwart them.

“This is a condition with multiple pathologies,” said Cynthia Lemere, immediate past chair of the medical and scientific advisory group of the Alzheimer’s Association. “There’s a lot of research going on right now.”

While there are many causes of dementias, much of the research revolves around Alzheimer’s, which accounts for 60%-70% of all cases. According to the Alzheimer’s Association, more than 6.2 million people are living with Alzheimer’s disease, a number expected to double by 2050.

The federal government spends about $3.1 billion annually on Alzheimer’s research. Another $250 million comes from the Alzheimer’s Association, and last year the American Heart Association announced a joint brain health research project with Bill Gates, as well as support for a global networking effort among research centers to accelerate early detection and treatment of Alzheimer’s and related dementias.

Many drugs are being tested. Some work by going after what is considered one of the hallmarks of the disease – beta-amyloid protein. When this protein builds up in the brain, it clumps together to form plaques that stick in between nerve cells, interfering with the cells’ ability to communicate.

Lemere, an associate professor of neurology in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School in Boston, has spent the past two decades working on an Alzheimer’s vaccine and antibodies that would attack amyloid plaques.

While trials have shown some potential, it has been difficult to get sufficient amounts of antibodies to cross the blood-brain barrier, she said. Nonetheless, “there are three or four drugs in this class coming down the pipeline that look promising.” A drug that targets amyloid plaque received conditional approval from the Food and Drug Administration this summer and requires further testing to verify its benefits.

A newer area of investigation focuses on drugs to stop the spread of a protein called tau, needed to stabilize the structure of nerve cells. In the brains of people with Alzheimer’s disease, tau changes its structure and aggregates inside the cells, causing tangles to form. The tangles block nutrients and any communication from moving through the cells, which eventually die. That’s when symptoms appear.

“Alzheimer’s disease doesn’t start when you begin to see memory loss. It starts 15-25 years earlier, when these plaques and tangles are forming,” Lemere said. “When you have them both for a long period of time, neurodegeneration starts.”

So far, researchers have seen the best results with patients who are in the earliest stages of Alzheimer’s, Lemere said. “Previous clinical trials have shown that these drugs do not work well for people with moderate to severe Alzheimer’s disease. If someone has already lost 40% of their hippocampal neurons, clearing plaque won’t bring those back. That’s why we still need to continue to find ways to help those in later stages of the disease.”

What’s causing beta-amyloid to accumulate in the first place remains unclear. Some believe it may be an immune system response to viral infections, such as herpes, and may even be linked to the bacteria in gum disease.

“It turns out that amyloid plays a role in protecting the brain from infection,” said Dr. Mitchell Elkind, immediate past president of the American Heart Association. He is a professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City.

When an infection attacks the brain, beta-amyloid may be overproduced as part of an immune response, he said. One avenue of investigation hypothesizes that anti-viral agents could therefore prevent Alzheimer’s or slow progression of the disease based on the theory that “if we eliminate the inciting insult of the infection, perhaps we can decrease the amount of amyloid. That’s an exciting possibility.”

Studying COVID-19 may help, Elkind said. “For those of us interested in the concept that infections may worsen dementia, COVID provides a great model because there is so much of it around. It can help us answer the question of whether a virus can cause long-term cognitive decline. We don’t know yet.”

When viruses and bacteria activate the immune system, they also produce inflammation, which researchers believe contributes to plaque development.

“Inflammation is a hot button now for Alzheimer’s disease research,” Elkind said. Investigators are exploring whether anti-inflammatory agents can be used to ward off symptoms.

Lemere said she believes the most promising approach may be combinations of drugs that help the immune cells in the brain do their job while tamping down inflammation.

“That is going to be the wave of the future,” she said. “Maybe an anti-inflammatory agent with a tau antibody to prevent the downstream neurodegeneration.”

But even if researchers succeed in developing drugs that clear the brain of amyloid plaques and tau tangles, it won’t stop other forms of dementia, said Dr. Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai Health System in New York City.

About 10% of dementias are vascular – they’re linked to strokes or issues with poor blood flow to the brain. Others have mixed dementia, which can be a combination of Alzheimer’s, vascular and other less common types of dementia.

Sano’s center works with people who often develop dementias related to Type 2 diabetes and heart disease risk factors, such as high blood pressure, and these “have a very different profile of cognitive deficits.” For example, people with diabetes begin with greater problems with executive functions, such as the ability to plan and organize. Memory may be less impaired.

Lifestyle behaviors remain an important avenue for preventing vascular dementia, she said. Controlling blood pressure, cholesterol and blood sugar levels and making other lifestyle changes, such as quitting smoking, exercising, eating a nutritious diet and losing weight – metrics the AHA has dubbed Life’s Simple 7 – all have been shown to help maintain good brain health as people age.

This has to start early, Elkind said. “It’s not your blood pressure in your 70s and 80s that causes dementia, but what it was in your 40s and 50s.”

One of the best things people can do is exercise, Lemere said. “It promotes cardiovascular health, which is related to brain health. It’s anti-inflammatory and it promotes better sleep. Lack of sleep is a risk factor for Alzheimer’s disease, and exercise is one of the biggest ways people can stave off or reduce their risk for dementia.”

Source: American Heart Association

Highly Potent, Stable Nanobodies Stop Sars-CoV-2

Göttingen researchers have developed mini-antibodies that efficiently block the coronavirus Sars-CoV-2 and its dangerous new variants. These so-called nanobodies bind and neutralize the virus up to 1000 times better than previously developed mini-antibodies. In addition, the scientists optimized their mini-antibodies for stability and resistance to extreme heat. This unique combination makes them promising agents to treat Covid-19. Since nanobodies can be produced at low costs in large quantities, they could meet the global demand for Covid-19 therapeutics. The new nanobodies are currently in preparation for clinical trials.

Antibodies help our immune system to fend off pathogens. For example, the molecules attach to viruses and neutralize them so that they can no longer infect cells. Antibodies can also be produced industrially and administered to acutely ill patients. They then act like drugs, relieving symptoms and shortening recovery from the disease. This is established practice for treating hepatitis B and rabies. Antibodies are also used for treating COVID-19 patients. However, producing these molecules on an industrial scale is too complex and expensive to meet worldwide demand. Nanobodies could solve this problem.

Scientists at the Max Planck Institute for Biophysical Chemistry in Göttingen (Germany) and the University Medical Center Göttingen have now developed mini-antibodies (also known as VHH antibodies or nanobodies) that unite all the properties required for a potent drug against Covid-19. “For the first time, they combine extreme stability and outstanding efficacy against the virus and its Alpha, Beta, Gamma, and Delta mutants,” emphasizes Dirk Görlich, director at the Max Planck Institute for Biophysical Chemistry.

At first glance, the new nanobodies hardly differ from anti-Sars-CoV-2 nanobodies developed by other labs. They are all directed against a crucial part of the coronavirus spikes, the receptor-binding domain that the virus deploys for invading host cells. The nanobodies block this binding domain and thereby prevent the virus from infecting cells.

“Our nanobodies can withstand temperatures of up to 95 °C without losing their function or forming aggregates,” explains Matthias Dobbelstein, professor and director of the University Medical Center Göttingen’s Institute of Molecular Oncology. “For one thing, this tells us that they might remain active in the body long enough to be effective. For another, heat-resistant nanobodies are easier to produce, process, and store.”

Single, double, and triple nanobodies

The simplest mini-antibodies developed by the Göttingen team already bind up to 1000 times more strongly to the spike protein than previously reported nanobodies. They also bind very well to the mutated receptor-binding domains of the Alpha, Beta, Gamma, and Delta strains. “Our single nanobodies are potentially suitable for inhalation and thus for direct virus neutralization in the respiratory tract,” Dobbelstein says. “In addition, because they are very small, they could readily penetrate tissues and prevent the virus from spreading further at the site of infection.”

A ‘nanobody triad’ further improves binding: The researchers bundled three identical nanobodies according to the symmetry of the spike protein, which is comprised of three identical building blocks with three binding domains. “With the nanobody triad, we literally join forces: In an ideal scenario, each of the three nanobodies attaches to one of the three binding domains,” reports Thomas Güttler, a scientist in Görlich’s team. “This creates a virtually irreversible bond. The triple will not let release the spike protein and neutralizes the virus even up to 30,000-fold better than the single nanobodies.” Another advantage: The larger size of the nanobody triad expectedly delays renal excretion. This keeps them in the body for longer and promises a longer-lasting therapeutic effect.

As a third design, the scientists produced tandems. These combine two nanobodies that target different parts of the receptor-binding domain and together can bind the spike protein. “Such tandems are extremely resistant to virus mutations and the resulting ‘immune escape’ because they bind the viral spike so strongly”, explains Metin Aksu, a researcher in Görlich’s team.

For all nanobody variants – monomeric, double as well as triple – the researchers found that very small amounts are sufficient to stop the pathogen. If used as a drug, this would allow for a low dosage and thus for fewer side effects and lower production costs.

“Our nanobodies originate from alpacas and are smaller and simpler than conventional antibodies,” Görlich says. To generate the nanobodies against Sars-CoV-2, the researchers immunized three alpacas – Britta, Nora, and Xenia from the herd at the Max Planck Institute for Biophysical Chemistry – with parts of the coronavirus spike protein. The mares then produced antibodies, and the scientists drew a small blood sample from the animals. For the alpacas, the mission was then complete, as all further steps were carried out with the help of enzymes, bacteria, so-called bacteriophages, and yeast. “The overall burden on our animals is very low, comparable to vaccination and blood testing in humans,” Görlich explains.

Görlich’s team extracted around one billion blueprints for nanobodies from the alpacas’ blood. What then followed was a laboratory routine perfected over many years: The biochemists used bacteriophages to select the very best nanobodies from the initially vast pool of candidates. These were then tested for their efficacy against Sars-CoV-2 and further improved in successive rounds of optimization.

Not every antibody is ‘neutralizing’. Researchers of Dobbelstein’s group therefore determined if and how well the nanobodies prevent the viruses from replicating in cultured cells in the lab. “By testing a wide range of nanobody dilutions, we find out which quantity suffices to achieve this effect,” explains Antje Dickmanns from Dobbelstein’s team. Her colleague Kim Stegmann adds: “Some of the nanobodies were really impressive. Less than a millionth of a gram per liter of medium was enough to completely prevent infection. In the case of the nanobody triads, even another twenty-fold dilution was sufficient.“

Also effective against current coronavirus variants

Over the course of the coronavirus pandemic, new virus variants have emerged and rapidly became dominant. These variants are often more infectious than the strain that first appeared in Wuhan (China). Their mutated spike protein can also ‘escape’ neutralization by some originally effective antibodies of infected, recovered, or vaccinated persons. This makes it more difficult even for an already trained immune system to eliminate the virus. This problem also affects previously developed therapeutic antibodies and nanobodies.

This is where the new nanobodies show their full potential, as they are also effective against the major coronavirus variants of concern. The researchers had inoculated their alpacas with part of the spike protein of the first known Sars-CoV-2 virus, but remarkably, the animals’ immune system also produced antibodies that are active against the different virus variants. “Should our nanobodies prove ineffective against a future variant, we can reimmunize the alpacas. Since they have already been vaccinated against the virus, they would very quickly produce antibodies against the new variant,” Güttler asserts confidently.

Therapeutic application in view

The Göttingen team is currently preparing the nanobodies for therapeutic use. Dobbelstein emphasizes: “We want to test the nanobodies as soon as possible for safe use as a drug so that they can be of benefit to those seriously ill with Covid-19 and those who have not been vaccinated or cannot build up an effective immunity.” The team is supported by experts in technology transfer: Dieter Link (Max Planck Innovation), Johannes Bange (Lead Discovery Center, Dortmund, Germany), and Holm Keller (kENUP Foundation). The Max Planck Foundation provides financial support for the project.

The receptor-binding domain of Sars-CoV-2 is known to be a good candidate for a protein vaccine but so far difficult to manufacture economically on a large scale and in a form, which activates the immune system against the virus. Bacteria programmed accordingly produce incorrectly folded material. The Göttingen researchers discovered a solution for this problem: They identified special nanobodies that enforce correct folding in bacterial cells, without obstructing the crucial neutralizing part of the receptor-binding domain. This might allow for vaccines that can be produced inexpensively, can be quickly adapted to new virus variants, and can be distributed with simple logistics even in countries with little infrastructure. “The fact that nanobodies can help with protein folding was previously not known and is extremely interesting for research and pharmaceutical applications,” Görlich says.

Source: Max-Planck-Gesellschaft

Researchers Develop Wearable Sensor for Detecting Atrial Fibrillation

Advanced devices developed by a mechanical engineering team at the University of Hong Kong (HKU) has proven to be useful for detecting potential stroke patients and helping machines mimic human brain functions.

In a collaboration with Nanjing University, Dr Paddy K.L. Chan, Associate Professor at the Department of Mechanical Engineering, developed a novel wearable electrocardiogram (ECG) sensor by integrating flexible, ultra-thin organic semiconductors into a flexible polyimide substrate. Powered by button battery, the sensor has outstanding signal amplification properties with a gain larger than 10,000, which allows it to detect electrophysiological signal, or f-wave with a frequency of 357 beats per minute (BPM), which indicates atrial fibrillation.

Conventional portable ECG sensors cannot easily detect the f-wave due to its weak amplitude. Atrial fibrillation is the most common arrhythmia associated with the increased risk of stroke or heart failure. The high signal detection capability stems from the ultralow subthreshold swing (SS) in the organic field effect transistors (OFETs).

Dr Chan’s study showed the ECG sensor managed to pick up unusual signals from patients with atrial fibrillation, while conventional electrodes could not.

“People wearing the new sensors can also enjoy freedom of movement, run around or even take a shower if they want, not being attached to a machine. We have seen a breakthrough in application with the use of a new device structure,” he said. The finding has been published in Nature Communications, in the article entitled “Sub-thermionic, ultra-high-gain organic transistors and circuits.”

Dr Chan’s previous breakthrough in developing the staggered structure monolayer OFETs, the material used in the latest experiment, was published in Advanced Materials. A US patent was also filed for the innovation. In the latest work, his team has advanced the application of the monolayer OFETs to flexible substrate for wearable electronic applications.

“The subthreshold swing is an important parameter in transistor or inverter operation as it implies how much voltage change is needed to turn the device from “off” state to “on” state. Our devices provide a record low subthreshold swing device which ensures low operating power and high sensitivity,” Dr Chan said.

His team also succeeded in adding ‘memory’ or collected signal, information to an organic transistor, which paves the way for advanced machine learning to mimic human brain functions.

The work has been published in Nature Communications, in another article entitled “Mimicking associative learning using an ion-trapping non-volatile synaptic organic electrochemical transistor”.

“Our paper explains the physics behind how information can be stored in a device,” said Dr Chan. “It sets the stage for the next generation of computer learning through the enhancement of the ‘learning function’ of a device. For example, we can integrate the memory transistors with optical sensors for image processing and computation at the same time. The memory transistors are building blocks for the artificial neural network that can perform signal recognition or learn like a human brain.”

Dr Chan’s team successfully added the “ion retainer” polytetrahydrofuran (PTHF) into a conductive organic polymer PEDOT:TOS. The PTHF can significantly slow down the move in-and-out of the ions in the PEDOT:TOS channel layer and maintain them at the desired conductance state. Multi-conductance levels, which can be considered as “memory levels”, were achieved. The experiment was held jointly with Northwestern University.

There is vast room for research in this area of human-machine interface, with unthinkable benefits for mankind. “There are unlimited possibilities when it comes to the applications of such interface,” added Dr Chan. In the meantime, however, he said that his focus would be on developing sophisticated circuit using advanced materials.

Source: HKU

Researchers Find Potential Path to a Broadly Protective COVID-19 Vaccine Using T Cells

Rachel Leeson wrote . . . . . . . . .

Gaurav Gaiha, MD, DPhil, a member of the Ragon Institute of MGH, MIT and Harvard, studies HIV, one of the fastest-mutating viruses known to humankind. But HIV’s ability to mutate isn’t unique among RNA viruses — most viruses develop mutations, or changes in their genetic code, over time. If a virus is disease-causing, the right mutation can allow the virus to escape the immune response by changing the viral pieces the immune system uses to recognize the virus as a threat, pieces scientists call epitopes.

To combat HIV’s high rate of mutation, Gaiha and Elizabeth Rossin, MD, PhD, a Retina Fellow at Massachusetts Eye and Ear, a member of Mass General Brigham, developed an approach known as structure-based network analysis. With this, they can identify viral pieces that are constrained, or restricted, from mutation. Changes in mutationally constrained epitopes are rare, as they can cause the virus to lose its ability to infect and replicate, essentially rendering it unable to propagate itself.

When the pandemic began, Gaiha immediately recognized an opportunity to apply the principles of HIV structure-based network analysis to SARS-CoV-2, the virus that causes COVID-19. He and his team reasoned that the virus would likely mutate, potentially in ways that would allow it to escape both natural and vaccine-induced immunity. Using this approach, the team identified mutationally constrained SARS-CoV-2 epitopes that can be recognized by immune cells known as T cells. These epitopes could then be used in a vaccine to train T cells, providing protective immunity. Recently published in Cell, this work highlights the possibility of a T cell vaccine which could offer broad protection against new and emerging variants of SARS-CoV-2 and other SARS-like coronaviruses.

From the earliest stages of the COVID-19 pandemic, the team knew it was imperative to prepare against potential future mutations. Other labs already had published the protein structures (blueprints) of roughly 40% of the SARS-CoV-2 virus, and studies indicated that patients with a robust T cell response, specifically a CD8+ T cell response, were more likely to survive COVID-19 infection.

Gaiha’s team knew these insights could be combined with their unique approach: the network analysis platform to identify mutationally constrained epitopes and an assay they had just developed, a report on which is currently in press at Cell Reports, to identify epitopes that were successfully targeted by CD8+ T cells in HIV-infected individuals. Applying these advances to the SARS-CoV-2 virus, they identified 311 highly networked epitopes in SARS-CoV-2 likely to be both mutationally constrained and recognized by CD8+ T cells.

“These highly networked viral epitopes are connected to many other viral parts, which likely provides a form of stability to the virus,” says Anusha Nathan, a medical student in the Harvard-MIT Health Sciences and Technology program and co–first author of the study. “Therefore, the virus is unlikely to tolerate any structural changes in these highly networked areas, making them resistant to mutations.”

You can think of a virus’s structure like the design of a house, explains Nathan. The stability of a house depends on a few vital elements, like support beams and a foundation, which connect to and support the rest of the house’s structure. It is therefore possible to change the shape or size of features like doors and windows without endangering the house itself. Changes to structural elements, like support beams, however, are far riskier. In biological terms, these support beams would be mutationally constrained — any significant changes to size or shape would risk the structural integrity of the house and could easily lead to its collapse.

Highly networked epitopes in a virus function as support beams, connecting to many other parts of the virus. Mutations in such epitopes can risk the virus’s ability to infect, replicate, and ultimately survive. These highly networked epitopes, therefore, are often identical, or nearly identical, across different viral variants and even across closely related viruses in the same family, making them an ideal vaccine target.

The team studied the identified 311 epitopes to find which were both present in large amounts and likely to be recognized by the vast majority of human immune systems. They ended up with 53 epitopes, each of which represents a potential target for a broadly protective T cell vaccine. Since patients who have recovered from COVID-19 infection have a T cell response, the team was able to verify their work by seeing if their epitopes were the same as ones that had provoked a T cell response in patients who had recovered from COVID-19. Half of the recovered COVID-19 patients studied had T cell responses to highly networked epitopes identified by the research team. This confirmed that the epitopes identified were capable of inducing an immune reaction, making them promising candidates for use in vaccines.

“A T cell vaccine that effectively targets these highly networked epitopes,” says Rossin, who is also a co–first author of the study, “would potentially be able to provide long-lasting protection against multiple variants of SARS-CoV-2, including future variants.”

By this time, it was February 2021, more than a year into the pandemic, and new variants of concern were showing up across the globe. If the team’s predictions about SARS-CoV-2 were correct, these variants of concerns should have had little to no mutations in the highly networked epitopes they had identified.

The team obtained sequences from the newly circulating B.1.1.7 Alpha, B.1.351 Beta, P1 Gamma, and B.1.617.2 Delta SARS-CoV-2 variants of concern. They compared these sequences with the original SARS-CoV-2 genome, cross-checking the genetic changes against their highly networked epitopes. Remarkably, of all the mutations they identified, only three mutations were found to affect highly networked epitopes sequences, and none of the changes affected the ability of these epitopes to interact with the immune system.

“Initially, it was all prediction,” says Gaiha, an investigator in the MGH Division of Gastroenterology and senior author of the study. “But when we compared our network scores with sequences from the variants of concern and the composite of circulating variants, it was like nature was confirming our predictions.”

In the same time period, mRNA vaccines were being deployed and immune responses to those vaccines were being studied. While the vaccines induce a strong and effective antibody response, Gaiha’s group determined they had a much smaller T cell response against highly networked epitopes compared to patients who had recovered from COVID-19 infections.

While the current vaccines provide strong protection against COVID-19, Gaiha explains, it’s unclear if they will continue to provide equally strong protection as more and more variants of concern begin to circulate. This study, however, shows that it may be possible to develop a broadly protective T cell vaccine that can protect against the variants of concern, such as the Delta variant, and potentially even extend protection to future SARS-CoV-2 variants and similar coronaviruses that may emerge.

Source: Massachusetts General Hospital