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Caltech space solar power project ends first in-space mission with successes and lessons

Last June, Caltech’s Space Solar Power Demonstrator (SSPD-1) launched into space to demonstrate and test three technological innovations needed to make space solar power a reality, as we reported in Mindplex News.

Now, with SSPD-1’s mission in space concluded, engineers on Earth are celebrating the testbed’s successes and learning important lessons that will help chart the future of space solar power. All of the experiments aboard SSPD-1 were ultimately successful.

“Solar power beamed from space at commercial rates (‘lighting the globe’), is still a future prospect. But this critical mission demonstrated that it should be an achievable future,” says Caltech President Thomas F. Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. 

SSPD-1 represents a major milestone in a project that has been underway for more than a decade, consisting of three main experiments, each testing a different technology are ultra-lightweight, cheap, flexible, and deployable:

  • DOLCE (Deployable on-Orbit ultraLight Composite Experiment) will eventually become a kilometer-scale constellation to serve as a power station. It had two problems, which were fixed.
  • ALBA: photovoltaic (PV) cells to enable an assessment of the types of cells that can withstand punishing space environments. They tested various designs.
  • MAPLE (Microwave Array for Power-transfer Low-orbit Experiment): an array of flexible, lightweight microwave-power transmitters to demonstrate wireless power transmission at distance in space. MAPLE demonstrated its ability to transmit power wirelessly in space and to direct a beam to Earth—a first in the field. “These observations have already led to revisions in the design of various elements of MAPLE to maximize its performance over extended periods of time,” says Hajimiri, Bren Professor of Electrical Engineering and Medical Engineering and co-director of SSPP.

SSPD-1 will remain in orbit to support continued testing and demonstration of the vehicle’s Microwave Electrothermal Thruster engines. It will ultimately deorbit and disintegrate in Earth’s atmosphere. Meanwhile, the SSPP team continues work in the lab, studying the feedback from SSPD-1 to identify the next set of fundamental research challenges for the project to tackle.  

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Machine learning + automated experiments accelerate drug-design process

Researchers from the University of Cambridge have developed a platform that combines automated experiments with AI to predict how chemicals will react with one another, and could accelerate the design process for new drugs.

Predicting how molecules forr the discovery and manufacture of new pharmaceuticals has been a trial-and-error expensive and process, and the reactions often fail.

Reactome

Now the researchers have developed a data-driven “reactome” approach, inspired by genomics, where automated experiments are combined with machine learning to understand chemical reactivity, greatly speeding up the process.

Their results, reported in the journal Nature Chemistry, are the product of a collaboration between Cambridge and Pfizer.

“The reactome could change the way we think about organic chemistry,” said Dr Emma King-Smith from Cambridge’s Cavendish Laboratory, the paper’s first author. The reactome approach picks out relevant correlations between reactants, reagents, and performance of the reaction from the data, and points out gaps in the data itself. The data is generated from very fast, or high throughput, automated experiments.

Machine learning for faster drug design

In a related paper, published in Nature Communications, the team developed a machine learning approach that enables chemists to introduce precise transformations to pre-specified regions of a molecule, enabling faster drug design.

The approach allows chemists to tweak complex molecules—like a last-minute design change—without having to make them from scratch.

Citation: King-Smith, E., Berritt, S., Bernier, L. et al. Probing the chemical ‘reactome’ with high-throughput experimentation data. Nat. Chem. (2024). https://doi.org/10.1038/s41557-023-01393-w

Citation: King-Smith, E., Faber, F.A., Reilly, U. et al. Predictive Minisci late stage functionalization with transfer learning. Nat Commun 15, 426 (2024). 10.1038/s41467-023-42145-1 (open-access)

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Catalytic combo converts greenhouse gas CO2 to solid carbon nanofibers

Scientists at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory and Columbia University have developed a way to convert carbon dioxide (CO2), a potent greenhouse gas, into carbon nanofibers.

The new method, which uses tandem electrochemical and thermochemical reactions, runs at relatively low temperatures and ambient pressure.

Locking carbon away

As the scientists describe in the journal Nature Catalysis, this approach could successfully lock carbon away in a useful solid form to offset or even achieve negative carbon emissions.

Unlike current methods, “you can put the carbon nanofibers into cement to strengthen the cement,” said Jingguang Chen, a professor of chemical engineering at Columbia with a joint appointment at Brookhaven Lab who led the research. “That would lock the carbon away in concrete for at least 50 years, potentially longer. By then, the world should be shifted to primarily renewable energy sources that don’t emit carbon.”

As a bonus, the process also produces hydrogen gas (H2), a promising alternative fuel that, when used, creates zero emissions.

The tandem two-step 

“We found a process that can occur at about a relatively low 400 degrees Celsius, which is a much more practical, industrially achievable temperature.”

The trick was to break the reaction into stages and to use two different types of catalysts—materials that make it easier for molecules to come together and react.

The scientists started by realizing that carbon monoxide (CO) is a much better starting material than CO2 for making carbon nanofibers (CNF). Then they backtracked to find the most efficient way to generate CO from CO2.

For the second step, the scientists turned to a heat-activated thermocatalyst made of an iron-cobalt alloy. It operates at temperatures around 400 degrees Celsius, significantly milder than a direct CO2-to-CNF conversion would require. They also discovered that adding a bit of extra metallic cobalt greatly enhances the formation of the carbon nanofibers.

Truly carbon-negative

“By coupling electrocatalysis and thermocatalysis, we are using this tandem process to achieve things that cannot be achieved by either process alone,” Chen said.

If these processes are driven by renewable energy, the results would be truly carbon-negative, opening new opportunities for CO2 mitigation, the researchers say.

Citation: Xie, Z., Huang, E., Garg, S. et al. CO2 fixation into carbon nanofibres using electrochemical–thermochemical tandem catalysis. Nat Catal (2024). https://doi.org/10.1038/s41929-023-01085

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How to get more out of Moore’s Law and advance electronics

Moore’s Law, a fundamental scaling principle for electronic devices, forecasts that the number of transistors on a chip will double every two years, ensuring more computing power—but a limit exists.

Today’s most advanced chips house nearly 50 billion transistors within a space no larger than your thumbnail. The task of cramming even more transistors into that confined area has become more and more difficult, according to Penn State researchers.

3D integration

In a study published Jan. 10 in the journal Nature, Saptarshi Das, an associate professor of engineering science and mechanics and co-corresponding author of the study, and his team suggest a remedy: seamlessly implementing 3D integration with 2D materials.

In the semiconductor world, 3D integration means vertically stacking multiple layers of semiconductor devices. This approach facilitates the packing of more silicon-based transistors onto a computer chip, commonly referred to as “More Moore,” but also permits the use of transistors made from 2D materials to incorporate diverse functionalities within various layers of the stack, a concept known as “More than Moore.”

With the work outlined in the study, Saptarshi and the team demonstrate feasible paths beyond scaling current tech to achieve both More Moore and More than Moore through monolithic 3D integration. Monolithic 3D integration is a fabrication process wherein researchers directly make the devices on the one below, as compared to the traditional process of stacking independently fabricated layers.

Highest density

“Monolithic 3D integration offers the highest density of vertical connections as it does not rely on bonding of two pre-patterned chips — which would require microbumps where two chips are bonded together — so you have more space to make connections,” said Najam Sakib, graduate research assistant in engineering science and mechanics and co-author of the study.

Monolithic 3D integration faces significant challenges, though, according to Darsith Jayachandran, graduate research assistant in engineering science and mechanics and co-corresponding author of the study, since conventional silicon components would melt under the processing temperatures.

“One challenge is the process temperature ceiling of 450 degrees Celsius (C) for back-end integration for silicon-based chips — our monolithic 3D integration approach drops that temperate significantly to less than 200 C,” Jayachandran said, explaining that the process temperature ceiling is the maximum temperature allowed before damaging the prefabricated structures. “Incompatible process temperature budgets make monolithic 3D integration challenging with silicon chips, but 2D materials can withstand temperatures needed for the process.”

The researchers used existing techniques for their approach, but they are the first to successfully achieve monolithic 3D integration at this scale using 2D transistors made with 2D semiconductors called transition metal dichalcogenides.

Energy-efficient vertical stacking

The ability to vertically stack the devices in 3D integration also enabled more energy-efficient computing because it solved a surprising problem for such tiny things as transistors on a computer chip: distance.

“By stacking devices vertically on top of each other, you’re decreasing the distance between devices, and therefore, you’re decreasing the lag and also the power consumption,” said Rahul Pendurthi, graduate research assistant in engineering science and mechanics and co-corresponding author of the study.

By decreasing the distance between devices, the researchers achieved “More Moore.” By incorporating transistors made with 2D materials, the researchers met the “More than Moore” criterion as well. The 2D materials are known for their unique electronic and optical properties, including sensitivity to light, which makes these materials ideal as sensors.

This is useful, the researchers said, as the number of connected devices and edge devices — things like smartphones or wireless home weather stations that gather data on the ‘edge’ of a network — continue to increase.

“’More Than Moore’ refers to a concept in the tech world where we are not just making computer chips smaller and faster, but also with more functionalities,” said Muhtasim Ul Karim Sadaf, graduate research assistant in engineering science and mechanics and co-author of the study. “It is about adding new and useful features to our electronic devices, like better sensors, improved battery management or other special functions, to make our gadgets smarter and more versatile.”

Using 2D devices for 3D integration has several other advantages, the researchers said. One is superior carrier mobility, which refers to how an electrical charge is carried in semiconductor materials. Another is being ultra-thin, enabling the researchers to fit more transistors on each tier of the 3D integration and enable more computing power.

3D integration at a massive scale

While most academic research involves small-scale prototypes, this study demonstrated 3D integration at a massive scale, characterizing tens of thousands of devices. According to Das, this achievement bridges the gap between academia and industry and could lead to future partnerships where industry leverages Penn State’s 2D materials expertise and facilities.

The advance in scaling was enabled by the availability of high-quality, wafer-scale transition metal dichalcogenides developed by researchers at Penn State’s Two-Dimensional Crystal Consortium (2DCC-MIP), a U.S. National Science Foundation (NSF) Materials Innovation Platform and national user facility.

“This breakthrough demonstrates yet again the essential role of materials research as the foundation of the semiconductor industry and U.S. competitiveness,” said Charles Ying, program director for NSF’s Materials Innovation Platforms. “Years of effort by Penn State’s Two-Dimensional Crystal Consortium to improve the quality and size of 2D materials have made it possible to achieve 3D integration of semiconductors at a size that can be transformative for electronics.”

According to Das, this technological advancement is only the first step.

“Our ability to demonstrate, at wafer scale, a huge number of devices shows that we have been able to translate this research to a scale which can be appreciated by the semiconductor industry,” Das said. “We have put 30,000 transistors in each tier, which may be a record number. This puts Penn State in a very unique position to lead some of the work and partner with the U.S. semiconductor industry in advancing this research.”

The NSF and Army Research Office supported this research.

Citation: Jayachandran, D., Pendurthi, R., Sadaf, M.U.K. et al. Three-dimensional integration of two-dimensional field-effect transistors. Nature 625, 276–281 (2024). https://doi.org/10.1038/s41586-023-06860-5

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Transparent brain-computer interface can read deep neural activity from the surface

Researchers at the University of California San Diego have developed a neural implant that provides information about activity deep inside the brain while sitting on its surface.

The implant is made up of a thin, transparent and flexible polymer strip that is packed with a dense array of graphene electrodes.

A minimally invasive brain-computer interface

The technology, tested in transgenic mice, is intended to create a minimally invasive brain-computer interface (BCI) that provides high-resolution data about deep neural activity by using recordings from the brain surface.

The work was published on Jan. 11 in Nature Nanotechnology.

This work overcomes the limitations of current neural implant technologies. Existing surface arrays, for example, are minimally invasive, but they lack the ability to capture information beyond the brain’s outer layers.

In contrast, electrode arrays, such as Neuralink, with thin needles that penetrate the brain are capable of probing deeper layers, but they often lead to inflammation and scarring, compromising signal quality over time.

The implant is a thin, transparent and flexible polymer strip that conforms to the brain’s surface. The strip is embedded with a high-density array of tiny, circular graphene electrodes, each measuring 20 micrometers in diameter. Each electrode is connected by a micrometers-thin graphene wire to a circuit board.

In tests on transgenic mice, the implant enabled the researchers to capture high-resolution information about two types of neural activity–electrical activity and calcium activity–at the same time. When placed on the surface of the brain, the implant recorded electrical signals from neurons in the outer layers.

Imaging deep neurons

At the same time, the researchers used a two-photon microscope to shine laser light through the implant to image calcium spikes from neurons located as deep as 250 micrometers below the surface. The researchers found a correlation between surface electrical signals and calcium spikes in deeper layers.

This correlation enabled the researchers to use surface electrical signals to train neural networks to predict calcium activity—not only for large populations of neurons, but also individual neurons—at various depths.

“The neural network model is trained to learn the relationship between the surface electrical recordings and the calcium ion activity of the neurons at depth,” said Kuzum. “Once it learns that relationship, we can use the model to predict the depth activity from the surface.”

Enables longer-duration experiments in which the subject is free to move around and perform complex behavioral tasks

An advantage of being able to predict calcium activity from electrical signals is that it overcomes the limitations of imaging experiments. When imaging calcium spikes, the subject’s head must be fixed under a microscope. Also, these experiments can only last for an hour or two at a time.

“Since electrical recordings do not have these limitations, our technology makes it possible to conduct longer duration experiments in which the subject is free to move around and perform complex behavioral tasks,” said study co-first author Mehrdad Ramezani, an electrical and computer engineering Ph.D. student in Kuzum’s lab. “This can provide a more comprehensive understanding of neural activity in dynamic, real-world scenarios.”

Designing and fabricating the neural implant

The technology owes its success to several innovative design features: transparency and high electrode density combined with machine learning methods. 

“This new generation of transparent graphene electrodes embedded at high density enables us to sample neural activity with higher spatial resolution,” said Kuzum. “As a result, the quality of signals improves significantly. What makes this technology even more remarkable is the integration of machine learning methods, which make it possible to predict deep neural activity from surface signals.”

Transparency

Transparency is one of the key features of this neural implant. Traditional implants use opaque metal materials for their electrodes and wires, which block the view of neurons beneath the electrodes during imaging experiments. In contrast, an implant made using graphene is transparent, which provides a completely clear field of view for a microscope during imaging experiments.

“Seamless integration of recording electrical signals and optical imaging of the neural activity at the same time is only possible with this technology,” said Kuzum. “Being able to conduct both experiments at the same time gives us more relevant data because we can see how the imaging experiments are time-coupled to the electrical recordings.”

To make the implant completely transparent, the researchers used super thin, long graphene wires instead of traditional metal wires to connect the electrodes to the circuit board. However, fabricating a single layer of graphene as a thin, long wire is challenging because any defect will render the wire nonfunctional, explained Ramezani. “There may be a gap in the graphene wire that prevents the electrical signal from flowing through, so you basically end up with a broken wire.”

The researchers addressed this issue using a clever technique. Instead of fabricating the wires as a single layer of graphene, they fabricated them as a double layer doped with nitric acid in the middle. “By having two layers of graphene on top of one another, there’s a good chance that defects in one layer will be masked by the other layer, ensuring the creation of fully functional, thin and long graphene wires with improved conductivity,” said Ramezani.

According to the researchers, this study demonstrates the most densely packed transparent electrode array on a surface-sitting neural implant to date. Achieving high density required fabricating extremely small graphene electrodes. This presented a considerable challenge, as shrinking graphene electrodes in size increases their impedance—this hinders the flow of electrical current needed for recording neural activity.

Microfabrication technique

To overcome this obstacle, the researchers used a microfabrication technique developed by Kuzum’s lab that involves depositing platinum nanoparticles onto the graphene electrodes. This approach significantly improved electron flow through the electrodes while keeping them tiny and transparent.

“We are expanding the spatial reach of neural recordings with this technology,” said study senior author Duygu Kuzum, a professor in the Department of Electrical and Computer Engineering at the UC San Diego Jacobs School of Engineering. “Even though our implant resides on the brain’s surface, its design goes beyond the limits of physical sensing in that it can infer neural activity from deeper layers.”

Next steps

The team will next focus on testing the technology in different animal models, with the ultimate goal of human translation in the future.

Kuzum’s research group is also dedicated to using the technology to advance fundamental neuroscience research. They are sharing the technology with labs across the U.S. and Europe, contributing to diverse studies ranging from understanding how vascular activity is coupled to electrical activity in the brain to investigating how place cells in the brain are so efficient at creating spatial memory.

To make this technology more widely available, Kuzum’s team has applied for a National Institutes of Health (NIH) grant to fund efforts in scaling up production and facilitating its adoption by researchers worldwide.

“This technology can be used for so many different fundamental neuroscience investigations, and we are eager to do our part to accelerate progress in better understanding the human brain,” said Kuzum.

This study was a collaborative effort among multiple research groups at UC San Diego. The team, led by Kuzum, one of the world leaders in developing multimodal neural interfaces, includes nanoengineering professor Ertugrul Cubukcu, who specializes in advanced micro- and nanofabrication techniques for graphene materials; electrical and computer engineering professor Vikash Gilja, whose lab integrates domain-specific knowledge from the fields of basic neuroscience, signal processing, and machine learning to decode neural signals; and neurobiology and neurosciences professor Takaki Komiyama, whose lab focuses on investigating neural circuit mechanisms that underlie flexible behaviors.

Citation: Ramezani, M., Kim, JH., Liu, X. et al. High-density transparent graphene arrays for predicting cellular calcium activity at depth from surface potential recordings. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-023-01576-z

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How to train your brain to overcome tinnitus

An international research team has developed an app that they say can reduce the debilitating impact of tinnitus in weeks, using a training course and sound therapy delivered via a smartphone app. 

The team from universities in Australia, New Zealand, France and Belgium report these findings today in the journal Frontiers in Audiology and Otology. 

The initial research trial worked with 30 sufferers. Almost two-thirds experienced a “clinically significant improvement.” The team is now planning larger trials in the UK, in collaboration with University College London Hospital. 

Introducing MindEar

“Tinnitus is common, affecting up to one in four people. It is mostly experienced by older adults but can appear for children,” said Dr Fabrice Bardy, an audiologist at Waipapa Taumata Rau, University of Auckland, lead author of the paper, and co-founder of MindEar, a company set up to commercialize the MindEar technology.

Millions looking for a solution

Tinnitus is not a disease in itself. It’s usually a symptom of another underlying health condition, such as damage to the auditory system or tension occurring in the head and neck.

For some, tinnitus goes away without intervention. For others, it can be debilitatingly life-changing, affecting hearing, mood, concentration, sleep and in severe cases, causing anxiety or depression, Bardy notes. “About 1.5 million people in Australia, 4 million in the UK, and 20 million in the USA have severe tinnitus.”

“One of the most common misconceptions about tinnitus is that there is nothing you can do about it; that you just have to live with it,” he says. “This is simply not true. Professional help from those with expertise in tinnitus support can reduce the fear and anxiety attached to the sound patients experience.” 

“Cognitive behavioral therapy is known to help people with tinnitus, but it requires a trained psychologist. That’s expensive, and often difficult to access,” says Professor Suzanne Purdy, Professor of Psychology at Waipapa Taumata Rau, University of Auckland. 

“Even before we are born, our brains learn to filter out sounds that we determine to be irrelevant, such as the surprisingly loud sound of blood rushing past our ears, explains Purdy. As we grow, our brains further learn to filter out environmental noises such as a busy road, an air conditioner or sleeping partners.

“Unlike an alarm, tinnitus occurs when a person hears a sound in the head or ears, when there is no external sound source or risk presented in the environment and yet the mind responds with a similar alert response.

“The sound is perceived as an unpleasant, irritating, or intrusive noise that can’t be switched off. The brain focuses on it insistently, further training our mind to pay even more attention.

“Tinnitus is not a disease in itself. It’s usually a symptom of another underlying health condition, such as damage to the auditory system or tension occurring in the head and neck.”

Cognitive behavioral therapy + mindfulness + relaxation exercises + sound therapy

Enter MindEar. “MindEar uses a combination of cognitive behavioral therapy, mindfulness and relaxation exercises as well as sound therapy to help you train your brain’s reaction so that we can tune out tinnitus. The sound you perceive fades in the background and is much less bothersome,” she says. 

An app, “MindEar,” is available free for iPhone or Android smartphone users.

“In our trial, two-thirds of users of our bot saw improvement after 16 weeks. This was shortened to only 8 weeks when patients additionally had access to an online psychologist,” says Bardy. 

“MindEar aims to help people to practice focus through a training program, equipping the mind and body to suppress stress hormones and responses, and thus reducing the brain’s focus on tinnitus.

“Although there is no known cure for tinnitus, there are management strategies and techniques that help many sufferers find relief. Based on the evidence from this trial, the MindEar team are optimistic that there is a more accessible, rapidly available and effective tool available for the many of those affected by tinnitus still awaiting support.”

MindEar is based on the research work of an international multi-disciplinary team composed of audiologists (Dr Laure Jacquemin, Dr Michael Maslin), psychologists (Prof Suzanne Purdy and Dr Cara Wong) and ENTs (Prof Hung Thai Van), led by Bardy, based at the University of Auckland.

Citation: Bardy, F., Jacquemin, L., Wong, C. L., Maslin, M. R., & Purdy, S. C. (2024). Delivery of internet-based cognitive behavioral therapy combined with human-delivered telepsychology in tinnitus sufferers through a chatbot-based mobile app. Frontiers in Audiology and Otology, 1, 1302215. https://doi.org/10.3389/fauot.2023.1302215 (open-access)

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Putting your child in front of a TV might hurt their ability to process the world—new data

Babies and toddlers exposed to television or video viewing may be more likely to exhibit atypical sensory behaviors, according to data from researchers at Drexel’s College of Medicine published today in the journal JAMA Pediatrics.

Children may become disengaged and disinterested in activities, seeking more intense stimulation in an environment, or being overwhelmed by sensations like loud sounds or bright lights, according to the researchers.

They found that by 33 months, children exposed to greater TV viewing by their second birthday were more likely to develop atypical sensory processing behaviors, such as “sensation seeking” and “sensation avoiding,” as well as “low registration”—being less sensitive or slower to respond to stimuli, such as their name being called.

The team pulled 2011-2014 data on television or DVD-watching by babies and toddlers at 12–18 and 24–months from the National Children’s Study of 1,471 children (50% male) nationwide.

The findings suggest:

  • At 12 months, any screen exposure compared to no screen viewing was associated with a 105% greater likelihood of exhibiting “high” sensory behaviors instead of “typical” sensory behaviors related to low registration at 33 months 
  • At 18 months, each additional hour of daily screen time was associated with 23% increased odds of exhibiting “high” sensory behaviors related to later sensation avoiding and low registration.
  • At 24 months, each additional hour of daily screen time was associated with a 20% increased odds of “high” sensation seeking, sensory sensitivity, and sensation avoiding at 33 months.

Important implications

The findings add to a growing list of concerning health and developmental outcomes linked to screen time in infants and toddlers, including language delay, autism spectrum disorder, behavioral issues, sleep struggles, attention problems and problem-solving delays.

“This association could have important implications for attention deficit hyperactivity disorder and autism, as atypical sensory processing is much more prevalent in these populations,” said lead author Karen Heffler, MD, an associate professor of Psychiatry in Drexel’s College of Medicine.

“Repetitive behavior, such as that seen in autism spectrum disorder, is highly correlated with atypical sensory processing. Future work may determine whether early life screen time could fuel the sensory brain hyperconnectivity seen in autism spectrum disorders, such as heightened brain responses to sensory stimulation.”

The American Academy of Pediatrics (AAP) discourages screen time for babies under 18–24 months. Live video chat is considered by the AAP to be okay, as there may be benefit from the interaction that takes place. AAP recommends time limitations on digital media use for children 2 to 5 years to typically no more than 1 hour per day.

“Parent training and education are key to minimizing, or hopefully even avoiding, screen time in children younger than two years,” said senior author David Bennett, PhD, a professor of Psychiatry in Drexel’s College of Medicine.”

Digital media

Although the current paper looked strictly at television or DVD watching, and not media viewed on smartphones or tablets, it does provide some of the earliest data linking early-life digital media exposure with later atypical sensory processing across multiple behaviors.

The authors said future research is needed to better understand the mechanisms that drive the association between early-life screen time and atypical sensory processing.

Citation: Heffler KF, Acharya B, Subedi K, Bennett DS. Early-Life Digital Media Experiences and Development of Atypical Sensory Processing. JAMA Pediatr. Published online January 08, 2024. https://jamanetwork.com/journals/jamapediatrics/article-abstract/2813443

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Novel compound protects against infection by virus that causes COVID-19, preliminary studies show

Dana-Farber Cancer Institute scientists have discovered in a study that a version of a “stapled lipopeptide” compound may protect against infection by the coronavirus that causes COVID-19, as noted today in the journal Nature Communications. 

The scientists have launched a human clinical trial of this compound by chemically stabilizing a key coronavirus peptide molecule. If the compound proves effective as a nasal spray in the trial, it could be the basis for a new drug to prevent or treat COVID-19, say the study authors. 

Lipopeptide compounds foil a mechanism used by many types of viruses to enter and infect cells, say the reserchers. These compounds may also be effective against other dangerous and potentially deadly viruses, such as RSV, Ebola, and Nipah, as the authors also demonstrate in their study.

A critical gap in protecting people from COVID-19 infection

Vaccines, monoclonal antibodies, and small-molecule drugs have played a crucial role in protecting people from life-threatening COVID-19 infection, but “there remains a critical gap in the treatment arsenal,” says Loren Walensky, MD, PhD, Physician and Principal Investigator, Linde Program in Cancer Chemical Biology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Walensky led the research at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL). 

Needed: fast-acting, easy-to-administer and resistance-proof agents

“The constant evolution of the virus and the emergence of new variants has markedly decreased the effectiveness of immune-based approaches, requiring periodic reformulation of vaccines,” Walensky explained.

“What has been missing are fast-acting, easy-to-administer, and resistance-proof agents that can be used before or after exposure to the virus to directly prevent infection or reduce symptoms.

“Our study is an encouraging indication that stapled lipopeptides offer that potential. The results were very encouraging,” Walensky remarks. “The animals in each group that received the inhibitor maintained their weight, an indication that they remained well despite viral exposure. 

“Examination of their noses showed a relative drop in viral titers compared to the untreated control group. And evaluation of their lung tissue found that the animals were significantly protected from severe pneumonia, a common complication of COVID-19.”

Unlike mRNA vaccines, the stapled lipopeptides developed by Walensky’s lab act directly on SARS-CoV-2 (the coronavirus responsible for COVID-19) by interfering with the ability to infect healthy cells. This is especially promising for people with weakened immune systems, either due to their disease or treatment with immunosuppressive agents, such as chemotherapy.

“Imagine being able to protect yourself from COVID-19 or other disruptive respiratory viruses with a simple nasal spray that you could use to avoid infection at a large gathering or after exposure to a close contact who turns out to test positive for SARS-CoV-2,” said Walensky.

Digging deeper

Walensky’s lab has pioneered the development and application of stapled peptides for nearly 20 years.  These unique agents consist of natural peptides—a stretch of amino acids in a defined sequence whose bioactive structure is chemically stabilized by an installed “staple” and, in this case, further linked to a lipid, which is believed to help concentrate the stapled peptide at the site of viral infection—the membrane surface of the otherwise healthy cell. 

The new study shows that stapled lipopeptides are exceptionally stable, resisting extremes of temperature and chemical conditions, an important feature for persistence both inside and outside the body. The design strategy not only prevents peptide degradation in the body upon administration, but also remedies prior challenges with shipment and storage, such as the required cold chain for COVID-19 vaccines.

In 2010, Walensky’s lab first developed double-stapled peptides that target the same key step in the process by which the human immunodeficiency virus (HIV) binds to, and then infects, human cells, causing AIDS.  The stapled peptides mimicked the virus’s “landing gear,” a bundle of six coils or “helices” of the virus that comes together, enabling the virus to fuse with the membrane of the host cell. 

The therapeutic approach, known as fusion inhibition, prevents the virus from entering the cell to off-load its nucleic acid blueprint, which otherwise turns the cell into a virus-producing factory.  The stapled peptide, which mimics one of the coiled regions, disrupts formation of the fusion apparatus, halting infection at its source.

In 2014, Walensky’s team developed analogous stapled peptides targeting this same feature of the RSV virus, which can cause severe respiratory illness and even respiratory failure in the elderly and very young alike.  They showed that administering the stapled peptide as a nose drop could prevent RSV infection in mice and also prevent the spread of established nasal infection from migrating to the lungs.

When the COVID-19 pandemic broke out in early 2020, Walensky’s lab promptly converted one of the coiled motifs of the SARS-CoV-2 six-helix bundle into a stapled peptide in an effort to develop a therapeutic for pre- and post-exposure prophylaxis.

“Remarkably, the viral peptide sequence that we use to block the fusion apparatus is 100% identical between SARS-CoV-2 and SARS1, which emerged as a deadly respiratory virus in 2003,” notes Walensky.  He points out that, in contrast to the viral sequences that mutate frequently to evade immune-based therapies, the virus’s fusion sequences are rarely altered due to the critical role of six-helix bundle assembly in promoting viral infection.

In cooperation with researchers expert in highly pathogenic viruses at the NEIDL, Walensky’s team began developing dozens of stapled peptide fusion inhibitors for anti-viral testing, altering the location of the staple and the linker between the staple and the lipid, to determine which version worked best against the broadest spectrum of SARS-CoV-2 variants. Ironically, as the virus evolved to evade vaccines and monoclonal antibodies, the more effective the stapled lipopeptides became, owing to the essential nature of the fusion mechanism they target.

Then, in partnership with the laboratory of Richard Bowen, DVM, PhD, of Colorado State University and the newly formed Red Queen Therapeutics of Cambridge, Massachusetts that licensed the Dana-Farber technology, the Walensky lab began testing the inhibitors in hamsters.  The studies evaluated a lead stapled lipopeptide as a preventive and therapeutic agent.  The animals were randomly selected to receive an inhibitor before and/or after nasal inoculation with SARS-CoV-2.

“Similar to what we saw with RSV, nasal treatment with a stapled peptide fusion inhibitor – even if given after inoculation with SARS-CoV-2 – prevented the infection from adversely affecting the lungs and causing severe disease,” Walensky comments.

A second set of studies explored whether the inhibitors could help reduce transmission of the virus from one hamster to another.  Again, the results were encouraging.  “Animals that weren’t treated consistently lost weight.  Those that received treatment, either before or after exposure to an infected hamster, preserved their weight,” Walensky notes.  Correspondingly, viral loads in the noses and lungs of treated animals were lower than in untreated animals.

The fact that many viruses with pandemic potential rely on the six-helix bundle to enter and infect cells suggests that stapled lipopeptides developed by Walensky’s lab can be adapted to block or reduce infection by other viruses “on demand.”

“Red Queen Therapeutics was founded on the conviction that this novel technology from the Walensky lab would be broadly applicable in successfully combating viral threats, using a pre- and post-exposure prophylaxis paradigm, and COVID presents a proving ground as well as an important opportunity in its own right,” said Ron Moss, M.D., CEO of Red Queen Therapeutics. “We are excited to validate data in this publication with our human trials in SARS-CoV-2 now under way and anticipate having data to share later this quarter,” he added.

“This approach has the potential to fill an important gap in our arsenal against COVID-19 and other viruses that cause severe respiratory and hemorrhagic diseases,” Walensky relates.  “Imagine being able to protect yourself from COVID-19 or other disruptive respiratory viruses with a simple nasal spray that you could use to avoid infection at a large gathering or after exposure to a close contact who turns out to test positive for SARS-CoV-2. 

That is the promise this work holds, not only for otherwise healthy individuals, but especially for immunocompromised patients who remain most at risk of severe infection. As a Dana-Farber chemical biology lab that specializes in studying mechanisms of cancer chemoresistance in children, my group has also been interested in tackling the secondary causes of morbidity and mortality in our patients, and that includes life-threatening infections by treatment-resistant bacteria and viruses.     

The research was supported by the Dana-Farber Cancer Institute, a grant from the Massachusetts Consortium on Pathogen Readiness and the National Institutes of Health to the NEIDL, and the Pre-clinical Services Program of the National Institute for Allergy and Infectious Diseases, which funded in part the animal testing performed at Colorado State University.

Citation: Bird, G.H., Patten, J.J., Zavadoski, W. et al. A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential. Nat Commun 15, 274 (2024). https://www.nature.com/articles/s41467-023-44361-1 (open-access)

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Game-changing organoid model to study human cerebellar development and disease

USC scientists have pioneered a novel human brain organoid model that generates all the major cell types of the cerebellum. This a hindbrain region predominantly made up of two cell types necessary for movement, cognition, and emotion: granule cells and Purkinje neurons. 

This marks the first time that scientists have succeeded in growing Purkinje cells, which possess the molecular and electrophysiological features of functional neurons in an all-human system. 

The cerebellum controls movement and plays important roles in cognitive functions, including language, spatial processing, working memory, executive functions, and emotional processing.  

Targeting conditions like autism and ataxia disorders

Degeneration of Purkinje cells is associated with various neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder and cerebellar ataxia, a condition that affects muscle movement. 

Other neurons within the organoids—both excitatory neurons that share information, and inhibitory neurons that inhibit the sharing of information—formed circuits and showed coordinated network activity, demonstrating that they were also functional nerve cells. 

These breakthroughs in organoid-directed brain modeling have been published recently in the journal Cell Stem Cell.

New treatments for brain tumor, other diseases

The organoid model creates a platform for discovering new treatments for variety of diseases. Organoids form human-specific progenitor cells, which are associated with medulloblastoma, the most prevalent metastatic brain tumor in children. This makes the organoids a potentially useful model for studying and finding treatments for this pediatric cancer.

This project was funded by the Robert E. and May R. Wright Foundation, The Eli and Edythe Broad Foundation, and the Edward Mallinckdot, Jr. Foundation.

Citation: Alexander Atamian et al. 2024. Human cerebellar organoids with functional Purkinje cells. Cell Stem Cell. DOI: https://doi.org/10.1016/j.stem.2023.11.013 (open-access)

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How to bypass the blood-brain barrier to deliver healing antibodies

The blood-brain barrier blocks the entry of antibodies into the brain as protection. But this also limits the potential use of antibody therapeutics to treat brain diseases, such as brain tumors.

More than 100 FDA-approved therapeutic antibodies are used by medical teams to treat cancers and autoimmune, infectious and metabolic diseases. Finding ways to transport therapeutic antibodies from the peripheral blood stream into the central nervous system could create effective treatments that act in the brain, say researchers at the University of Alabama at Birmingham. 

Bypassing the blood-brain barrier

In a study published in the journal Frontiers in Cell and Developmental Biology, they report that the therapeutic antibody trastuzumab (also used as coating material for transplantable devices and a human monoclonal IgG1 antibody), was able to penetrate the blood-brain barrier in a mouse model. (Trastuzumab is used to treat breast cancer and several other cancers.) The biocompatible polymer used to achieve that was poly 2-methacryloyloxyethyl phosphorylcholine (PMPC).

“This simple methodology has great potential to serve as the platform to not only repurpose the current antibody therapeutics, but also encourage the design of novel antibodies for the treatment of brain diseases,” said Masakazu Kamata, Ph.D., leader of the study and an associate professor in the UAB Department of Microbiology.

Safe, non-toxic delivery of antibodies

In a mouse model, the polymer-modified trastuzumab did not induce neurotoxicity, did not show adverse effects in the liver, and did not disrupt the integrity of the blood-brain barrier.

“Those findings collectively indicate that PMPC conjugation achieves effective brain delivery of therapeutic antibodies, such as trastuzumab, without induction of adverse effects, at least in the liver, the blood-brain barrier or the brain,” Kamata said.

Other researchers seeking to breech the blood-brain barrier have investigated various ligands other than PMPC to boost transport, such as ligands derived from microbes and toxins, or endogenous proteins like lipoproteins. These generally have had undesirable surface properties — such as being highly immunogenic, highly hydrophobic or charged. PMPC does not exhibit those undesirable traits.

Support came from National Institutes of Health grants CA232015 and MH130183, an O’Neal Comprehensive Cancer Center at UAB Pre-R01 award, and National Science Foundation grant DMR-2208831.

Citation: Ren, J., Jepson, C. E., Nealy, S. L., Kuhlmann, C. J., Osuka, S., Azolibe, S. U., Blucas, M. T., Kharlampieva, E., & Kamata, M. (2023). Site-oriented conjugation of poly(2-methacryloyloxyethyl phosphorylcholine) for enhanced brain delivery of antibody. Frontiers in Cell and Developmental Biology, 11, 1214118. https://doi.org/10.3389/fcell.2023.1214118 https://doi.org/10.3389/fcell.2023.1214118

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