Nanobody Penetrates Brain Cells to Halt the Progression of Parkinson’s

Researchers from the Johns Hopkins University School of Medicine have helped develop a nanobody capable of getting through the tough exterior of brain cells and untangling misshapen proteins that lead to Parkinson’s disease, Lewy body dementia, and other neurocognitive disorders. The research, published last month in Nature Communications, was led by Xiaobo Mao, an associate professor of neurology at the School of Medicine, and included scientists at the University of Michigan, Ann Arbor. Their aim was to find a new type of treatment that could specifically target the misshapen proteins, called alpha-synuclein, which tend to clump together and gum up the inner workings of brain cells. Emerging evidence has shown that the alpha-synuclein clumps can spread from the gut or nose to the brain, driving the disease progression.

Nanobodies—miniature versions of antibodies, which are proteins in the blood that help the immune system find and attack foreign pathogens—are natural compounds in the blood of animals such as llamas and sharks and are being studied to treat autoimmune diseases and cancer in humans. In theory, antibodies have the potential to zero in on clumping alpha-synuclein proteins, but have a hard time getting through the outer covering of brain cells. To squeeze through these tough brain cell coatings, the researchers decided to use nanobodies instead. The researchers had to shore up the nanobodies to help them keep stable within a brain cell. To do this, they genetically engineered them to rid them of chemical bonds that typically degrade inside a cell. Tests showed that without the bonds, the nanobody remained stable and was still able to bind to misshapen alpha-synuclein.

The team made seven similar types of nanobodies, known as PFFNBs, that could bind to alpha-synuclein clumps. Of the nanobodies they created, onePFFNB2—did the best job of glomming onto alpha-synuclein clumps and not single molecules, or monomer of alpha-synuclein, which are not harmful and may have important functions in brain cells. Additional tests in mice showed that the PFFNB2 nanobody cannot prevent alpha-synuclein from collecting into clumps, but it can disrupt and destabilize the structure of existing clumps.

The structure of alpha-synuclein clumps (left) was disrupted by the nanobody PFFNB2. The debris from the disrupted clump is shown on the right.

Strikingly, we induced PFFNB2 expression in the cortex, and it prevented alpha-synuclein clumps from spreading to the mouse brain’s cortex, the region responsible for cognition, movement, personality, and other high-order processes,” says Ramhari Kumbhar, the co-first author and a postdoctoral fellow at the School of Medicine.

The success of PFFNB2 in binding harmful alpha-synuclein clumps in increasingly complex environments indicates that the nanobody could be key to helping scientists study these diseases and eventually develop new treatments,” Mao says.


Tumors Partially Destroyed with Sound Don’t Come Back

Noninvasive sound technology developed at the University of Michigan (U-M) breaks down liver tumors in rats, kills cancer cells and spurs the immune system to prevent further spread—an advance that could lead to improved cancer outcomes in humans. By destroying only 50% to 75% of liver tumor volume, the rats’ immune systems were able to clear away the rest, with no evidence of recurrence or metastases in more than 80% of animals.

The 700kHz, 260-element histotripsy ultrasound array transducer used in Prof. Xu’s lab

Even if we don’t target the entire tumor, we can still cause the tumor to regress and also reduce the risk of future metastasis,” said Zhen Xu, professor of biomedical engineering at U-M and corresponding author of the study in Cancers. Results also showed the treatment stimulated the rats’ immune responses, possibly contributing to the eventual regression of the untargeted portion of the tumor and preventing further spread of the cancer.

The treatment, called histotripsy, noninvasively focuses ultrasound waves to mechanically destroy target tissue with millimeter precision. The relatively new technique is currently being used in a human liver cancer trial in the United States and Europe. In many clinical situations, the entirety of a cancerous tumor cannot be targeted directly in treatments for reasons that include the mass’ size, location or stage. To investigate the effects of partially destroying tumors with sound, this latest study targeted only a portion of each mass, leaving behind a viable intact tumor. It also allowed the team, including researchers at Michigan Medicine and the Ann Arbor VA Hospital, to show the approach’s effectiveness under less than optimal conditions.

Histotripsy is a promising option that can overcome the limitations of currently available ablation modalities and provide safe and effective noninvasive liver tumor ablation,” said Tejaswi Worlikar, a doctoral student in biomedical engineering. “We hope that our learnings from this study will motivate future preclinical and clinical histotripsy investigations toward the ultimate goal of clinical adoption of histotripsy treatment for liver cancer patients.”

Liver cancer ranks among the top 10 causes of cancer related deaths worldwide and in the U.S. Even with multiple treatment options, the prognosis remains poor with five-year survival rates less than 18% in the U.S. The high prevalence of tumor recurrence and metastasis after initial treatment highlights the clinical need for improving outcomes of liver cancer. Where a typical ultrasound uses sound waves to produce images of the body’s interior, U-M engineers have pioneered the use of those waves for treatment. And their technique works without the harmful side effects of current approaches such as radiation and chemotherapy.

Our transducer, designed and built at U-M, delivers high amplitude microsecond-length ultrasound pulses—acoustic cavitation—to focus on the tumor specifically to break it up,” Xu said. “Traditional ultrasound devices use lower amplitude pulses for imaging.”


Tiny Bubbles Destroy Tumours in Seven Minutes

Following her diagnosis with liver cancer last June, 68-year-old Sheila Riley braced herself for painful and gruelling treatmentsSurgery, chemotherapy, radio-therapy and even ablation — where heat is used to destroy tumours — are some of medicine’s most effective tools against cancer, but the potential side-effects can be hard to bear. In fact, Sheila was spared these thanks to a radical new form of therapy that uses tiny bubbles of gas to destroy tumours within minutes and doesn’t leave a mark on the body. She was one of the first patients in the UK to undergo histotripsy, where focused ultrasound waves are directed from outside the body to destroy tumours by generating thousands of exploding gas bubbles. So rapid is the procedure that her tumour was obliterated painlessly — in under seven minutes.

It was amazing,’ says the grandmother of eight, who had the treatment last August at St James’s University Hospital in Leeds. ‘I didn’t need any medication — not even painkillers afterwards,’ adds Sheila, who lives in Bradford with her partner Frank, 70. ‘I was able to go shopping the next day, and two days after my treatment I was out with friends. It didn’t even leave a mark on my skin.

It is now hoped the procedure can help those with tumours in other parts of the bodyHistotripsy was pioneered by researchers at the University of Michigan in the U.S. and relies on a process called cavitation — creating an empty space inside something solid — to eradicate cancer. First, a beam of ultrasound energy is directed through the skin to the tumour site. As the beam hits the targeted spot, it activates thousands of pockets of gas that occur naturally in tissue throughout the body, even tumours, as a result of the respiratory process. These tiny pockets of gas are usually dormant, but when blasted with the sound waves, they expand, vibrate and explode, forming a high-energy cloud of microbubbles in the tumour. As they rapidly expand and collapse, the bubbles break up surrounding cancerous tissue, liquifying it into a solution that then gets passed out of the body as waste.

Unlike existing treatments such as microwave ablation, where a heat-generating probe is used to ‘cook’ tumour cells, there is no heat that might damage surrounding healthy tissue, making cavitation potentially safer. This capacity for ultrasound to destroy tissue has been known about for years but was not previously adopted as a cancer treatment because it was too difficult to control the bubble clouds and avoid damaging healthy tissue.

However, the process has now been fine-tuned and the energy source can be better directed inside the tumour, avoiding the risk of nearby healthy tissue or organs being affected. An international trial is now under way looking at histotripsy for liver cancer. The chief investigator, Professor Tze Min Wah, a senior consultant interventional radiologist at St James’s University Hospital, believes cavitation could transform cancer treatment. ‘Rather than using heat, radiation or surgery to remove the tumour, the bubble cloud created by histotripsy is so powerful that it ruptures the tumour but doesn’t damage the tissue around it,’ she says.


Solar Cells with 30-year Lifetimes

A new transparency-friendly solar cell design could marry high efficiencies with 30-year estimated lifetimes, research led by the University of Michigan has shown. It may pave the way for windows that also provide solar power.

Solar energy is about the cheapest form of energy that mankind has ever produced since the industrial revolution,” said Stephen Forrest, Professor of Electrical Engineering, who led the research. “With these devices used on windows, your building becomes a power plant.”

While silicon remains king for solar panel efficiency, it isn’t transparent. For window-friendly solar panels, researchers have been exploring organic—or carbon-basedmaterials. The challenge for Forrest’s team was how to prevent very efficient organic light-converting materials from degrading quickly during use.

The strength and the weakness of these materials lie in the molecules that transfer the photogenerated electrons to the electrodes, the entrance points to the circuit that either uses or stores the solar power. These materials are known generally as “non-fullerene acceptors” to set them apart from the more robust but less efficient “fullerene acceptors” made of nanoscale carbon mesh. Solar cells made with non-fullerene acceptors that incorporate sulfur can achieve silicon-rivaling efficiencies of 18%, but they do not last as long.

The team, including researchers at North Carolina State University and Tianjin University and Zhejiang University in China, set out to change that. In their experiments, they showed that without protecting the sunlight-converting material, the efficiency fell to less than 40% of its initial value within 12 weeks under the equivalent of 1 sun’s illumination.

Non-fullerene acceptors cause very high efficiency, but contain weak bonds that easily dissociate under high energy photons, especially the UV [ultraviolet] photons common in sunlight,” said Yongxi Li, U-M assistant research scientist in electrical engineering and computer science and first author of the paper in Nature Communications.



An “unhackablecomputer chip lived up to its name in its first bug bounty competition, foiling over 500 cybersecurity researchers who were offered tens of thousands of dollars to analyze it and three other secure processor technologies for vulnerabilities. MORPHEUS, developed by computer science researchers at the University of Michigan, weathered the three-month virtual program DARPA dubbed the Finding Exploits to Thwart Tampering—or FETTBug Bounty without a single successful attack. In bug bounty programs, organizations or software developers offer compensation or other incentives to individuals who can find and report bugs or vulnerabilities.

DARPA, the Defense Advanced Research Projects Agency, partnered with the Department of Defense’s Defense Digital Service and Synack, a crowdsourced security platform, to conduct FETT, which ran from June through August 2020. It also tested technologies from MIT, Cambridge University, Lockheed Martin and nonprofit tech institute SRI International. The U-M team achieved its results by abandoning a cornerstone of traditional computer security—finding and eliminating software bugs, says team leader Todd Austin, the S. Jack Hu Collegiate Professor of Computer Science and Engineering. MORPHEUS works by reconfiguring key bits of its code and data dozens of times per second, turning any vulnerabilities into dead ends for hackers.

MORPHEUS blocks potential attacks by encrypting and randomly reshuffling key bits of its own code and data twenty times per second. 

Imagine trying to solve a Rubik’s Cube that rearranges itself every time you blink,” Austin said. “That’s what hackers are up against with MORPHEUS. It makes the computer an unsolvable puzzle.”

MORPHEUS has previously proven itself in the lab, but the FETT Bug Bounty marks the first time that it was exposed to a group of skilled cybersecurity researchers from around the globe. Austin says its success is further proof that computer security needs to move away from its traditional bugs-and-patches paradigm. “Today’s approach of eliminating security bugs one by one is a losing game,” he said. “Developers are constantly writing code, and as long as there is new code, there will be new bugs and security vulnerabilities. With MORPHEUS, even if a hacker finds a bug, the information needed to exploit it vanishes within milliseconds. It’s perhaps the closest thing to a future-proof secure system.”

For FETT, the MORPHEUS architecture was built into a computer system that housed a mock medical database. Computer experts were invited to try to breach it remotely. MORPHEUS was the second-most popular target of the seven processors evaluated.



Arms Nerves Trained To Control Movements of Prosthetic Fingers

Today’s artificial limbs can look very natural, and now an innovative process makes prosthetic hands move more naturally as well. In an innovative experiment, scientists have shown that the nerves in patients’ arms can be trained to control the movements of prosthetic fingers and thumbs.

“This is the biggest advance in motor control for people with amputations in many years,” said Paul Cederna, a professor of plastic surgery and biomedical engineering at the University of Michigan.

A challenge to powering prosthetics has been the minute signals put out by an amputee’s nerves. Cederna’s team boosted the signal by wrapping tiny bits of muscle around nerve endings, according to their study published in Science Translational Medicine.

As the nerves grow into the muscle, the person’s thoughts can create a muscle twitch that produces a signal big enough to be picked up by tiny wires connected to a nearby computer, which tells the prosthetic hand to move.

Our ultimate goal is to have prosthetic limbs that the person views as a part of their body,” Cederna said. In an example of how well the system works, a woman who was nervously tapping her own fingers prompted the prosthetic to tap right along with it, Cederna said. “It was just doing what the other hand was doing, like it was a part of her,” he noted. “This worked the very first time we tried it. There’s no learning for the participants. All of the learning happens in our algorithms. That’s different from other approaches.

The procedure also worked for another amputee in the study who had lost not only his hand, but also part of his arm. “It’s the coolest part of what they’ve shown,” said Lee Fisher, an assistant professor in the University of Pittsburgh’s department of physical medicine and rehabilitation and bioengineering.


Cartilage-like Material Boosts Batteries Durability

Your knees and your smartphone battery have some surprisingly similar needs, a University of Michigan professor has discovered, and that new insight has led to a “structural battery” prototype that incorporates a cartilage-like material to make the batteries highly durable and easy to shape.The idea behind structural batteries is to store energy in structural components—the wing of a drone or the bumper of an electric vehicle, for example. They’ve been a long-term goal for researchers and industry because they could reduce weight and extend range. But structural batteries have so far been heavy, short-lived or unsafe.

In a study published in ACS Nano, the researchers describe how they made a damage-resistant rechargeable zinc battery with a cartilage-like solid electrolyte. They showed that the batteries can replace the top casings of several commercial drones. The prototype cells can run for more than 100 cycles at 90 percent capacity, and withstand hard impacts and even stabbing without losing voltage or starting a fire.


A battery that is also a structural component has to be light, strong, safe and have high capacity. Unfortunately, these requirements are often mutually exclusive,” said Nicholas Kotov, the Joseph B. and Florence V. Cejka Professor of Engineering, who led the research.

To sidestep these trade-offs, the researchers used zinc—a legitimate structural material—and branched nanofibers that resemble the collagen fibers of cartilageAhmet Emrehan Emre, a biomedical engineering PhD candidate, sandwiches a thin sheet of a cartilage-like material between a layer of zinc on top and a layer of manganese oxide underneath to form a battery

Nature does not have zinc batteries, but it had to solve a similar problem,” Kotov said. “Cartilage turned out to be a perfect prototype for an ion-transporting material in batteries. It has amazing mechanics, and it serves us for a very long time compared to how thin it is. The same qualities are needed from solid electrolytes separating cathodes and anodes in batteries.”

In our bodies, cartilage combines mechanical strength and durability with the ability to let water, nutrients and other materials move through it. These qualities are nearly identical to those of a good solid electrolyte, which has to resist damage from dendrites while also letting ions flow from one electrode to the other.


Harvesting Clean Hydrogen Fuel Through Artificial Photosynthesis

A new, stable artificial photosynthesis device doubles the efficiency of harnessing sunlight to break apart both fresh and salt water, generating hydrogen that can then be used in fuel cells.

The device could also be reconfigured to turn carbon dioxide back into fuel.

Hydrogen is the cleanest-burning fuel, with water as its only emission. But hydrogen production is not always environmentally friendly. Conventional methods require natural gas or electrical power. The method advanced by the new device, called direct solar water splitting, only uses water and light from the sun.

If we can directly store solar energy as a chemical fuel, like what nature does with photosynthesis, we could solve a fundamental challenge of renewable energy,” said Zetian Mi, a professor of electrical and computer engineering at the University of Michigan who led the research while at McGill University in Montreal.

Faqrul Alam Chowdhury, a doctoral student in electrical and computer engineering at McGill, said the problem with solar cells is that they cannot store electricity without batteries, which have a high overall cost and limited life.

The device is made from the same widely used materials as solar cells and other electronics, including silicon and gallium nitride (often found in LEDs). With an industry-ready design that operates with just sunlight and seawater, the device paves the way for large-scale production of clean hydrogen fuel.

Previous direct solar water splitters have achieved a little more than 1 percent stable solar-to-hydrogen efficiency in fresh or saltwater. Other approaches suffer from the use of costly, inefficient or unstable materials, such as titanium dioxide, that also might involve adding highly acidic solutions to reach higher efficiencies. Mi and his team, however, achieved more than 3 percent solar-to-hydrogen efficiency.