Llama power: Tiny llama nanobodies neutralize different noroviruses. Can they improve human anti-viral therapies?

Peer-Reviewed Publication

BAYLOR COLLEGE OF MEDICINE

Human noroviruses cause acute gastroenteritis, a global health problem for which there are no vaccines or antiviral drugs. Although most healthy patients recover completely from the infection, norovirus can be life-threatening in infants, the elderly and people with underlying diseases. Estimates indicate that human noroviruses cause approximately 684 million illnesses and 212,000 deaths annually.

“Human noroviruses are highly diverse,” said first author Dr. Wilhelm Salmen, a graduate student in Dr. B V Venkataram Prasad’s lab while he was working on this project and currently a postdoctoral fellow at the University of Michigan. “Noroviruses are categorized into10 groups, of which groups GI, GII, GIV, GVIII and GIX infect humans. Viruses in the GII.4 subgroup are the most predominant in human populations.”

Noroviruses also are notorious for periodically giving rise to new variants, particularly those of GII.4 norovirus, that can evade the immune response the body has developed against previous variants, like some flu viruses and coronaviruses do. The diversity of norovirus groups and the recurring emergence of new variants are some of the factors challenging the development of effective preventive and therapeutic approaches to control this serious disease.

In the current study published in the journal Nature Communications, Salmen, Prasad and their colleagues investigated a novel strategy to neutralize human noroviruses. They tested whether tiny antibodies produced by llamas, called nanobodies, could effectively neutralize human norovirus infection in the lab. The unexpected findings reveal that nanobodies could be developed as a therapeutic agent against human norovirus.

Llama nanobodies may give an upper hand

Llamas and related animals such as camels and alpacas, produce antibodies for protection against disease just like people do. However, compared to people’s antibodies, llama’s are about a tenth of the size of human antibodies.  Llama’s nanobodies have been developed against viruses such as those causing hepatitis B, influenza, human immunodeficiency, polio and other diseases.

“Our collaborators from Argentina, Dr. Marina Bok and Dr. Viviana Parreño at the Institute of Virology and Technology Innovation, had prepared nanobodies from llamas that were inoculated with human norovirus-like particles from different strains,” Salmen said. “We worked with one nanobody named M4, which bound to the predominant GII.4 strain, testing its ability to neutralize different norovirus strains, that is, to prevent them from infecting human cells.” 

The researchers tested the ability of the nanobodies to prevent live viruses from infecting human intestinal organoids or mini guts grown in the lab. Mini guts are models of human intestinal cells, closely representing actual small intestine tissue and its functions, that enable scientists to study how noroviruses work and to test potential therapies.

“It was really unexpected to see that the M4 nanobody not only interacted and neutralized the currently circulating pandemic GII.4 strain but also its older variants,” said Prasad, Alvin Romansky Chair in Biochemistry and professor in the Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology and the Department of Molecular Virology and Microbiology at Baylor. He also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center and corresponding author of the work.

The researchers used crystallography and other techniques to look closely at the interactions between nanobodies and noroviruses to try to understand how the M4 nanobody recognizes and neutralizes a variety of noroviruses when they expected it would recognize only the GII.4 strain used to generate M4.

“We discovered that this little nanobody can recognize a part of the norovirus that all the different noroviruses that we tested have in common,” Salmen said.

The team discovered that the M4 nanobody recognized a hidden pocket in the norovirus particles that would be exposed only when the particles underwent a structural change. “The traditional thinking is that viral particles are in a very stable compact state, but in reality these particles ‘breathe’ considerably,” Salmen said. “Recent studies have shown that the structure of norovirus particles is dynamic, alternating between a resting or compact conformation and a raised conformation.”

“We think that the raised state is important for the virus to bind to cells and infect them,” Prasad said. “We also think that when the viral particles are in the raised state, the hidden pocket is exposed and available for the nanobody to bind to it and, acting like a wedge, to keep the particle in an elevated, potentially unstable state, preventing it from collapsing back down into the compact, more stable resting state.”

“Our findings suggest that trapping the viral particles in an elevated, unstable state disassembles the particles, which kills the virus. This effectively would stop the infection as it blocks the transmission chain, preventing the virus from spreading from cell to cell,” Salmen said.

“This study is also remarkable in confirming that the human norovirus must change its 3D confirmation, from compact to raised, to infect people,” said co-author Dr. Mary Estes, Distinguished Service Professor of Virology and Microbiology and Cullen Foundation Endowed Chair at Baylor. She also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Also, this work reveals the importance of considering viral particle dynamics when designing vaccines.”  

Other contributors to this work include Liya Hu, Natthawan Chaimongkol, Khalil Ettayebi, Stanislav V. Sosnovtsev, Kaundal Soni, B. Vijayalakshmi Ayyar, Sreejesh Shanker, Frederick H. Neill, Banumathi Sankaran, Robert L. Atmar and Kim Y. Green. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Institute for Virology and Technology Innovation-Argentina, National Institutes of Health and Lawrence Berkeley Laboratory.

This study was supported in part by the National Institutes of Health grants P30 GM124169-01, P30 CA125123 and P01 AI057788, and a grant from the Robert Welch Foundation (Q1279). Further support was provided by a Fulbright Program grant and by the Division of Intramural Research, NIAID, NIH.

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JOURNAL

Nature Communications

DOI

10.1038/s41467-023-42146-0 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Human tissue samples

ARTICLE TITLE

A single nanobody neutralizes multiple epochally evolving human noroviruses by modulating capsid plasticity.

 

Very early treatment of newborns with HIV could result in medication-free remission for many babies

Evidence that an early treatment protocol could change the course of HIV infection in children

Peer-Reviewed Publication

ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO

An unexpectedly high percentage of children, who were born with HIV and started treatment within 48 hours of life, exhibit biomarkers by 2 years of age that may make them eligible to test for medication-free remission, according to a multinational study published in Lancet HIV.

“Moving away from reliance on daily antiretroviral therapy (ART) to control HIV would be a huge improvement to the quality of life of these children,” said Protocol Co-Chair and senior author Ellen Chadwick, MD, former Director of Section of Pediatric, Adolescent and Maternal HIV Infection at Ann & Robert H. Lurie Children’s Hospital of Chicago and Professor of Pediatrics at Northwestern University Feinberg School of Medicine.

The proof-of-concept study was charged with replicating the case of HIV remission as seen in the “Mississippi baby” that was reported in 2013. In that case, the infant started ART at 30 hours of life, was treated for 18 months, and achieved 27 months of ART-free remission before the virus rebounded. Typically, if ART is stopped, the virus rebounds within a month.

The study included a three-drug ART regimen initiated within 48 hours of life, with the fourth drug added within 2-4 weeks. This is very early treatment compared to the standard of care where three-drug ART may not begin until 2- 3 months of age. In the U.S., however, based on earlier findings from this study, very early treatment is now the norm for infants at high risk of acquiring HIV infection from their mother.

“With earlier treatment, we hope to limit or prevent the establishment of viral reservoirs in the body. These viral reservoirs hold small amounts of hidden virus which are hard to reach with ART. By shrinking these reservoirs, we expect to increase the amount of time that patients can be in remission, without needing daily ART,” said co-author Jennifer Jao, MD, MPH, from Lurie Children’s, who is the Protocol Co-Chair with Dr. Chadwick. She is a Professor of Pediatrics at Northwestern University Feinberg School of Medicine and holds the Susan B. DePree Founders' Board Professorship in Pediatric, Adolescent, and Maternal HIV Infection.

Dr. Chadwick adds: “Another benefit of smaller viral reservoirs might be that newer treatments such as long-acting antibody therapies or therapeutic vaccines could potentially be used instead of daily ART.”

“Our results show a higher percentage of children might be eligible to interrupt therapy than we expected, and the next step is to stop ART and see how many children actually achieve remission,” said Dr. Chadwick. “If even one child achieves remission, that would be considered a success. Today, newer more effective and better tolerated HIV medications are available for infants than when the study began, strengthening the prospect of limiting viral reservoirs and testing for possible remission in infants and children with HIV. Overall, this is an exciting advancement and an opportunity to change the course of pediatric HIV infection.”

The study was conducted in 11 countries – Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, USA, Zambia and Zimbabwe.

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH), all components of the National Institutes of Health (NIH), under Award Numbers UM1AI068632-15 (IMPAACT LOC), UM1AI068616-15 (IMPAACT SDMC), and UM1AI106716-09 (IMPAACT LC), and by NICHD contract number HHSN275201800001I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Research at Ann & Robert H. Lurie Children’s Hospital of Chicago is conducted through Stanley Manne Children’s Research Institute, which is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is a nonprofit organization committed to providing access to exceptional care for every child. It is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report. Lurie Children’s is the pediatric training ground for Northwestern University Feinberg School of Medicine.

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JOURNAL

The Lancet HIV

DOI

10.1016/S2352-3018(23)00236-9 

 

Key to fatty liver disease and its consequences for billions of people

Why some people remain relatively healthy with fatty liver disease and some go onto potentially life-threatening illness has been a mystery. Until now.

Peer-Reviewed Publication

MONASH UNIVERSITY

Key to fatty liver disease and its consequences for billions of people

The global rise in obesity and diabetes is leading to an epidemic in fatty liver disease affecting 20-30 per cent of the world’s population. Almost a third of people with fatty liver disease go on to develop an advanced form of the disease, known as non-alcoholic steatohepatitis (NASH) that can progress to cirrhosis and end-stage liver disease, or even liver cancer, and is a major risk factor for cardiovascular disease.

Why some people remain relatively healthy with fatty liver disease and some go onto potentially life-threatening illness has been a mystery. Until now.

A study published today in The Journal of Clinical Investigation led by Professor Tony Tiganis from Monash University’s Biomedicine Discovery Institute, has shown that the levels of the NOX4 protein change as the disease progresses – rising in the early stages of the disease to protect the liver, but declining as the liver disease gets worse.

The researchers found that removing NOX4 in obese mice led to NASH and liver damage. And when NOX4 levels were artificially raised in these mice they were protected from NASH and liver damage.

Importantly, the discovery provides evidence for a therapeutic avenue for a disease whose prevalence is predicted to balloon by 63 per cent from 2015 to 2030.

According to Professor Tiganis, the precise mechanisms that govern the transition to NASH and liver damage have remained unclear. 

“It has been perplexing why the majority of patients with fatty liver disease don’t progress to more severe disease,” he said.

The researchers have shown that this is because NOX4 is induced when the liver first starts to accumulate fat and activates a complex adaptive program that protects the liver. It is only when NOX4 levels decline and this adaptive program is abrogated that obese patients with fatty liver progress to NASH and liver damage.

Importantly, previous studies by Professor Tiganis and others have shown that the raising of NOX4 levels in skeletal muscle or in the heart after exercise protects against damage and promote muscle and cardiac function and prevent the metabolic decline otherwise associated with ageing.

“Compounds that bolster the activity of NOX4, or the adaptive program that NOX4 instigates, may be highly beneficial, countering not only the development of NASH, but also improving skeletal and cardiac function, as well as metabolic health,” Professor Tiganis said.

Such compounds are found naturally in cruciferous vegetables, such as broccoli or cauliflower.

 

 

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JOURNAL

Journal of Clinical Investigation

DOI

10.1172/JCI162533 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Mitochondrial- and NOX4-dependent antioxidant defence mitigates progression to non-alcoholic steatohepatitis in obesity

 

Sage partners with Overton on free-to-use tool that empowers researchers to uncover their policy impact

Sage Policy Profiles demonstrates the influence of research on global policymaking

Business Announcement

SAGE

Sage has launched a tool to empower researchers to discover the real-world impact of their work on policy. Sage Policy Profiles lets researchers easily see specific citations of their work in policy documents and then illustrate and share that work’s impact graphically. The tool is powered by Overton, which hosts an extensive repository of global policy documents, guidelines, think-tank publications, and working papers.

The free-of-charge, browser-based tool shows researchers where their work appears in evidence-based policies, offering insights into how policymakers make use of their research. Sage Policy Profiles presents these results in a personalized dashboard from which researchers can export citations and present their policy impact visually.

"Here at Sage, we've long focused on making sure everyone outside of the social and behavioral science community can see—and make use of—the clear benefits this research brings to tackle wicked problems,” said Ziyad Marar, president of Global Publishing at Sage. “The launch of Sage Policy Profiles is really the other side of that coin, allowing researchers themselves to both see how important their work is and then be able to alert a wider audience to that very real impact,” he continued. “We believe it will help widen the research impact conversation so that it centers not just on scholarly progress but on societal good."

Additional functionalities include:

• Identifying second-order citations where policies citing their work have continued to influence subsequent discussions and decisions.

• Personalized alerts that inform users when cited or mentioned in new policy documents.

• Exporting results into PowerPoint for presenting.

• Creating a shareable link to personalized dashboards.

“The current system we have for assessing research impact and researchers has real flaws, but we don’t need to overhaul the whole thing to make meaningful improvements for researchers who want their work to be useful,” said Euan Adie, founder and managing director of Overton. “We share with Sage the belief that there are incremental improvements we can make, and Sage Policy Profiles is an important next step.”

Sage is committed to broadening how research impact is defined, shifting the focus from purely scholarly dimensions to encompass its contributions to policy, practice, and the public. Recognizing that such a transformation will require time and dedication, Sage, as an independent company, is committed to this goal for the long term.

While researchers in all disciplines can benefit from the tool, given social and behavioral sciences (SBS) outsized impact in the policy world, Sage has housed it on Social Science Space to bring attention to the unique, real-world value of SBS.

 # # #

About Sage

Sage is a global academic publisher of books, journals, and library resources with a growing range of technologies to enable discovery, access, and engagement. Believing that research and education are critical in shaping society, 24-year-old Sara Miller McCune founded Sage in 1965. Today, we are controlled by a group of trustees charged with maintaining our independence and mission indefinitely. 

Our guaranteed independence means we’re free to:

• Do more – supporting an equitable academic future, furthering disciplines that drive social change, and helping social and behavioral science make an impact

• Work together – building lasting relationships, championing diverse perspectives, and co-creating resources to transform teaching and learning

• Think long-term – experimenting, taking risks, and investing in new ideas

About Overton

Overton is the world’s largest collection of policy documents, parliamentary transcripts, government guidance, and think tank research. We make this data available through the Overton.io web application, reports, and an API. Our users include funders, universities, academic journals, and journalists.

Presenting: Ultrasound-based printing of 3D materials—potentially inside the body

Peer-Reviewed Publication

AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE (AAAS)

A new approach to three-dimensional (3D) printing uses ultrasound waves to create objects from sonically cured inks. The approach enables volumetric 3D printing even in opaque media or at deep penetration depths, including, potentially, inside the body. 3D printing technologies are poised to revolutionize manufacturing processes for a wide range of applications. Volumetric printing, an emerging 3D printing technique, can build objects faster and with better surface quality than printing methods that build objects layer-by-layer. Most existing volumetric printing techniques rely on light to trigger photopolymerization in optically transparent inks. However, light scattering by the inks themselves, the presence of functional additives within the inks, and light-blocking by already cured portions of the build limit the material choices and the build sizes feasible, particularly in configurations that require deep light penetration. Compared to light waves, ultrasound waves can penetrate much deeper into materials and can, in principle, be used to trigger polymerization. Here, Xiao Kuang and colleagues present a new approach to volumetric printing they call deep-penetrating acoustic volumetric printing (DAVP), which uses focused ultrasound waves and “sono-ink.” The sono-ink the authors developed overcomes key challenges of acoustic volumetric printing by using a thermally responsive adaptive acoustic absorber to form a viscous gel that prevents streaming flow while simultaneously initiating a heat-triggered polymerization. In tests, DVAP allowed the authors to print objects quickly from various nanocomposite materials at a millimeter scale – and several centimeters deep in opaque media. As a proof of concept, Kuang et al. applied DAVP to high-speed, high-resolution through-tissue manufacturing and minimally invasive medicine. Through experiments in ex vivo tissues infused with sono-ink, the authors demonstrate the in situ fabrication of artificial bone and of a left atrial appendage closure. In a related Perspective, Yuxing Yao and Mikhail Shapiro discuss the DAVP approach, its limitations, and its potential uses, including minimally invasive medical procedures. “It is conceivable that the running shoes of the future could be printed with the same acoustic method that repairs bones,” Yao and Shapiro write.

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JOURNAL

Science

DOI

10.1126/science.adi1563 

ARTICLE TITLE

Self-enhancing sono-inks enable deep-penetrating acoustic volumetric printing

ARTICLE PUBLICATION DATE

8-Dec-2023

Soundwaves harden 3D-printed treatments in deep tissues

A specialized ink hardens when exposed to focused ultrasound waves, transforming into biologically compatible structures

Peer-Reviewed Publication

DUKE UNIVERSITY

 

IMAGE: 

DAVP PRINTS 3D CONSTRUCTS BY CURING SONO-INKS WITH FOCUSED ULTRASOUND WAVES. THE SONO-THERMAL EFFECT TRIGGERS THE DECOMPOSITION OF THE SONO-INKS TO FORM POLYMER NETWORKS AT THE ULTRASOUND FOCAL ZONE.

view more 

CREDIT: JUNJIE YAO, DUKE UNIVERSITY; SHRIKE YU ZHANG, HARVARD MEDICAL SCHOOL.

DURHAM, N.C. -- Engineers at Duke University and Harvard Medical School have developed a bio-compatible ink that solidifies into different 3D shapes and structures by absorbing ultrasound waves. Because it responds to sound waves rather than light, the ink can be used in deep tissues for biomedical purposes ranging from bone healing to heart valve repair.

This work appears on December 7 in the journal Science.

The uses for 3D-printing tools are ever increasing. Printers create prototypes of medical devices, design flexible, lightweight electronics, and even engineer tissues used in wound healing. But many of these printing techniques involve building the object point-by-point in a slow and arduous process that often requires a robust printing platform.

To circumvent these issues over the past several years, researchers developed a photo-sensitive ink that responds directly to targeted beams of light and quickly hardens into a desired structure. While this printing technique can substantially improve the speed and quality of a print, researchers can only use transparent inks for the prints, and biomedical purposes are limited, as light can’t reach beyond a few millimeters deep into tissue.

Now, Y. Shrike Zhang, associate bioengineer at Brigham and Women’s Hospital and associate professor at Harvard Medical School, and Junjie Yao, associate professor of biomedical engineering at Duke, have developed a new printing method called deep-penetrating acoustic volumetric printing, or DVAP, that resolves these problems. This new technique involves a specialized ink that reacts to soundwaves rather than light, enabling them to create biomedically useful structures at unprecedented tissue depths.

“DVAP relies on the sonothermal effect, which occurs when soundwaves are absorbed and increase the temperature to harden our ink,” explained Yao, who designed the ultrasound printing technology for DVAP. “Ultrasound waves can penetrate more than 100 times deeper than light while still spatially confined, so we can reach tissues, bones and organs with high spatial precision that haven’t been reachable with light-based printing methods.”

The first component of DVAP involves a sonicated ink, called sono-ink, that is a combination of hydrogels, microparticles and molecules designed to specifically react to ultrasound waves. Once the sono-ink is delivered into the target area, a specialized ultrasound printing probe sends focused ultrasound waves into the ink, hardening portions of it into intricate structures. These structures can range from a hexagonal scaffold that mimics the hardness of bone to a bubble of hydrogel that can be placed on an organ.

“The ink itself is a viscous liquid, so it can be injected into a targeted area fairly easily, and as you move the ultrasound printing probe around, the materials in the ink will link together and harden,” said Zhang, who designed the sono-ink in his lab at the Brigham. “Once it’s done, you can remove any remaining ink that isn’t solidified via a syringe.”

The different components of the sono-ink enable the researchers to adjust the formula for a wide variety uses. For example, if they want to create a scaffold to help heal a broken bone or make up for bone loss, they can add bone mineral particles to the ink. This flexibility also allows them to engineer the hardened formula to be more durable or more degradable, depending on its use. They can even adjust the colors of their final print.

The team conducted three tests as a proof-of-concept of their new technique. The first involved using the ink to seal off a section in a goat’s heart. When a human has nonvalvular atrial fibrillation, the heart won’t beat correctly, causing blood to pool in the organ. Traditional treatment often requires open-chest surgery to seal off the left atrial appendage to reduce the risk of blood clots and heart attack.

Instead, the team used a catheter to deliver their sono-ink to the left atrial appendage in a goat heart that was placed in a printing chamber. The ultrasound probe then delivered focused ultrasound waves through 12 mm of tissue, hardening the ink without damaging any of the surrounding organ. Once the process was complete, the ink was safely bonded to the heart tissue and was flexible enough to withstand movements that mimicked the heart beating.

Next, the team tested the potential for DVAP’s use for tissue reconstruction and regeneration. After creating a bone defect model using a chicken leg, the team injected the sono-ink and hardened it through 10 mm of sample skin and muscle tissue layers. The resulting material bonded seamlessly to the bone and didn’t negatively impact any of the surrounding tissues.

Finally, Yao and Zhang showed that DVAP could also be used for therapeutic drug delivery. In their example, they added a common chemotherapy drug to their ink, which they delivered to sample liver tissue. Using their probe, they hardened the sono-ink into hydrogels that slowly release the chemotherapy and diffuse into the liver tissue.

“We’re still far from bringing this tool into the clinic, but these tests reaffirmed the potential of this technology,” said Zhang. “We’re very excited to see where it can go from here.”

“Because we can print through tissue, it allows for a lot of potential applications in surgery and therapy that traditionally involve very invasive and disruptive methods,” said Yao. “This work opens up an exciting new avenue in the 3D printing world, and we’re excited to explore the potential of this tool together.”

Representative DAVP for deep-tissue printing and minimally invasive therapy 

In this example, DAVP is used to close the left atrial appendage (LAA) in a goat heart, which can reduce the risk of forming blood clots inside the heart. The printed construct conforms to the heart wall, and is highly stretchable. DAVP does not need to open the chest for such a heart surgery.

DAVP for left atrial appendage [VIDEO] | 

This movie shows the printing process of DAVP to close the left atrial appendage within minutes. The thermal image shows the temperature rise during the printing.

CREDIT

Junjie Yao, Duke University; Shrike Yu Zhang, Harvard Medical School

Hardened Sono-Ink (appearing in red) in a model of a heart. DAVP prints 3D constructs by curing sono-inks with focused ultrasound waves.

CREDIT

Alex Sanchez, Duke University; Junjie Yao, Duke University; Y. Shrike Zhang, Harvard Medical School

JOURNAL

Science

DOI

10.1126/science.adi1563 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Self-Enhancing Sono-Inks Enable Deep-Penetrating Acoustic Volumetric Printing

ARTICLE PUBLICATION DATE

7-Dec-2023

COI STATEMENT

Y. Shrike Zhang consults for Allevi by 3D Systems and sits on the scientific advisory board and holds options of Xellar, neither of which participated in or biased this work.

 

Physicists ‘entangle’ individual molecules for the first time, hastening possibilities for quantum information processing

In work that could lead to more robust quantum computing, Princeton researchers have succeeded in forcing molecules into quantum entanglement.

Peer-Reviewed Publication

PRINCETON UNIVERSITY

 

IMAGE: 

LASER SETUP FOR COOLING, CONTROLLING, AND ENTANGLING INDIVIDUAL MOLECULES.

view more 

CREDIT: PHOTO BY RICHARD SODEN, DEPARTMENT OF PHYSICS, PRINCETON UNIVERSITY

For the first time, a team of Princeton physicists have been able to link together individual molecules into special states that are quantum mechanically “entangled.” In these bizarre states, the molecules remain correlated with each other—and can interact simultaneously—even if they are miles apart, or indeed, even if they occupy opposite ends of the universe. This research was recently published in the journal Science.

“This is a breakthrough in the world of molecules because of the fundamental importance of quantum entanglement,” said Lawrence Cheuk, assistant professor of physics at Princeton University and the senior author of the paper. “But it is also a breakthrough for practical applications because entangled molecules can be the building blocks for many future applications.”

These include, for example, quantum computers that can solve certain problems much faster than conventional computers, quantum simulators that can model complex materials whose behaviors are difficult to model, and quantum sensors that can measure faster than their traditional counterparts.

“One of the motivations in doing quantum science is that in the practical world it turns out that if you harness the laws of quantum mechanics, you can do a lot better in many areas,” said Connor Holland, a graduate student in the physics department and a co-author on the work.

The ability of quantum devices to outperform classical ones is known as “quantum advantage.” And at the core of quantum advantage are the principles of superposition and quantum entanglement. While a classical computer bit can assume the value of either 0 or 1, quantum bits, called qubits, can simultaneously be in a superposition of 0 and 1. The latter concept, entanglement, is a major cornerstone of quantum mechanics, and occurs when two particles become inextricably linked with each other so that this link persists, even if one particle is light years away from the other particle. It is the phenomenon that Albert Einstein, who at first questioned its validity, described as “spooky action at a distance.” Since then, physicists have demonstrated that entanglement is, in fact, an accurate description of the physical world and how reality is structured. 

“Quantum entanglement is a fundamental concept,” said Cheuk, “but it is also the key ingredient that bestows quantum advantage.”

But building quantum advantage and achieving controllable quantum entanglement remains a challenge, not least because engineers and scientists are still unclear about which physical platform is best for creating qubits. In the past decades, many different technologies—such as trapped ions, photons, superconducting circuits, to name only a few—have been explored as candidates for quantum computers and devices. The optimal quantum system or qubit platform could very well depend on the specific application.

Until this experiment, however, molecules had long defied controllable quantum entanglement. But Cheuk and his colleagues found a way, through careful manipulation in the laboratory, to control individual molecules and coax them into these interlocking quantum states. They also believed that molecules have certain advantages—over atoms, for example—that made them especially well-suited for certain applications in quantum information processing and quantum simulation of complex materials. Compared to atoms, for example, molecules have more quantum degrees of freedom and can interact in new ways.

“What this means, in practical terms, is that there are new ways of storing and processing quantum information,” said Yukai Lu, a graduate student in electrical and computer engineering and a co-author of the paper. “For example, a molecule can vibrate and rotate in multiple modes. So, you can use two of these modes to encode a qubit. If the molecular species is polar, two molecules can interact even when spatially separated.”

Nonetheless, molecules have proven notoriously difficult to control in the laboratory because of their complexity. The very degrees of freedom that make them attractive also make them hard to control, or corral, in laboratory settings.

Cheuk and his team addressed many of these challenges through a carefully thought-out experiment. They first picked a molecular species that is both polar and can be cooled with lasers. They then laser-cooled the molecules to ultracold temperatures where quantum mechanics takes centerstage. Individual molecules were then picked up by a complex system of tightly focused laser beams, so-called “optical tweezers.” By engineering the positions of the tweezers, they were able to create large arrays of single molecules and individually position them into any desired one-dimensional configuration. For example, they created isolated pairs of molecules and also defect-free strings of molecules.

Next, they encoded a qubit into a non-rotating and rotating state of the molecule. They were able to show that this molecular qubit remained coherent, that is, it remembered its superposition. In short, the researchers demonstrated the ability to create well-controlled and coherent qubits out of individually controlled molecules.

To entangle the molecules, they had to make the molecule interact. By using a series of microwave pulses, they were able to make individual molecules interact with one another in a coherent fashion. By allowing the interaction to proceed for a precise amount of time, they were able to implement a two-qubit gate that entangled two molecules. This is significant because such an entangling two-qubit gate is a building block for both universal digital quantum computing and for simulation of complex materials.

The potential of this research for investigating different areas of quantum science is large, given the innovative features offered by this new platform of molecular tweezer arrays. In particular, the Princeton team is interested in exploring the physics of many interacting molecules, which can be used to simulate quantum many-body systems where interesting emergent behavior such as novel forms of magnetism can appear.

“Using molecules for quantum science is a new frontier and our demonstration of on-demand entanglement is a key step in demonstrating that molecules can be used as a viable platform for quantum science,” said Cheuk.

In a separate article published in the same issue of Science, an independent research group led by John Doyle and Kang-Kuen Ni at Harvard University and Wolfgang Ketterle at the Massachusetts Institute of Technology achieved similar results.

“The fact that they got the same results verify the reliability of our results,” Cheuk said. “They also show that molecular tweezer arrays are becoming an exciting new platform for quantum science.”

The study, “On-Demand Entanglement of Molecules in a Reconfigurable Optical Tweezer Array,” by Connor M. Holland, Yukai Lu, and Lawrence W. Cheuk was published in Science on December 8, 2023. DOI: 10.1126/science.adf4272

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JOURNAL

Science

DOI

10.1126/science.adf4272 

METHOD OF RESEARCH

Experimental study

ARTICLE TITLE

On-Demand Entanglement of Molecules in a Reconfigurable Optical Tweezer Array

ARTICLE PUBLICATION DATE

8-Dec-2023

 

Two studies demonstrate on-demand quantum entanglement in ultracold molecules

Peer-Reviewed Publication

AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE (AAAS)

The controlled creation of quantum entanglement with molecules has been a long-standing challenge in quantum science. Now, in two new studies, researchers report a method for tailoring the quantum states of individual molecules to achieve quantum entanglement on demand. Their strategy presents a promising new platform for the advancement of quantum technologies such as computation and sensing. Quantum entanglement is one of the key defining features of quantum mechanics. It is central to many quantum applications. Because of their rich internal structure and long-lived rotational states, ultracold molecules have been proposed as promising candidates for qubits in quantum computing and quantum simulations. However, while entanglement has been achieved in various atomic, photonic, and superconducting platforms, controlling and manipulating entanglement between molecules on demand experimentally has been difficult. Now, in two different studies, Yicheng Bao and colleagues and Conner Holland and colleagues report a method to achieve controlled quantum entanglement of calcium fluoride (CaF) molecules. Bao et al. and Holland et al. make use of the long-range dipolar interaction between pairs of laser-cooled CaF molecules trapped in a reconfigurable optical tweezer array and successfully demonstrate the creation of a Bell state – an important class of entangled quantum state characterized by maximal entanglement between two qubits. The Bell state is a foundational concept for many quantum technologies. Both studies show that two CaF molecules located in neighboring optical tweezers and placed close enough to sense their respective long-range electric dipolar interaction led to an interaction between tweezer pairs, which dynamically created a Bell state out of the two previously uncorrelated molecules. “The demonstrated manipulation and characterization of entanglement of individually tailored molecules by Bao et al. and Holland et al. paves the way for developing new versatile platforms for quantum technologies,” writes Augusto Smerzi in a related Perspective.

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JOURNAL

Science

DOI

10.1126/science.adf8999 

ARTICLE TITLE

Dipolar spin-exchange and entanglement between molecules in an optical tweezer array

ARTICLE PUBLICATION DATE

8-Dec-2023