In a preclinical study conducted at MGH and published in Science Advances, the researchers tested the biomaterial — which includes a novel protein called SA-FasL that promotes immune tolerance and is tethered to the surface of microgel beads — in a nonhuman primate model of type 1 diabetes. The material was mixed with islets and then transplanted to a bioengineered pouch formed by the omentum — a fold of fatty tissue that hangs from the stomach and covers the intestines. After transplantation, animals received a single anti-rejection drug (rapamycin) for three months.

“Our strategy to create a local immune-privileged environment allowed islets to survive without long-term immunosuppression and achieved robust blood glucose control in all diabetic nonhuman primates during a six-month study period,” says lead author Ji Lei, MD, MBA, an associate immunologist at MGH and an assistant professor of Surgery at Harvard Medical School. “We believe that our approach allows the transplants to survive and control diabetes for much longer than six months without anti-rejection drugs because surgical removal of the transplanted tissue at the end of the study resulted in all animals promptly returning to a diabetic state.”

Lei, who is also director of the Human Islet/Cell Processing Special Service cGMP Facility at MGH, notes that transplanting islets to the omentum has several advantages over the current clinical approach of transplanting to the liver. “Unlike the liver, the omentum is a non-vital organ allowing its removal should undesired complications be encountered,” he explains. “Thus, the omentum is a safer location for transplants to treat diabetes and may be particularly well suited for stem-cell-derived beta cells and bio-engineered cells.”

Co-corresponding author James F. Markmann, MD, PhD, chief of the Division of Transplant Surgery and director of Clinical Operations at the Transplant Center at MGH stresses that the non-human primate study is a highly relevant pre-clinical animal model. “This localized immunomodulatory strategy succeeded without long-term immunosuppression and shows great potential for application to type 1 diabetes patients,” he says.

A clinical trial is being planned based on the researchers’ results.

Additional study authors include María M. Coronel, Esma S. Yolcu, Hongping Deng, Orlando Grimany-Nuno, Michael D. Hunckler, Vahap Ulker, Zhihong Yang, Kang M. Lee, Alexander Zhang, Hao Luo, Cole W. Peters, Zhongliang Zou, Tao Chen, Zhenjuan Wang, Colleen S. McCoy, Ivy A. Rosales, Haval Shirwan and Andrés J. García.

This work was supported by the Juvenile Diabetes Research Foundation, the National Institutes of Health, and the National Science Foundation.

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In people living with Type 1 diabetes, their immune system can malfunction, causing it to attack itself, said Haval Shirwan, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, and one of the study’s lead authors.

“The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections,” Shirwan said. “Type 1 diabetes develops when the immune system misidentifies the insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is eliminated, the immune system’s command-and-control mechanism kicks in to eliminate any rogue cells. However, if this mechanism fails, diseases such as Type 1 diabetes can manifest.”

Diabetes affects the body’s ability to produce or use insulin, a hormone which helps regulate how blood sugar is used in the body. People living with Type 1 diabetes do not make insulin, and therefore are unable to control their blood sugar levels. That loss of control can lead to life-threatening complications such as heart disease, kidney damage and eye damage.

Over the last two decades, Shirwan and Esma Yolcu, a professor of child health and molecular microbiology and immunology in the MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys “rogue” immune cells from causing diabetes or rejection of transplanted pancreatic islets by attaching a molecule called FasL to the surface of the islets.

“A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die,” said Yolcu, one of the study’s first authors. “Therefore, our team pioneered a technology that enabled the production of a novel form of FasL and its presentation on transplanted pancreatic islet cells or microgels to prevent being rejected by rogue cells. Following insulin-producing pancreatic islet cell transplantation, rogue cells mobilize to the graft for destruction but are eliminated by FasL engaging Fas on their surface.”

One advantage of this new method is the opportunity to potentially forgo a lifetime of taking immunosuppressive drugs, which counteract the immune system’s ability to seek and destroy a foreign object when introduced into the body, such as an organ, or in this case, cell, transplant.

“The major problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as high instances of developing cancer,” Shirwan said. “So, using our technology, we found a way that we can modulate or train the immune system to accept, and not reject, these transplanted cells.”

Their method utilizes technology included in a U.S. patent filed by the University of Louisville and Georgia Tech, and has since been licensed by a commercial company with plans to pursue FDA approval for human testing. To develop the commercial product, the MU researchers collaborated with Andres García and the team at Georgia Tech to attach FasL to the surface of microgels with a proof-of-efficacy in a small animal model. Then, they joined with Jim Markmann and Ji Lei from Harvard to assess the efficacy of the FasL-microgel technology in a large animal model, which is published in this study.

Incorporating the power of NextGen

This study represents a significant milestone in the process of bench-to-bedside research, or how laboratory results are directly incorporated into use by patients in order to help treat different diseases and disorders, a hallmark of MU’s most ambitious research initiative, the NextGen Precision Health initiative.

Highlighting the promise of personalized health care and the impact of large-scale interdisciplinary collaboration, the NextGen Precision Health initiative is bringing together innovators like Shirwan and Yolcu from across MU and the UM System’s three other research universities in pursuit of life-changing precision health advancements. It’s a collaborative effort to leverage the research strengths of MU toward a better future for the health of Missourians and beyond. The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in the state-of-the-art research facility.

“I think by being at the right institution with access to a great facility like the Roy Blunt NextGen Precision Health building, will allow us to build on our existing findings and take the necessary steps to further our research, and make the necessary improvements, faster,” Yolcu said.

Shirwan and Yolcu, who joined the faculty at MU in spring 2020, are part of the first group of researchers to begin working in the NextGen Precision Health building, and after working at MU for nearly two years they are now among the first researchers from NextGen to have a research paper accepted and published in a high-impact, peer-reviewed academic journal.

“FasL microgels induce immune acceptance of islet allografts in nonhuman primates,” was published in Science Advances, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided by grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-S-B) and the National Institutes of Health (U01 AI132817) as well as a Juvenile Diabetes Research Foundation Post-Doctoral Fellowship and a National Science Foundation Graduate Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Other authors on the study include Ji Lei, Hongping Deng, Zhihong Yang, Kang Lee, Alexander Zhang, Cole Peters, Zhongliang Zou, Zhenjuan Wang, Ivy Rosales and James Markmann at Harvard; Michael Hunckler, and Andrés J. García at Georgia Institute of Technology (Georgia Tech); Hao Luo at the General Hospital of Western Theater Command in Chengdu, China; Tao Chen at Xiamen University Medical School in Xiamen, China; and Colleen McCoy at Massachusetts Institute of Technology. The study’s authors would also like to acknowledge Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Deng, Rudy Matheson and Nikolaos Serifis for their technical contributions.

Potential conflicts of interest are also noted. Three of the study’s authors, García, Shirwan and Yolcu, are inventors on a U.S. patent application filed by the University of Louisville and the Georgia Tech Research Corporation (16/492441, filed Feb. 13, 2020). In addition, García and Shirwan are co-founders of iTolerance, and García, Shirwan and Markmann serve on the scientific advisory board for iTolerance.

Researchers from Texas A&M University recently showcased superior tensile superelasticity by fabricating a shape memory alloy through laser powder bed fusion, nearly doubling the maximum superelasticity reported in literature for 3D printing.

Nickel-titanium shape memory alloys have various applications due to their ability to return to their original shape upon heating or upon removal of the applied stress. Therefore, they can be used in biomedical and aerospace fields for stents, implants, surgical devices and aircraft wings. However, developing and properly fabricating these materials requires extensive research to characterize functional properties and examine the microstructure.

“Shape memory alloys are smart materials that can remember their high-temperature shapes,” said Dr. Lei Xue, a former doctoral student in the Department of Materials Science and Engineering and the first author of the publication. “Although they can be utilized in many ways, fabricating shape memory alloys into complex shapes requires fine-tuning to ensure the material exhibits the desired properties.”

Laser powder bed fusion is an additive manufacturing technique that presents a way to produce nickel-titanium shape memory alloys effectively and efficiently, offering a pathway to quick manufacturing or prototyping. This technique, similar to polymer 3D printing, uses a laser to fuse metal or alloy powders layer by layer. The layer-by-layer process is beneficial because it can create parts with complex geometries that would be impossible in traditional manufacturing.

“Using a 3D printer, we spread the alloy powder over a substrate and then use the laser to melt the powder, forming one full layer,” said Xue. “We repeat this layering, scanning the same or different patterns until the desired structure is formed.”

Unfortunately, most nickel-titanium materials cannot withstand the current laser powder bed fusion process, often resulting in printing defects such as porosity, warping or delamination caused by large thermal gradient and brittleness from oxidation. In addition, the laser can change the composition of the material due to evaporation during printing.

To combat this issue, the researchers used an optimization framework they created in a previous study, which can determine optimal process parameters to achieve defect-free structure and specific material properties.

With this framework, as well as the change in composition and refined process parameters, the researchers fabricated nickel-titanium parts that consistently exhibited a room temperature tensile superelasticity of 6% in the as-printed condition (without post-fabrication heat treatment). This level of superelasticity is nearly double the amount previously seen in literature for 3D printing.

The ability to produce shape memory alloys through 3D printing with increased superelasticity means the materials are more capable of handling applied deformation. Using 3D printing to develop these superior materials will reduce the cost and time of the manufacturing process.

In the future, the researchers hope their discoveries will lead to increased use of printed nickel-titanium shape memory alloys in biomedical and aerospace applications.

“This study can serve as a guide on how to print nickel-titanium shape memory alloys with desired mechanical and functional characteristics,” said Xue. “If we can tailor the crystallographic texture and microstructure, there are far more applications these shape memory alloys can be used in.”

This research was funded by the U.S. Army Research Laboratory, the National Priorities Research Program grant, the Qatar National Research Fund and the U.S. National Science Foundation grant.

Other contributors to the publication include materials science and engineering department head Dr. Ibrahim Karaman; materials science and engineering professors Dr. Kadri Can Atli and Dr. Raymundo Arroyave; former materials science and engineering student Dr. Abhinav Srivastava and current student Nathan Hite; Wm Michael Barnes ’64 Department of Industrial Systems and Engineering professor Dr. Alaa Elwany; industrial systems and engineering student Chen Zhang; and U.S. Army Research Laboratory researchers Dr. Asher C. Leff, Dr. Adam A. Wilson and Dr. Darin J. Sharar.

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If bacteria or viruses attack living cells or other foreign substances appear in them, the danger sensor with the abbreviation NLRP3 is activated. “The protein deposits in the brain that are characteristic of Alzheimer’s disease, the so-called amyloid-ß plaques, can also set NLRP3 in motion,” says Prof. Dr. Matthias Geyer from the Institute for Structural Biology at the University Hospital Bonn, referring to earlier studies. As these previous studies by the researchers show, this reaction increasingly fuels itself: The inflammatory reaction triggered by NLRP3 promotes the further deposition of amyloid-ß plaques and contributes significantly to the disease process.

Once activated, several NLRP3 proteins attach to each other and in this way form the nucleus for a thread-like structure at which more and more proteins gather. “The reaction kicks in as soon as about a dozen of the NLRP3 molecules are present,” Geyer reports. In theory, an infinite number of NLRP3 molecules can join together and extend the thread-like structure — scientifically called a “filament” — further and further. Inga Hochheiser from Prof. Geyer’s team has now been able to show the direction in which this filament grows and continues to expand. “We were able to gain these insights using cryo-electron microscopy. This method makes it possible to observe protein molecules with up to 80,000-fold magnification and thus make them directly visible,” says Hochheiser.

“Still image” of the thread-like structure under the microscope

In tiny steps, the scientist drizzled NLRP3 isolated from cells onto a sample carrier and flash-froze this mixture. This provided the researchers with a kind of “still image” under the cryo-electron microscope. The emerging thread-like structure of NLRP3 molecules arranged side by side was thus visualized. “These individual images made it possible to understand how the filaments elongate, just like in a film,” says Hochheiser. As the molecules fall differently on the sample carrier when drizzled, they can be seen from different perspectives under the microscope. These different views can be combined on the computer to create a three-dimensional image. The results showed that the filaments only form in one direction. “This allowed us to visualize part of the inflammatory apparatus and literally read the direction of growth,” says Prof. Geyer, who led the study and is a member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Area “Life and Health” at the University of Bonn.

Stopping chronic inflammatory diseases

“The technical challenge was to find the transitions in the thread-like structures and make them visible in the image,” says Prof. Dr. Elmar Behrmann from the Institute for Biochemistry at the University of Cologne. “The new findings now allow us to target the growing end of the inflammatory response using antibodies or drugs,” Hochheiser explains. This brings the researchers closer to their goal of stopping the further build-up of the inflammatory apparatus and thus counteracting chronic inflammation.

Participating institutions and funding:

In addition to the Institute of Structural Biology and the Institute of Innate Immunity of the University Hospital Bonn, the Institute of Biochemistry of the University of Cologne and The Walter and Eliza Hall Institute of Medical Research in Melbourne (Australia) are involved in the study. Measurements were carried out at the research center caesar in Bonn and at the Rudolf Virchow Center at the University of Würzburg. The study was funded by the Else Kröner-Fresenius Foundation and the German Research Foundation.

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But a team of investigators co-led by Georgia Institute of Technology researcher Andrés García overcame this hurdle in previous small animal studies. Their technique uses synthetic hydrogel particles called microgels. The microgels present a potent immunomodulatory protein called SA-FasL to modulate the body’s immune response, allowing the transplanted insulin-producing cells to safely do their job, regulating blood glucose levels, and fighting diabetes.

A new study in the journal Science Advances from García and his collaborators moves this hopeful treatment strategy closer to the clinic.

“Immunosuppression is a significant problem for patients, but in our prior work we showed that this biomaterial, this microgel, is a potent immunomodulatory molecule, and can induce permanent acceptance of the new cells,” said García, the Petit Chair in Bioengineering and Regents’ Professor in the George W. Woodruff School of Mechanical Engineering and executive director of the Petit Institute for Bioengineering and Bioscience.

“But that study was done in mice, and the immune system of a mouse if very different from a human’s,” García added. “And in the progression toward clinical use, you really need to test this strategy in a large animal model.”

Now, they have. García and his fellow researchers from the University of Missouri and Massachusetts General Hospital explain their results in the new paper.

Their study, funded by the Juvenile Diabetes Research Foundation, demonstrates how co-transplanting islet cells with SA-FasL-microgels reversed diabetic symptoms while overcoming the immune response in nonhuman primates. The researchers without using immunosuppressants, which can have dangerous side effects.

The microgels essentially teach the immune system to accept the graft, interrupting the body’s inclination to reject the transplant and circumventing the need for continuous immunosuppression.

“Those immunosuppressive regimens are toxic to the patient, so a major goal in the field has been to develop approaches that will allow you to put in this graft and get it to function without chronic immunosuppression,” said García.

Because the biomaterial can be created in a lab and shipped anywhere, the new therapeutic is essentially off-the-shelf. And now that they’ve proven the strategy works in nonhuman primates, García and his collaborators are confident that patients with type 1 diabetes could have a powerful new treatment option.

García is co-founder of the company that licensed the technology, iTolerance, which is already discussing plans for human clinical trials with the U.S. Food and Drug Administration.

“We are pretty pumped — this is very exciting, and these are hopeful results for people fighting type 1 diabetes,” said García, corresponding author and part of a 20-person research team. “This work wouldn’t have been possible with this team science approach.”

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“Sperm epigenetic clock associates with pregnancy outcomes in the general population,” (link to article here), published in the journal Human Reproduction, found that sperm epigenetic aging clocks may act as a novel biomarker to predict couples’ time to pregnancy. The findings also underscore the importance of the male partner in reproductive success.

“Chronological age is a significant determinant of reproductive capacity and success among couples attempting pregnancy, but chronological age does not encapsulate the cumulative genetic and external — environmental conditions — factors, and thus it serves as a proxy measure of the ‘true’ biological age of cells,” said J. Richard Pilsner, Ph.D., lead author of the study. Dr. Pilsner is the Robert J. Sokol, M.D., Endowed Chair of Molecular Obstetrics and Gynecology and director of Molecular Genetics and Infertility at WSU’s C.S. Mott Center for Human Growth and Development. “Semen quality outcomes utilizing World Health Organization guidelines have been used to assess male infertility for decades, but they remain poor predictors of reproductive outcomes. Thus, the ability to capture the biological age of sperm may provide a novel platform to better assess the male contribution to reproductive success, especially among infertile couples.”

Sperm epigenetic aging is the biological, rather than the chronological, aging of sperm. The study found a 17% lower cumulative probability of pregnancy after 12 months for couples with male partners in older compared to younger sperm epigenetic aging categories. The study involved 379 male partners of couples who discontinued the use of contraception for the purpose of becoming pregnant.

The study also found a higher epigenetic aging of sperm in men who smoked.

The results, Dr. Pilsner said, indicate that higher sperm epigenetic aging is associated with a longer time to become pregnant in couples not assisted by fertility treatment, and among couples that achieved pregnancy, with shorter gestation.

The strong association between sperm epigenetic aging and pregnancy probability and its slowing or reversal through lifestyle choices and/or pharmacological interventions warrants further investigation. In addition, because older fathers have an increased risk of children with adverse neurological outcomes, it is important to understand the potential relation of sperm epigenetic aging on children’s health and development.

“There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population,” Dr. Pilsner said. “These data show that our sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment. While chronological age of both partners remains a significant predictor of reproductive success, our clocks likely recapitulate both external and internal factors that drive the biological aging of sperm. Such a summary measure of sperm biological age is of clinical importance, as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions.”

Dr. Pilsner advised that because those studied were largely Caucasian, greater and more diverse cohorts are necessary to confirm the association between sperm epigenetic aging and couple pregnancy success in other races and ethnicities.

The research was funded in part by grants from the National Institute of Environmental Health Sciences of the National Institutes of Health (R01ES028298 and P30 ES020957); and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358).

When thinking about quantum mechanical systems, single photons and well-​isolated ions and atoms may spring to mind, or electrons spreading through a crystal. More exotic in the context of quantum mechanics are genuinely mechanical quantum systems; that is, massive objects in which mechanical motion such as vibration is quantized. In a series of seminal experiments, quintessential quantum-​mechanical features have been observed in mechanical systems, including energy quantization and entanglement. However, with a view to putting such systems to use in fundamental studies and technological applications, observing quantum properties is but a first step. The next one is to master the handling of mechanical quantum objects, so that their quantum states can be controlled, measured, and eventually exploited in device-​like structures. The group of Yiwen Chu in the Laboratory of Solid State Physics at ETH Zurich has now made major progress in that direction. Writing in Nature Physics, they report the extraction of information from a mechanical quantum system without destroying the precious quantum state. This advance paves the path to applications such as quantum error correction, and beyond.

Massive quantum mechanics

The ETH physicists employ as their mechanical system a slab of high-​quality sapphire, a little under half a millimetre thick. On its top sits a thin piezoelectrical transducer that can excite acoustic waves, which are reflected at the bottom and thus extend across a well-​defined volume inside the slab. These excitations are the collective motion of a large number of atoms, yet they are quantized (in energy units known as phonons) and can be subjected, in principle at least, to quantum operations in very much the same ways as the quantum states of atoms, photons and electrons can be. Intriguingly, it is possible to interface the mechanical resonator with other quantum systems, and with superconducting qubits in particular. The latter are tiny electronic circuits in which electromagnetic energy states are quantized, and they are currently one of the leading platforms for building scalable quantum computers. The electromagnetic fields associated with the superconducting circuit enable the coupling of the qubit to the piezoelectrical transducer of the acoustic resonator, and thereby to its mechanical quantum states.

In such hybrid qubit-resonator devices, the best of two worlds can be combined. Specifically, the highly developed computational capabilities of superconducting qubits can be used in synchrony with the robustness and long lifetime of acoustical modes, which can serve as quantum memories or transducers. For such applications, however, merely coupling qubit and resonator states will be not enough. For example, a straightforward measurement of the quantum state in the resonator destroys it, making repeated measurements impossible. What is needed instead is the capability to extract information about the mechanical quantum state in a more gentle, well-​controlled manner.

The non-​destructive path

Demonstrating a protocol for such so-​called quantum non-​demolition measurements is what Chu’s doctoral students Uwe von Lüpke, Yu Yang and Marius Bild, working with Branco Weiss fellow Matteo Fadel and with support from semester project student Laurent Michaud, now achieved. In their experiments there is no direct energy exchange between the superconducting qubit and the acoustic resonator during the measurement. Instead, the properties of the qubit are made to depend on the number of phonons in the acoustic resonator, with no need to directly ‘touch’ the mechanical quantum state — think about a theremin, the musical instrument in which the pitch depends on the position of the musician’s hand without making physical contact with the instrument.

Creating a hybrid system in which the state of the resonator is reflected in the spectrum of the qubit is highly challenging. There are stringent demands on how long the quantum states can be sustained both in the qubit and in the resonator, before they fade away due to imperfections and perturbations from the outside. So the task for the team was to push the lifetimes of both the qubit and the resonator quantum states. And they succeeded, by making a series of improvements, including a careful choice of the type of superconducting qubit used and encapsulating the hybrid device in a superconducting aluminium cavity to ensure tight electromagnetic shielding.

Quantum information on a need-​to-know basis

Having successfully pushed their system into the desired operational regime (known as the ‘strong dispersive regime’), the team were able to gently extract the phonon-​number distribution in their acoustic resonator after exciting it with different amplitudes. Moreover, they demonstrated a way to determine in one single measurement whether the number of phonons in the resonator is even or odd — a so-​called parity measurement — without learning anything else about the distribution of phonons. Obtaining such very specific information, but no other, is crucial in a number of quantum-​technological applications. For instance, a change in parity (a transition from an odd to an even number or vice versa) can signal that an error has affected the quantum state and that correcting is needed. Here it is essential, of course, that the to-​be-corrected state is not destroyed.

Before an implementation of such error-​correction schemes is possible, however, further refinement of the hybrid system is necessary, in particular to improve the fidelity of the operations. But quantum error correction is by far not the only use on the horizon. There is an abundance of exciting theoretical proposals in the scientific literature for quantum-​information protocols as well as for fundamental studies that benefit from the fact that the acoustic quantum states reside in massive objects. These provide, for example, unique opportunities for exploring the scope of quantum mechanics in the limit of large systems and for harnessing the mechanical quantum systems as a sensor.

The collective movement of biological organisms is a common phenomenon in the natural world. Insects and fish, for instance, tend to move in swarms. Often, collective movement also occurs at the cellular level, such as when cancer cells migrate from a tumour or bacteria form a biofilm. The collaboration of many individuals can give rise to so-called emergent behaviour — new characteristics that would not otherwise exist in this form. “In physics, collectivity creates such important processes as phase transitions, superconductivity, and magnetic properties,” explains Prof. Dr Ulrich Schwarz, head of the “Physics of Complex Biosystems” working group at the Institute for Theoretical Physics of Heidelberg University. In an interdisciplinary study together with Prof. Dr Friedrich Frischknecht (malaria research) and Prof. Dr Karl Rohr (biomedical image analysis), he has shown that collective movement can also occur in Plasmodium, the causative agent of malaria.

The single-celled organism is injected into the skin through a mosquito bite, developing first in the liver and then later in the blood. Because Plasmodium acts as a single cell in most of its stages, until now its collective properties were hardly studied. In the salivary gland of the mosquito, the parasite has a long and curved shape, similar to a crescent moon, and is known as a sporozoite. “As soon as sporozoites are injected into the skin by the mosquito, individual parasites begin to quickly move toward the blood vessels. This is the critical phase of the infection, because it is successful only if a pathogen reaches the blood stream,” stresses Prof. Frischknecht.

In their studies at the Center for Infectious Diseases of Heidelberg University Hospital, Friedrich Frischknecht and his team discovered that the parasites in infected salivary glands can be mobilised as a collective. To do so, the salivary glands are dissected from the mosquito and carefully pressed between two small glass plates. The researchers were surprised to discover that the crescent moon-shaped cells form rotating vortices in the new preparation. They are reminiscent of the collective movements of bacteria or fish, although they differ in that they always rotate in the same direction. The parasite vortices therefore have a chiral character and — likewise unexpectedly — fluctuate in size. According to Prof. Frischknecht, these oscillations point to emergent characteristics, since they are possible only in the collective of the moving cells and grow stronger in larger vortices.

To understand these phenomena more precisely, the experimental data were analysed quantitatively. The groups of Ulrich Schwarz and Karl Rohr, head of the Biomedical Computer Vision Group at BioQuant Centre of Heidelberg University, used cutting-edge methods of image processing for this purpose. They were able to track individual parasites in the rotating vortices and measure both their speed and curvature. Using so-called agent-based computer simulations, it was possible to precisely identify those laws that can explain all aspects of the experimental observations. The interplay of active movement, curved shape of the cell, and chirality in conjunction with mechanical flexibility is sufficient to explain the sorting and oscillation phenomena in the parasite vortices. The oscillations the scientists observed arise because the movement of the individual pathogens is converted into elastic energy that is stored in the vortex. “Our new model system offers the opportunity to better understand the physics of collectives with elastic properties and perhaps render them usable for technical applications in the future,” states the physicist Ulrich Schwarz.

In the next step, the researchers will investigate exactly how the chirality of movement comes about. The structure of sporozoites suggests different possibilities that can be studied in experiments with genetic mutations. Initial computer simulations have already shown that the right- and left-turning parasites quickly segregate and generate separate vortex systems. A better understanding of the underlying molecular mechanisms could open up new avenues to disrupt sporozoite movement at the onset of every malaria infection. “In any event, our study has shown that the mechanics of the pathogens play an extremely important and heretofore overlooked role — a finding that also opens up new perspectives for medical interventions,” explains the infectiologist Friedrich Frischknecht.

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