Why are some people better able to fight off the flu than others? Part of the answer, according to a new study, is related to the first flu strain we encounter in childhood.
Scientists from UCLA and the University of Arizona have found that people’s ability to fight off the flu virus is determined not only by the subtypes of flu they have had throughout their lives, but also by the sequence in which they are been infected by the viruses. Their study is published in the open-access journal PLoS Pathogens.
The research offers an explanation for why some people fare much worse than others when infected with the same strain of the flu virus, and the findings could help inform strategies for minimizing the effects of the seasonal flu.
In addition, UCLA scientists, including Professor James Lloyd-Smith, who also was a senior author of the PLoS Pathogens research, recently completed a study that analyzes travel-related screening for the new novel coronavirus 2019-nCoV.
The researchers report that screening travelers is not very effective for the 2019 coronavirus — that it will catch less than half of infected travelers, on average — and that most infected travelers are undetectable, meaning that they have no symptoms yet, and are unaware that they have been exposed. So stopping the spread of the virus is not a matter of just enhancing screening methods at airports and other travel hubs.
“This puts the onus on government officials and public health officials to follow up with travelers after they arrive, to isolate them and trace their contacts if they get sick later,” said Lloyd-Smith, a UCLA professor of ecology and evolutionary biology. Many governments have started to impose quarantines, or even travel bans, as they realize that screening is not sufficient to stop the spread of the coronavirus.
One major concern, Lloyd-Smith said, is that other countries, especially developing nations, lack the infrastructure and resources for those measures, and are therefore vulnerable to importing the disease.
“Much of the public health world is very concerned about the virus being introduced into Africa or India, where large populations exist do not have access to advanced medical care,” he said.
The researchers, including scientists from the University of Chicago and the London School of Tropical Hygiene and Medicine, have developed a free online app where people can calculate the effectiveness of travel screening based on a range of parameters.
Solving a decades-old question
The PLoS Pathogens study may help solve a problem that had for decades vexed scientists and health care professionals: why the same strain of the flu virus affects people with various degrees of severity.
A team that included some of the same UCLA and Arizona scientists reported in 2016 that exposure to influenza viruses during childhood gives people partial protection for the rest of their lives against distantly related influenza viruses. Biologists call the idea that past exposure to the flu virus determines a person’s future response to infections “immunological imprinting.”
The 2016 research helped overturn a commonly held belief that previous exposure to a flu virus conferred little or no immunological protection against strains that can jump from animals into humans, such as those causing the strains known as swine flu or bird flu. Those strains, which have caused hundreds of spillover cases of severe illness and death in humans, are of global concern because they could gain mutations that allow them to readily jump not only from animal populations to humans, but also to spread rapidly from person to person.
In the new study, the researchers investigated whether immunological imprinting could explain people’s response to flu strains already circulating in the human population and to what extent it could account for observed discrepancies in how severely the seasonal flu affects people in different age groups.
To track how different strains of the flu virus affect people at different ages, the team analyzed health records that the Arizona Department of Health Services obtains from hospitals and private physicians.
Two subtypes of influenza virus, H3N2 and H1N1, have been responsible for seasonal outbreaks of the flu over the past several decades. H3N2 causes the majority of severe cases in high-risk elderly people and the majority of deaths from the flu. H1N1 is more likely to affect young and middle-aged adults, and causes fewer deaths.
The health record data revealed a pattern: People first exposed to the less severe strain, H1N1, during childhood were less likely to end up hospitalized if they encountered H1N1 again later in life than people who were first exposed to H3N2. And people first exposed to H3N2 received extra protection against H3N2 later in life.
The researchers also analyzed the evolutionary relationships between the flu strains. H1N1 and H3N2, they learned, belong to two separate branches on the influenza “family tree,” said James Lloyd-Smith, a UCLA professor of ecology and evolutionary biology and one of the study’s senior authors. While infection with one does result in the immune system being better prepared to fight a future infection from the other, protection against future infections is much stronger when one is exposed to strains from the same group one has battled before, he said.
The records also revealed another pattern: People whose first childhood exposure was to H2N2, a close cousin of H1N1, did not have a protective advantage when they later encountered H1N1. That phenomenon was much more difficult to explain, because the two subtypes are in the same group, and the researchers’ earlier work showed that exposure to one can, in some cases, grant considerable protection against the other.
“Our immune system often struggles to recognize and defend against closely related strains of seasonal flu, even though these are essentially the genetic sisters and brothers of strains that circulated just a few years ago,” said lead author Katelyn Gostic, who was a UCLA doctoral student in Lloyd-Smith’s laboratory when the study was conducted and is now a postdoctoral fellow at the University of Chicago. “This is perplexing because our research on bird flu shows that deep in our immune memory, we have some ability to recognize and defend against the distantly related, genetic third cousins of the strains we saw as children.
“We hope that by studying differences in immunity against bird flus — where our immune system shows a natural ability to deploy broadly effective protection — and against seasonal flus — where our immune system seems to have bigger blind spots — we can uncover clues useful to universal influenza vaccine development.”
Around the world, influenza remains a major killer. The past two flu seasons have been more severe than expected, said Michael Worobey, a co-author of the study and head of the University of Arizona’s department of ecology and evolutionary biology. In the 2017-18 season, 80,000 people died in the U.S., more than in the swine flu pandemic of 2009, he said.
People who had their first bout of flu as children in 1955 — when the H1N1 was circulating but the H3N2 virus was not — were much more likely to be hospitalized with an H3N2 infection than an H1N1 infection last year, when both strains were circulating, Worobey said.
“The second subtype you’re exposed to is not able to create an immune response that is as protective and durable as the first,” he said.
The researchers hope that their findings could help predict which age groups might be severely affected during future flu seasons based on the subtype circulating. That information could also help health officials prepare their response, including decisions about who should receive certain vaccines that are only available in limited quantities.
The research was funded by the National Institutes of Health, the National Science Foundation, DARPA and the David and Lucile Packard Foundation. In 2018, the NIH’s National Institute of Allergy and Infectious Diseases announced a strategic plan to develop a universal flu vaccine.
The study’s co-authors are Rebecca Bridge of the Arizona Department of Health Services and Cecile Viboud of the Fogarty International Center at the NIH.
- Katelyn M. Gostic, Rebecca Bridge, Shane Brady, Cécile Viboud, Michael Worobey, James O. Lloyd-Smith. Childhood immune imprinting to influenza A shapes birth year-specific risk during seasonal H1N1 and H3N2 epidemics. PLOS Pathogens, 2019; 15 (12): e1008109 DOI: 10.1371/journal.ppat.1008109
Engineering researchers have developed a device the size of a wristwatch that can monitor an individual’s body chemistry to help improve athletic performance and identify potential health problems. The device can be used for everything from detecting dehydration to tracking athletic recovery, with applications ranging from military training to competitive sports.
“This technology allows us to test for a wide range of metabolites in almost real time,” says Michael Daniele, co-corresponding author of a paper on the work and an assistant professor of electrical and computer engineering at North Carolina State University and in the Joint Department of Biomedical Engineering at NC State and the University of North Carolina at Chapel Hill.
Metabolites are markers that can be monitored to assess an individual’s metabolism. So, if someone’s metabolite levels are outside of normal parameters, it could let trainers or health professionals know that something’s wrong. For athletes, it could also be used to help tailor training efforts to improve physical performance.
“For this proof-of-concept study, we tested sweat from human participants and monitored for glucose, lactate, pH and temperature,” Daniele says.
A replaceable strip on the back of the device is embedded with chemical sensors. That strip rests against a user’s skin, where it comes into contact with the user’s sweat. Data from the sensors in the strip are interpreted by hardware inside the device, which then records the results and relays them to a user’s smartphone or smartwatch.
“The device is the size of an average watch, but contains analytical equipment equivalent to four of the bulky electrochemistry devices currently used to measure metabolite levels in the lab,” Daniele says. “We’ve made something that is truly portable, so that it can be used in the field.”
While the work for this paper focused on measuring glucose, lactate and pH, the sensor strips could be customized to monitor for other substances that can be markers for health and athletic performance — such as electrolytes.
“We’re optimistic that this hardware could enable new technologies to reduce casualties during military or athletic training, by spotting health problems before they become critical,” Daniele says. “It could also improve training by allowing users to track their performance over time. For example, what combination of diet and other variables improves a user’s ability to perform?”
The researchers are now running a study to further test the technology when it is being worn by people under a variety of conditions.
“We want to confirm that it can provide continuous monitoring when in use for an extended period of time,” Daniele says.
“While it’s difficult to estimate what the device might cost consumers, it only costs tens of dollars to make. And the cost of the strips — which can last for at least a day — should be comparable to the glucose strips used by people with diabetes.
“We’re currently looking for industry partners to help us explore commercialization options for this technology,” Daniele says.
- Murat A. Yokus, Tanner Songkakul, Vladimir A. Pozdin, Alper Bozkurt, Michael A. Daniele. Wearable multiplexed biosensor system toward continuous monitoring of metabolites. Biosensors and Bioelectronics, 2020; 153: 112038 DOI: 10.1016/j.bios.2020.112038
Smart technology keeps getting smaller. There are smartphones, smartwatches and now, smart rings, devices that allow someone to use simple finger gestures to control other technology.
Researchers at the University of Washington have created AuraRing, a ring and wristband combination that can detect the precise location of someone’s index finger and continuously track hand movements. The ring emits a signal that can be picked up on the wristband, which can then identify the position and orientation of the ring — and the finger it’s attached to. The research team published these results Dec. 11 in Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies.
“We’re thinking about the next generation of computing platforms,” said co-lead author Eric Whitmire, who completed this research as a doctoral student at the Paul G. Allen School of Computer Science & Engineering. “We wanted a tool that captures the fine-grain manipulation we do with our fingers — not just a gesture or where your finger’s pointed, but something that can track your finger completely.”
AuraRing is composed of a coil of wire wrapped 800 times around a 3D-printed ring. A current running through the wire generates a magnetic field, which is picked up by three sensors on the wristband. Based on what values the sensors detect, the researchers can continuously identify the exact position of the ring in space. From there, they can determine where the user’s finger is located.
“To have continuous tracking in other smart rings you’d have to stream all the data using wireless communication. That part consumes a lot of power, which is why a lot of smart rings only detect gestures and send those specific commands,” said co-lead author Farshid Salemi Parizi, a doctoral student in electrical and computer engineering. “But AuraRing’s ring consumes only 2.3 milliwatts of power, which produces an oscillating magnetic field that the wristband can constantly sense. In this way, there’s no need for any communication from the ring to the wristband.”
With continuous tracking, AuraRing can pick up handwriting — potentially for short responses to text messages — or allow someone to have a virtual reality avatar hand that mimics what they’re doing with their actual hand. In addition, because AuraRing uses magnetic fields, it can still track hands even when they are out of sight, such as when a user is on a crowded bus and can’t reach their phone.
“We can also easily detect taps, flicks or even a small pinch versus a big pinch,” Salemi Parizi said. “This gives you added interaction space. For example, if you write ‘hello,’ you could use a flick or a pinch to send that data. Or on a Mario-like game, a pinch could make the character jump, but a flick could make them super jump.”
The researchers designed AuraRing to be ready to use as soon as it comes out of the box and not be dependent on a specific user. They tested the system on 12 participants with different hand sizes. The team compared the actual location of a participant’s finger to where AuraRing said it was. Most of the time, the system’s tracked location agreed with the actual location within a few millimeters.
This ring and wristband combination could be useful for more than games and smartphones, the team said.
“Because AuraRing continuously monitors hand movements and not just gestures, it provides a rich set of inputs that multiple industries could take advantage of,” said senior author Shwetak Patel, a professor in both the Allen School and the electrical and computer engineering department. “For example, AuraRing could detect the onset of Parkinson’s disease by tracking subtle hand tremors or help with stroke rehabilitation by providing feedback on hand movement exercises.”
The technology behind AuraRing is something that could be easily added to smartwatches and other wristband devices, according to the team.
“It’s all about super powers,” Salemi Parizi said. “You would still have all the capabilities that today’s smartwatches have to offer, but when you want the additional benefits, you just put on your ring.”
- Farshid Salemi Parizi, Eric Whitmire, Shwetak Patel. AuraRing. Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies, 2019; 3 (4): 1 DOI: 10.1145/3369831
New droplet-based electricity generator: A drop of water generates 140V power, lighting up 100 LED bulbs
Generating electricity from raindrops efficiently has gone one step further. A research team led by scientists from the City University of Hong Kong (CityU) has recently developed a droplet-based electricity generator (DEG), featured with a field-effect transistor (FET)-like structure that allows for high energy-conversion efficiency and instantaneous power density increased by thousands times compared to its counterparts without FET-like structure. This would help to advance scientific research of water energy generation and tackle the energy crisis.
The research was led together by Professor Wang Zuankai from CityU’s Department of Mechanical Engineering, Professor Zeng Xiao Cheng from University of Nebraska-Lincoln, and Professor Wang Zhong Lin, Founding Director and Chief Scientist from Beijing Institute of Nanoenergy and Nanosystems of Chinese Academy of Sciences. Their findings were published in the latest issue of journal Nature.
Efficiency of electrical energy conversion greatly improved
Hydropower is nothing new. About 70% of the earth’s surface is covered by water. Yet low-frequency kinetic energy contained in waves, tides, and even raindrops are not efficiently converted into electrical energy due to limitations in current technology. For example, a conventional droplet energy generator based on the triboelectric effect can generate electricity induced by contact electrification and electrostatic induction when a droplet hits a surface. However, the amount of charges generated on the surface is limited by the interfacial effect, and as a result, the energy conversion efficiency is quite low.
In order to improve the conversion efficiency, the research team has spent two years developing the DEG. Its instantaneous power density can reach up to 50.1 W/m2, thousands times higher than other similar devices without the use of FET-like design. And the energy conversion efficiency is markedly higher.
Professor Wang from CityU pointed out that there are two crucial factors for the invention. First, the team found that the continuous droplets impinging on PTFE, an electret material with a quasi-permanent electric charge, provides a new route for the accumulation and storage of high-density surface charges. They found that when water droplets continuously hit the surface of PTFE, the surface charges generated will accumulate and gradually reach a saturation. This new discovery helped to overcome the bottleneck of low charge density encountered in previous work.
Unique field-effect transistor-like structure
Another key feature of their design is a unique set of structures similar to a FET, which is a Nobel Prize in Physics winning innovation in 1956 and has become the basic building block of modern electronic devices nowadays. The device consists of an aluminium electrode, and an indium tin oxide (ITO) electrode with a film of PTFE deposited on it. The PTFE/ITO electrode is responsible for the charge generation, storage, and induction. When a falling water droplet hits and spreads on the PTFE/ITO surface, it naturally “bridges” the aluminium electrode and the PTFE/ITO electrode, translating the original system into a closed-loop electric circuit.
With this special design, a high density of surface charges can be accumulated on the PTFE through continuous droplet impinging. Meanwhile, when the spreading water connects the two electrodes, all the stored charges on the PTFE can be fully released for the generation of electric current. As a result, both the instantaneous power density and energy conversion efficiency are much higher.
“Our research shows that a drop of 100 microlitres (1 microlitre = one-millionth litre) of water released from a height of 15 cm can generate a voltage of over 140V. And the power generated can light up 100 small LED light bulbs,” said Professor Wang.
He added that the increase in instantaneous power density does not result from additional energy, but from the conversion of kinetic energy of water itself. “The kinetic energy entailed in falling water is due to gravity and can be regarded as free and renewable. It should be better utilized.”
Their research also shows that the reduction in relative humidity does not affect the efficiency of power generation. Also, both rainwater and seawater can be used to generate electricity.
Facilitates the sustainability of the world
Professor Wang hoped that the outcome of this research would help to harvest water energy to respond to the global problem of renewable energy shortage. “Generating power from raindrops instead of oil and nuclear energy can facilitate the sustainable development of the world,” he added.
He believed that in the long run, the new design could be applied and installed on different surfaces, where liquid in contact with solid, to fully utilize the low-frequency kinetic energy in water. This can range from the hull surface of ferry, coastline, to the surface of umbrellas or even inside water bottles.
Causes of cancer are being catalogued by a huge international study revealing the genetic fingerprints of DNA-damaging processes that drive cancer development. Researchers from the Wellcome Sanger Institute, Duke-NUS Medical School Singapore, University of California San Diego School of Medicine, the Broad Institute of MIT and Harvard and their collaborators around the world have achieved the most detailed list of these genetic fingerprints to date, providing clues as to how each cancer developed.
These fingerprints will allow scientists to search for previously unknown chemicals, biological pathways and environmental agents responsible for causing cancer.
The research, published in Nature today (5th February) as part of a global Pan-Cancer Project, will help understand the causes of cancer, informing prevention strategies, and help signpost new directions for cancer diagnosis and treatments.
Also published today in Nature and related journals, are 22 further studies from the Pan-Cancer Project. The collaboration involving more than 1,300 scientists and clinicians from 37 countries, analysed more than 2,600 genomes of 38 different tumour types. The project represents an unprecedented international exploration of cancer genomes, which significantly improves our fundamental understanding of cancer and zeros-in on mechanisms of cancer development.
In the UK, someone is diagnosed with cancer every two minutes, with 363,000 new cancer cases every year. The disease causes around 165,000 deaths in the UK annually.
Cancer is caused by genetic changes — mutations — in the DNA of a cell, allowing the cell to divide uncontrollably. Many known causes of cancer, such as UV light and tobacco smoking, leave a specific fingerprint of damage in the DNA, known as a mutational signature. These fingerprints can help understand how cancers develop, and potentially, how they can be prevented. However, past studies have not been large enough to identify all potential mutational signatures.
The fingerprint study identified new mutational signatures that had not been seen before, from single letter ‘typo’ mutations, to slightly larger insertions and deletions of genetic code. The result is the largest database of reference mutational signatures ever. Only about half of all the mutational signatures have known causes, however this resource can now be used to help find more of these causes and better understand cancer development.
Professor Steven Rozen, a senior author from Duke-NUS Medical School, Singapore, said: “Some types of these DNA fingerprints, or mutational signatures, reflect how the cancer could respond to drugs. Further research into this could help to diagnose some cancers and what drugs they might respond to.”
Professor Gad Getz, a senior author from the Broad Institute of MIT and Harvard, and Massachusetts General Hospital, said, “The availability of a large number of whole genomes enabled us to apply more advanced analytical methods to discover and refine mutational signatures and expand our study into additional types of mutations. Our new collection of signatures provides a more complete picture of biological and chemical processes that damage or repair DNA and will enable researchers to decipher the mutational processes that affect the genomes of newly sequenced cancers.”
Another study in the Pan-Cancer Project, published in Nature today, discovered that larger, more complex genetic changes that rearrange the DNA could also act as mutational signatures, and point towards causes of cancer. Researchers from the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and their collaborators found 16 of these signatures that spanned from rearrangements of single genes to entire chromosomes.
The global Pan-Cancer Project is the largest and most comprehensive study of whole cancer genomes yet. The collaboration has created a huge resource of primary cancer genomes, available to researchers worldwide to advance cancer research.
- Ludmil B. Alexandrov, Jaegil Kim, Nicholas J. Haradhvala, Mi Ni Huang, Alvin Wei Tian Ng, Yang Wu, Arnoud Boot, Kyle R. Covington, Dmitry A. Gordenin, Erik N. Bergstrom, S. M. Ashiqul Islam, Nuria Lopez-Bigas, Leszek J. Klimczak, John R. McPherson, Sandro Morganella, Radhakrishnan Sabarinathan, David A. Wheeler, Ville Mustonen, Gad Getz, Steven G. Rozen, Michael R. Stratton. The repertoire of mutational signatures in human cancer. Nature, 2020; 578 (7793): 94 DOI: 10.1038/s41586-020-1943-3
- Yilong Li, Nicola D. Roberts, Jeremiah A. Wala, Ofer Shapira, Steven E. Schumacher, Kiran Kumar, Ekta Khurana, Sebastian Waszak, Jan O. Korbel, James E. Haber, Marcin Imielinski, Joachim Weischenfeldt, Rameen Beroukhim, Peter J. Campbell. Patterns of somatic structural variation in human cancer genomes. Nature, 2020; 578 (7793): 112 DOI: 10.1038/s41586-019-1913-9
- The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature, 2020 DOI: 10.1038/s41586-020-1969-6
A Ludwig Cancer Research study has devised a new type of chimeric antigen-receptor (CAR) T cell — a family of promising immunotherapies for cancer — that can be switched on and off on demand. The study, led by Melita Irving of the Lausanne Branch of the Ludwig Institute for Cancer Research, George Coukos, director of the Branch, and their colleague Bruno Correia of the École Polytechnique Fédérale de Lausanne (EPFL), addresses a central conundrum of CAR-T therapies: their tendency to provoke potentially deadly runaway immune responses against healthy tissues in patients. Their report appears in the current issue of Nature Biotechnology.
“We wanted to develop a way to dampen CAR-T cell therapy as a safety mechanism in the event of an adverse reaction in a patient,” says Coukos. “To do that we designed CAR-T cells that can be reversibly inactivated with small molecules that can be given systemically and act rapidly.”
CAR-T cells are designed to detect specific molecular markers, or antigens, and destroy the cancer cells that bear them. To that end, researchers engineer a chimeric molecule, expressed on a T cell, that is stitched together from the functional units — or “domains” — of a few key proteins. The external part of the CAR protein does the antigen detecting. The inner part has two other key components. One is the signaling domain of a protein named CD3-zeta that is absolutely required to activate the T cell. The other is the signaling part of another protein, usually CD28, that supports the proliferation and survival of the activated T cell.
These cellular immunotherapies have been approved for the treatment of some blood cancers, and researchers are working on targeting them at solid tumors. But the treatment has significant risks. CAR-T cells can inadvertently elicit cascading, systemic immune reactions known as cytokine release syndrome, which can cause serious side effects.
Researchers have sought to blunt these risks by, for example, engineering CAR-T cells to commit suicide on demand or require a drug to become activated. “The former approach leads, however, to the waste of a very expensive immunotherapy, while the latter has been challenged by the short half-lives of the drugs,” says Irving. “Our approach offers novel and unique solutions to this difficult molecular engineering problem.”
To build their “STOP-CAR-T” system, the researchers stuck the CD3-zeta activation domain on one molecule and the antigen-detecting portion on the another. To link the two chains together, so that they’d function as a single unit, they added to each chain the interacting domains of two unrelated proteins that spontaneously pair up inside the cell. The researchers also ensured that the binding could be disrupted by existing small molecules administered systemically. Elegant computational modeling and protein engineering done in Correia’s laboratory identified ideal molecular partners for these binding domains and ensured that these newly added binding domains would not interfere with the complex protein interactions within the cell required for the signaling that activates T cells.
The researchers first confirmed in cell cultures that this two-protein CAR-T system — targeted to a prostate cancer antigen — worked as well as a similarly targeted but traditionally designed CAR-T system and could be switched off by a drug-like molecule. They then grew tumors expressing that antigen in the flanks of mice and showed that while both types of CAR-T cells could slow tumor growth, only the STOP-CAR-T system’s effects could be abrogated with the administration of the small molecule before or after the initiation of CAR-T therapy.
“This really shows that, in principle, we should be able to directly control the activity of the STOP-CAR T cells in patients,” says Irving.
The researchers are now developing a STOP-CAR-T system that can be controlled by an approved drug and tweaking the system in various ways to see if they can lower the amount of drug required to control the cells.
“This work itself, and its potential, is really exciting,” says Coukos, “but I think it is also illustrative of how well-orchestrated, multidisciplinary collaborations can yield significant scientific breakthroughs. Working with EPFL and our other partners in the region, we hope to bring STOP-CAR-T therapy as quickly as possible to cancer patients.”
This study was supported by Ludwig Cancer Research, the Biltema and ISREC Foundations, the European Research Council, the National Center of Competence for Molecular Systems Engineering, The Marie Sklodowska-Curie Actions, Whitaker and the National Research Foundation of Korea.
- Greta Giordano-Attianese, Pablo Gainza, Elise Gray-Gaillard, Elisabetta Cribioli, Sailan Shui, Seonghoon Kim, Mi-Jeong Kwak, Sabrina Vollers, Angel De Jesus Corria Osorio, Patrick Reichenbach, Jaume Bonet, Byung-Ha Oh, Melita Irving, George Coukos, Bruno E. Correia. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nature Biotechnology, 2020; DOI: 10.1038/s41587-019-0403-9
Scientists at the University of Groningen and the University Medical Center Groningen used molecular motors to manipulate the protein matrix on which bone marrow-derived mesenchymal stem cells are grown. Rotating motors altered the protein structure, which resulted in a bias of the stem cells to differentiate into bone cells (osteoblasts). Without rotation, the stem cells tended to remain multipotent. These results, which could be used in tissue engineering, were published in Science Advances on 29 January.
‘Cells are sensitive to the structure of the surface that they attach to,’ explains Patrick van Rijn, associate professor in Materiobiology and Nanobiomaterials. ‘And movement is an important driver in biology, especially continuous movement.’ That is why Van Rijn and Feringa and their colleagues decided to use molecular motors to manipulate the protein matrix on which stem cells are grown. The light-driven motor molecules were designed by the 2016 Nobel Laureate in Chemistry Ben Feringa.
The scientists linked molecular motors to a glass surface. Subsequently, the surface was coated with protein and either exposed to UV irradiation to power the motors or not exposed to it at all. After about an hour, the motor movement was stopped and cells were seeded onto the protein layer and left to attach. Finally, differentiation factors were added. These experiments showed that cells grown on protein that was submitted to the rotary motion of the molecular motors tended to specialize into bone cells more often, while cells seeded on protein that was not disturbed were more inclined to maintain their stem-cell properties.
Observations of the protein layer using atomic force microscopy and simulations of the interaction between the motor molecules and proteins, performed by Prof. Marrink’s research group, showed that the movement induced subtle structural changes in the protein matrix. ‘The movement of motor molecules interferes with the alpha-helices in the proteins, which causes structural changes,’ explains Van Rijn. He compares it to the difference in texture between an unwhipped egg white and a whipped one.
The change in the surface structure of the adhered protein affects how the cells attach, for example how much they stretch out. This sets off a signaling cascade that eventually leads to altered behavior, such as the differentiation into bone cells. Thus, molecular movement leads to nanoscopic changes in surface structure, which in turn leads to differences in cell attachment, cell morphology and eventually, cell differentiation. ‘It’s like a domino effect, where smaller stones consecutively topple slightly larger ones so that a large effect can be achieved with a small trigger.’
‘Changing the properties of a surface to affect cell fate has been used before,’ says Van Rijn. However, this was done primarily with switches, so there was just a change from one state to another. ‘In our study, we had continuous movement, which is much more in line with the continuous motion found in biological transport and communication systems. The fact that the motors are driven by light is important,’ Van Rijn adds. ‘Light can be carefully controlled in space and time. This would allow us to create complex geometries in the growth matrix, which then result in different properties for the cells.’ Therefore, light-controlled molecular motors could be a useful tool in tissue engineering.