Publisher Health

International research led by the Department of Medicine and Life Sciences (MELIS) at Pompeu Fabra University, in collaboration with Hospital del Mar, Hospital Clínic, Charité — Medical University of Berlin, and the universities of Oslo and Genoa, has developed a computational biology tool, based on multi-level network analysis, to achieve an integrated vision of multiple sclerosis. This tool could be used to study other complex diseases such as types of dementia.
Multiple sclerosis is an autoimmune disease of unknown cause that occurs when the immune system attacks the brain and spinal cord. It is a complex disease that is not always easy to diagnose and covers a wide range of biological scales, ranging from genes and proteins to cells and tissues, passing through the entire organism.
Symptoms of multiple sclerosis vary among patients, but the most common range from vision problems, asthenia, difficulty walking and keeping balance, to numbness or weakness in the arms and legs. All of them can appear and disappear or last over time.
The study published today in the journal Plos Computational Biology has conducted a multi-level network analysis of multiomic data (genomic, phosphoproteomic and cytomic), brain and retinal images and clinical data of 328 patients with multiple sclerosis and 90 healthy subjects. It is one of the first studies to date that simultaneously analyses data from very different scales, covering everything from genes to the whole organism. Thus, the new tool allows us to understand the complexity of chronic diseases.
“In this study we have analysed five levels at once: genes, proteins, cells, parts of the brain and behaviour. The proximity of the elements of each level in each person has determined the connection between the elements within each level and between levels and, through Boolean dynamics, considering each element as being active or inactive, and the introduction of disturbances in the system, we have made the elements of the network oscillate. Thus, we have managed to identify which elements of the different levels are related at the biological level,” says Jordi Garcia-Ojalvo, professor of Systems Biology and director of the Dynamical Systems Biology Laboratory at the UPF Department of Medicine and Life Sciences.
“In complex diseases, as in society, many things happen at once, and they do so on multiple scales and over time. So, for human beings, researchers and physicians, it is hard to visualize it if it is not by using these types of tools that allow us to discern and identify the related elements,” says Pablo Villoslada, an associate professor at the UPF Department of Medicine and Life Sciences, director of the Neurosciences programme of the Hospital del Mar Research Institute and head of the Neurology Service at Hospital del Mar, who co-led the study together with Garcia-Ojalvo.
Thanks to the enormous capacity of networks to simplify complex data, they have managed to reveal the correlation between the protein MK03, previously associated with multiple sclerosis, with the total count of T cells, immune system cells that help fight infections, the thickness of the layer of retinal nerve fibres and the timed gait test, which measures the time it takes a patient to walk 7.5 metres as quickly as possible.

Although the size of the study has not allowed validating the use of this correlation as a biomarker to diagnose and possibly treat multiple sclerosis, it has allowed an integrated view of this complex system and revealed the relationship between four biological scales: proteins, cells, tissues and behaviour.
“In complex diseases it is very difficult to have genetic biomarkers. They are often determined by multiple genes and there is a lot of “background noise.” And here we are studying sets of genes, proteins, and phenotypes, and if they are related to each other, we have an indication of the existence of the disease,” Garcia-Ojalvo adds.
“With multiple sclerosis we have to build a puzzle whose aspect we can more or less intuit. We are not totally in the dark, which is why we use systems biology, which informs us of the relevant relationships between the elements so that the puzzle is coherent, fits and we learn. And once we know how the disease works, we can find out how to deal with it,” Villoslada concludes.
This tool based on the relationship between basic biology and applied medicine could be applied to the study of other complex diseases such as Alzheimer’s and other types of dementia.

While combing through the human genome in 2007, computational geneticist Pardis Sabeti made a discovery that would transform her research career. As a then postdoctoral fellow at the Broad Institute of MIT and Harvard, Sabeti discovered potential evidence that some unknown mutation in a gene called LARGE1 had a beneficial effect in the Nigerian population. Other scientists had discovered that this gene was critical for the Lassa virus to enter cells. Sabeti wondered whether a mutation in LARGE1 might prevent Lassa fever — an infection that is caused by the Lassa virus, is endemic in West Africa, and can be deadly in some people while only mild in others.
To find out, Sabeti decided later in 2007, as a new faculty member at Harvard University, that one of the first projects her new lab at the Broad would take on would be a genome-wide association study (GWAS) of Lassa susceptibility. She reached out to her collaborator Christian Happi, now the Director of the African Center of Excellence for Genomics of Infectious Diseases (ACEGID) at Redeemer’s University in Nigeria, and together they launched the study.
Now, their groups and collaborators report the results of that study in Nature Microbiology — the first ever GWAS of a biosafety level 4 (BSL-4) virus. The team found two key human genetic factors that could help explain why some people develop severe Lassa fever, and a set of LARGE1 variants linked to a reduced chance of getting Lassa fever. The work could lay the foundation for better treatments for Lassa fever and other similar diseases. The scientists are already working on a similar genetics study of Ebola susceptibility.
The paper also describes the many challenges the team had to overcome during their 16-year collaborative effort, such as studying a dangerous virus and recruiting patients with a disease that is not well documented in West Africa. Dozens of scientists contributed to the work and spent seven years recruiting patients in Nigeria and Sierra Leone and many additional years establishing the research program and analyzing the results. “It truly took a village to get this done,” said Happi, a co-senior author along with Sabeti.
“Generations of people in our labs, across different institutions and countries, spent significant parts of their careers bringing this to fruition,” added Sabeti, an institute member at the Broad, a Howard Hughes Medical Institute investigator, a professor at the Center for Systems Biology and the Department of Organismic and Evolutionary Biology at Harvard University, and a professor in the Department of Immunology and Infectious Disease at the Harvard T. H. Chan School of Public Health.
The co-first authors of the study are Dylan Kotliar, an internal medicine resident at Brigham and Women’s Hospital and an MD/PhD student in Sabeti’s lab while the project was ongoing; Siddharth Raju, a graduate student in Sabeti’s lab; Shervin Tabrizi, a postdoctoral researcher at the Broad; and Ikponmwosa Odia, a researcher at Irrua Specialist Teaching Hospital in Nigeria.
Lassa learnings
Sabeti recalls the team’s early discussions when launching the project. They knew they had to be cautious at every step: To work with a BSL-4 virus, scientists must wear pressurized suits connected to HEPA-filtered air in a special containment lab. The virus causes fever, sore throat, coughing, and vomiting, but can quickly progress to organ failure in some people.

“This was an extremely challenging study to get off the ground,” said Kotliar, who worked on the project throughout his entire PhD in the Sabeti lab. “I think the battle scars, the things we’ve learned along the way about how to get a project like this done, are going to be important for future research into viruses in developing countries.”
Finding participants for the study would be challenging too. There are currently no FDA-approved diagnostics for Lassa, and Lassa virus cases are typically not documented. There are fewer than 1,000 cases reported each year in Nigeria, the most populous country where the virus is endemic, and cases are often in rural areas far from diagnostic centers, many of which don’t have the technology to detect the virus. Infections with other viruses, and genomic complexity among different strains of the same Lassa virus can complicate analysis. Moreover, African populations have been historically underrepresented in past genetic studies, which reduces statistical power in data analyses and can make it difficult to identify key genetic variants.
When Sabeti began thinking about how to start the project, she reached out to Happi, whom she knew through their mutual work on the malaria-causing pathogen, Plasmodium falciparum. With the help of collaborators including Peter Okokhere, a doctor treating Lassa patients at the Irrua Specialist Teaching Hospital, they began recruiting patients from both Nigeria and Sierra Leone. Then, they compared the genomes of about 500 people who’d had Lassa fever and nearly 2,000 who hadn’t.
In the Nigerian cohort, the team found that people with a set of variants in the LARGE1 gene — which modifies a cell receptor that binds to certain viruses — were less likely to get Lassa fever. Sabeti, Happi, and their colleagues also found genomic regions associated with Lassa fatality: in the LIF1 gene, which encodes an immune-signaling molecule, and, in the Nigerian cohort, the GRM7 gene, which is involved in the central nervous system. The team then used a large-scale screen called a massively parallel reporter assay to home in on which variants within these genomic regions might be functional and could be targets of new treatments.
Better detection
The researchers say that to improve detection and treatment of Lassa fever, more diagnostic centers and diagnostics that work in the field are needed, along with better health infrastructure to connect remote locations with major hospitals.

“This really highlights the need for continued investment in understanding African population genetics,” added Raju. “Even with a relatively limited sample set, we’ve increased our understanding of some African populations, specifically in immune-related genes — and that shows how much more there is to do going forward.”
Sixteen years after they first started thinking about the genetics of Lassa fever, Sabeti and Happi are excited about the study’s findings, which could explain the biological differences between mild and severe illness. They said the work also shows that, as thoughtful collaborations between countries, genome-wide association studies of BSL-4 viruses are possible. The researchers have already begun conducting a similar study of Ebola in Sierra Leone and Liberia, and other scientists are calling for increased pathogen surveillance and scientific training in Africa.
“We’re standing at a moment where we can actually start developing point-of-need diagnostics for Lassa virus and testing much more broadly,” Happi said. “We need better infrastructure, but I think we’ve shown that this kind of study is a worthwhile pursuit.”
This work was supported in part by the National Institute of Health, the German Research Foundation, and the Howard Hughes Medical Institute.

Cornell University researchers have identified a new way to harness the antioxidant and antibacterial properties of a botanical compound to make nanofiber-coated cotton bandages that fight infection and help wounds heal more quickly.
The findings are especially important given the increasing prevalence of multidrug-resistant bacteria.
Cotton gauze is one of the most common wound dressings; it’s inexpensive, readily available, comfortable and biocompatible. However, it doesn’t promote healing or fight infection.
“Cotton alone cannot provide an answer for these complications — it needs to be biofunctionalized,” said lead author Mohsen Alishahi, a doctoral student in fiber science who works in the NanoFibers and NanoTextiles (NanoFibTex) Laboratory.
Tamer Uyar, associate professor and the lab’s director, said one of its main research interests is developing functional fibers from sustainable materials and exploring their potential applications in medical textiles and drug delivery systems.
Researchers used lawsone, a red-orange compound found in henna leaves that has antioxidant, anti-inflammatory and antimicrobial properties, to boost the performance of cotton.
The experimental dressing had excellent antibacterial performance against gram-negative and gram-positive bacterial species, and effectively eradicated E. coli and staph bacteria in testing.

“The prolonged overuse of synthetic antibiotics in high concentrations has contributed to the rise of the deadly epidemic of multidrug-resistant microbes,” Uyar said. “So the use of natural and potent anti-bacterials such as lawsone may serve as an alternative to synthetic anti-bacterials.”
“Wound dressings should provide a suitable environment for facilitating healing and preventing infection,” Alishahi said. “Using totally natural materials such as cotton, cyclodextrin and lawsone, this dressing can facilitate both as it has comprehensive antioxidant and anti-bacterial activity.”
Alishahi said that the dressing would be particularly helpful for chronic wounds that are highly susceptible to infection, like diabetic ulcers and burns. The antioxidant and anti-inflammatory properties would also benefit more routine wounds by reducing the formation of scars.
This research was funded by Cotton Incorporated.

The macrophage is one of the body’s most important inhabitants. Meaning “big eater” in Greek, this immune cell consumes and digests problematic elements from microbes and cancer cells to dust and debris. Macrophages are especially important in the lungs, where they both fight bacterial infection and clear the lungs of excess surfactant, a protein- and lipid-rich layer that’s essential to healthy function but can create a sticky buildup if not controlled.
In a recent study, investigators from Rockefeller University and other institutions have discovered a never-before-documented genetic disorder that causes the improper functioning of these cells.
The researchers made their discovery by drawing an unexpected connection between a select group of sick children. Throughout their lives, these nine children had battled severe diseases such as pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent bacterial and viral infections that left them gasping for breath from often cyst-plagued lungs.
But as genomic data revealed, the children shared another characteristic: the absence of a chemical receptor that is supposed to call alveolar macrophages into action. It’s the first time that this missing receptor, called CCR2, has been linked to disease. The researchers, including Rockefeller’s Jean-Laurent Casanova and Institut Imagine’s Anna-Lena Neehus, recently published their results in Cell.
The study also found that the children are missing half of their alveolar macrophages, which are located in the air sacs of the lungs.
“It was surprising to find that CCR2 is so essential for alveolar macrophages to properly function,” says Casanova. “When it comes to lung defense and cleanup, people without it are operating at a double loss.”
Chemical communication
More formally known as C-C motif chemokine receptor 2, CCR2 sits on the surface of alveolar macrophages, a kind of monocyte (or white blood cell). It responds to the presence of a chemical ligand, or binding molecule, known as CCL-2, which is also expressed by monocytes.

The receptor and ligand work together to summon macrophages to the site of an infection, and to maintain the appropriate level of surfactant; too little can lead to collapsed lung tissue, and too much can result in narrowed airways.
It was among these immune cells that first author Neehus, of Casanova’s lab at the Institut Imagine in Paris, was seeking evidence of genetic deficiencies that might alter their behavior. While combing through the genomic data on 15,000 patients in a database, she found two Algerian sisters, then aged 13 and 10, who’d been diagnosed with severe PAP, a syndrome in which surfactant builds up and the gas exchange that takes place in alveoli is hindered.
About 90% of PAP cases are caused by antibodies that cripple a protein that stimulates the growth of infection-fighting white blood cells. The girls, however, didn’t have the PAP autoantibodies. Instead, they had no CCR2 — a newly identified genetic mutation. Perhaps its lack was connected to their pulmonary conditions, Neehus thought.
“It looked interesting and promising,” she recalls.
She soon found seven other children in the cohort who had the same CCR2 mutation and serious lung conditions: two more pairs of siblings, and one trio of siblings. They were from the United States and Iran.
Diminished capacity
To explore the impact the variant might have on the children, the researchers analyzed the children’s clinical histories, lung tissue samples, and genetic data.

Several key findings emerged. “First we discovered that these patients have only half the normal counts of pulmonary alveolar macrophages, which explains the different types of lesions they have across the pulmonary tissues,” says Casanova. With only half a crew, the reduced cleanup unit couldn’t keep up with its workload, leading to tissue injury.
The macrophages were otherwise normal, as were the children’s other immune cells.
Without CCR2 signaling, monocytes have no idea where they’re needed. In the study, a live-imaging analysis of the monocytes from the lungs of a 10-year-old girl with CCR2 deficiency showed the cells milling about aimlessly, unsure where to go. (See gif at top.) In contrast, live imaging of monocytes from a healthy control patient shows them migrating in the same direction, summoned by the teamwork of CCR2 and CCL-2.
A troubled inheritance
This directionlessness also makes those with a CCR2 deficiency more susceptible to mycobacterial infections, because the macrophages can’t find their way to the tissue clusters where mycobacteria take up residence, and thus digest the invaders.
This had dire effects for three of the children in the study, who developed bacterial infections after being vaccinated with a live-attenuated substrain of Mycobacterium bovis, an agent of tuberculosis. Their immune systems failed to assemble a legion of macrophages at the vaccination site in the shoulder, causing tissue destruction or hard nodes that had to be surgically removed, or lymph node infections. (All of the children were effectively treated with antibiotics.)
The children inherited the deficiency from their parents — and yet their parents were healthy. “Each of the parents carries one disease copy of the gene, and both parents gave the affected copy to their children,” says Neehus. “The parents aren’t affected because they each only have one copy, whereas the kids have two.”
Several children were the result of consanguineous marriages, in which the parents are related. The offspring of such pairings have a higher risk of inheriting the mutation that causes CCR2 to disappear.
The diagnostic test
The absence of CCR2 leads to another effect: an excess of the chemokine CCL-2. Lacking its receptor, CCL-2 builds up in the blood and plasma. This outcome may provide a diagnostic test for screening patients with unexplained lung or mycobacterial disease; the detection of high CCL-2 levels could provide some clarity about the condition’s genetic underpinnings.
In future research, Casanova and his team will mine their database of genomes for patients with gene mutations in CCL-2 rather than in its receptor, CCR2, to understand how such errors may influence the development of disease.
Neehus says, “With more follow-up studies, we could potentially cure the patients by using gene therapy to correct the mutation.”

A novel PET imaging technique can noninvasively detect active inflammation in the body before clinical symptoms arise, according to research published in the February issue of The Journal of Nuclear Medicine. Using a PET tracer that binds to proteins present on activated immune cells, the technique produces images of ongoing inflammation throughout the body, such as rheumatoid arthritis. This makes it easier for physicians to correctly diagnose and treat patients.
Rheumatoid arthritis is the most common type of inflammatory arthritis and affects 18 million people worldwide. It is a complex autoimmune disease characterized by chronic inflammation. This inflammation can cause the destruction of cartilage and bone, eventually leading to limitations, disabilities, loss of function, decreased quality of life, and possibly shortened life expectancy.
“A major interest of the rheumatology field is employing precision diagnostics to predict disease development in individuals with risk factors of rheumatoid arthritis,” said Fredrik Wermeling, PhD, associate professor and group leader at the Department of Medicine, Division of Rheumatology, Center for Molecular Medicine (CMM) at the Karolinska Institutet, in Solna, Sweden. “The hope is to find ways to identify such individuals even before they get sick, with the goal of being able to treat them so they never develop the disease.”
CD69 is one of the earliest cell surface markers seen on cells experiencing inflammation and is present in the tissue of patients with active rheumatoid arthritis. As such, researchers evaluated the performance of the CD69-targeting PET agent, 68Ga-DOTA-ZCAM241, for early disease detection in a mouse model of inflammatory arthritis.
In the study, mice were imaged with 68Ga-DOTA-ZCAM241 PET before and three, seven, and 12 days after induction of arthritis. Disease progression was monitored by clinical parameters, such as measuring body weight and scoring swelling in the paws. The uptake of 68Ga-DOTA-ZCAM241 in the paws was analyzed, and after the last PET scan, tissue biopsy samples analyzed for CD69 expression. A second group of mice received PET scans with a nonspecific control peptide.
Increased uptake of the CD69-directed tracer 68Ga-DOTA-ZCAM241 was seen in the paws of mice with induced inflammatory arthritis three days after induction, which preceded the appearance of clinical symptoms five to seven days after induction. The uptake of 68Ga-DOTA-ZCAM241 also correlated with the clinical score and disease severity. The nonspecific control peptide demonstrated only low binding.
“68Ga-DOTA-ZCAM241 is a potential candidate for PET imaging of activated immune cells during rheumatoid arthritis onset,” stated Olof Eriksson, PhD, associate professor and group leader of Translational PET Imaging at the Department of Medicinal Chemistry at Uppsala University, in Uppsala, Sweden. “We know that physicians are asking for better methods to image inflammation, for example in rheumatoid arthritis, and we hope this technology will be broadly used in many diseases that involve activated immune cells and inflammation.

The damage that air pollution can do is wide-ranging and well-known: The chemicals produced by human activities can trap heat in the atmosphere, change the chemistry of the oceans and harm human health in myriad ways.Now, a new study suggests that air pollution might also make flowers less attractive to pollinating insects. Compounds called nitrate radicals, which can be abundant in nighttime urban air, severely degrade the scent emitted by the pale evening primrose, reducing visits from pollinating hawk moths, researchers reported in Science on Thursday.This sensory pollution could have far-reaching effects, interfering with plant reproduction and decreasing the production of fruits that feed many species, including humans. It could also threaten pollinators, which rely on flower nectar for sustenance and are already experiencing global declines.“We worry a lot about exposure of humans to air pollution, but there’s a whole life system out there that’s also exposed to the same pollutants,” said Joel Thornton, an atmospheric chemist at the University of Washington and an author of the new study. “We’re really just uncovering how deep the impacts of air pollution go.”The project was led by Dr. Thornton; his colleague Jeff Riffell, a sensory neurobiologist and ecologist at the University of Washington; and their joint doctoral student, Jeremy Chan, who is now a researcher at the University of Naples.Lead author Jeremy Chan, now at the University of Naples, conducting field experiments in eastern Washington.Jeremy Chan/University of WashingtonWe are having trouble retrieving the article content.Please enable JavaScript in your browser settings.Thank you for your patience while we verify access. If you are in Reader mode please exit and log into your Times account, or subscribe for all of The Times.Thank you for your patience while we verify access.Already a subscriber? Log in.Want all of The Times? Subscribe.

Researchers have developed a spiral-shaped lens that maintains clear focus at different distances in varying light conditions. The new lens works much like progressive lenses used for vision correction but without the distortions typically seen with those lenses. It could help advance contact lens technologies, intraocular implants for cataracts and miniaturized imaging systems.
“Unlike existing multifocal lenses, our lens performs well under a wide range of light conditions and maintains multifocality regardless of the size of the pupil,” said Bertrand Simon from Photonics, Numerical and Nanosciences Laboratory (LP2N), a joint research unit between the Institut d’Optique Graduate School, the University of Bordeaux and the CNRS in France. “For potential implant users or people with age-related farsightedness, it could provide consistently clear vision, potentially revolutionizing ophthalmology.”
In Optica, Optica Publishing Group’s journal for high-impact research, the researchers describe the new lens, which they call the spiral diopter. Its spiraling features are arranged in a way that creates many separate points of focus — much like having multiple lenses in one. This makes it possible to see clearly at various distances.
“In addition to ophthalmology applications, the simple design of this lens could greatly benefit compact imaging systems,” said Simon. “It would streamline the design and function of these systems while also offering a way to accomplish imaging at various depths without additional optical elements. These capabilities, coupled with the lens’s multifocal properties, offer a powerful tool for depth perception in advanced imaging applications”
Creating a vortex of light
The inspiration for the spiral lens design came when the paper’s first author, Laurent Galinier from SPIRAL SAS in France, was analyzing the optical properties of severe corneal deformations in patients. This led him to conceptualize a lens with a unique spiral design that causes light to spin, like water going down a drain. This phenomenon, known as an optical vortex, creates multiple clear focus points, which allow the lens to provide clear focus at different distances.
“Creating an optical vortex usually requires multiple optical components,” said Galinier. “Our lens, however, incorporates the elements necessary to make an optical vortex directly into its surface. Creating optical vortices is a thriving field of research, but our method simplifies the process, marking a significant advancement in the field of optics.”
The researchers created the lens by using advanced digital machining to mold the unique spiral design with high precision. They then validated the lens by using it to image a digital ‘E,’ much like those used on an optometrist’s light-up board. The authors observed that the image quality remained satisfactory regardless of the aperture size used. They also discovered that the optical vortices could be modified by adjusting the topological charge, which is essentially the number of windings around the optical axis. Volunteers using the lenses also reported noticeable improvements in visual acuity at a variety of distances and lighting conditions.

Crossing disciplines
Bringing the new lens to fruition required combining the intuitively crafted design with advanced fabrication techniques through a cross-disciplinary collaboration. “The spiral diopter lens, first conceived by an intuitive inventor, was scientifically substantiated through an intensive research collaboration with optical scientists,” said Simon. “The result was an innovative approach to creating advanced lenses.”
The researchers are now working to better understand the unique optical vortices produced by their lens. They also plan to perform systematic trials of the lens’ ability to correct vision in people to comprehensively establish its performance and advantages in real-world conditions. In addition, they are exploring the possibility of applying the concept to prescription eyeglasses, which could potentially offer users clear vision across multiple distances.
“This new lens could significantly improve people’s depth of vision under changing lighting conditions,” said Simon. “Future developments with this technology might also lead to advancements in compact imaging technologies, wearable devices and remote sensing systems for drones or self-driving cars, which could make them more reliable and efficient.”

Biologists at the U.S. Department of Energy’s (DOE) Brookhaven National Laboratory have demonstrated a new way to boost the oil content of plant leaves and seeds. As described in the journal New Phytologist, the scientists identified and successfully altered key portions of a protein that protects newly synthesized oil droplets. The genetic alterations essentially protect the oil-protector protein so more oil can accumulate.
“Implementing this strategy in bioenergy or oil crop plants could help meet the growing demand for biodiesel fuel and/or nutritionally important plant oils,” said Brookhaven Lab biochemist John Shanklin, chair of the Lab’s Biology Department, who led the research.
Shanklin’s team has been working for years to boost plant oil accumulation, particularly in parts of plants such as leaves that generally don’t make a lot of oil. These vegetative tissues typically account for most of the plant biomass. Boosting their ability to accumulate oil would substantially increase the biomass energy content. And since vegetable oils are key feedstocks for making biodiesel, the strategy could turn crop plants into green factories for producing sustainable fuels.
Push, pull, protect
Much of the Brookhaven team’s focus has been implementing genetic strategies that biochemically push plant cells to make more oil and pull that newly synthesized oil into storage in lipid droplets — rather than shuttling it into building new plant parts.
“But once oil is made, it can be broken down, and the level of accumulation is the balance between synthesis and breakdown,” Shanklin explained.
So, the scientists have also used a third approach: cranking up production proteins that protect lipid droplets from being degraded.

One such protective protein naturally made by plants is known as oleosin. Oleosin becomes embedded in the oil-droplet membrane, blocking access to enzymes called lipases that initiate the breakdown of oil.
“We and others typically ramp up levels of this small protein to protect the lipid droplets,” Shanklin said.
But oleosin itself can be degraded, limiting its effectiveness. So, in the new work, Shanklin and his team set out to find a way to protect the oil protector.
“This was a complicated puzzle that lead author Sanket Anaokar worked creatively to solve,” Shanklin said. Anaokar is a Brookhaven Lab research associate in the Center for Advanced Bioenergy and Bioproducts Innovation (CABBI) program, a DOE-funded Bioenergy Research Center led by the University of Illinois Urbana-Champaign.
Deleting degradation signals
“We reasoned that if we could identify and remove the parts of oleosin that the degradation enzymes recognize — the degradation ‘signals’ — we could get oleosin to stick around and enhance oil accumulation,” Anaokar said.

Using clues from other groups that had used a different approach to tackle this problem, the scientists engineered variants of the oleosin protein and tested their effects in tobacco leaves. The team initially designed the variants to change all the amino acids hypothesized to be involved in the degradation of oleosin. Then, they reverted the mutations back one at a time and looked for the biggest changes in oil accumulation. In the end, this allowed them to identify a few key mutations that made oleosin significantly more resistant to breakdown.
“These changes made the variant forms of oleosin accumulate to higher levels — which in turn more efficiently protected the oil, so the oil levels also rose,” Shanklin said.
Plants expressing the most successful mix of genetic modifications accumulated 54% more oil in their leaves and 13% more in their seeds compared to unmodified plants.
Serendipitous surprise
One surprising finding was that the modifications to protect oil droplets did not have negative effects on plant growth or the ability of the seeds to germinate. This was surprising because plant seeds need to break down stored oil to fuel germination and the early stages of seedling growth — that is, until the plant has established itself and grown enough leaves for photosynthesis to kick in and fuel further growth.
“We initially had concerns that preventing oil breakdown during seed development would inhibit this ‘establishment’ process,” Shanklin said. “But we discovered that establishment is unaffected by the oleosin variants. This tells us that, during early growth, the plant uses another mechanism for breaking down oil so seedlings can get access to its stored energy.
“We don’t yet know what that process is, but it allows us to use oleosin variants to increase oil accumulation in vegetative tissue and seeds without impairing seedling growth,” Shanklin said.
This research was supported by the DOE Office of Science, via CABBI. It was initiated with support from the Renewable Oil Generated with Ultra-productive Energycane (ROGUE) program, also led by the University of Illinois. In addition to the biochemical and genetic studies in plants, the team used confocal microscopy at Brookhaven Lab’s Center for Functional Nanomaterials (CFN), a DOE Office of Science user facility.

Multiple sclerosis (MS) is a neurological disease that usually leads to permanent disabilities. It affects around 2.9 million people worldwide, and around 15,000 in Switzerland alone. One key feature of the disease is that it causes the patient’s own immune system to attack and destroy the myelin sheaths in the central nervous system. These protective sheaths insulate the nerve fibres, much like the plastic coating around a copper wire. Myelin sheaths ensure that electrical impulses travel quickly and efficiently from nerve cell to nerve cell. If they are damaged or become thinner, this can lead to irreversible visual, speech and coordination disorders.
So far, however, it hasn’t been possible to visualise the myelin sheaths well enough to use this information for the diagnosis and monitoring of MS.  Now researchers at ETH Zurich and University of Zurich, led by Markus Weiger and Emily Baadsvik from the Institute for Biomedical Engineering, have developed a new magnetic resonance imaging (MRI) procedure that maps the condition of the myelin sheaths more accurately than was previously possible. The researchers successfully tested the procedure on healthy people for the first time.
In the future, the MRI system with its special head scanner could help doctors to recognise MS at an early stage and better monitor the progression of the disease. The technology could also facilitate the development of new drugs for MS. But it doesn’t end there: the new MRI method could also be used by researchers to better visualise other solid tissue types such as connective tissue, tendons and ligaments.
Quantitative myelin maps
Conventional MRI devices capture only inaccurate, indirect images of the myelin sheaths. That’s because most of these devices work by reacting to water molecules in the body that have been stimulated by radio waves in a strong magnetic field. But the myelin sheaths, which wrap around the nerve fibres in several layers, consist mainly of fatty tissue and proteins. That said, there is some water — known as myelin water — trapped between these layers. Standard MRIs build their images primarily using the signals of the hydrogen atoms in this myelin water, rather than imaging the myelin sheaths directly.
The ETH researchers’ new MRI method solves this problem and measures the myelin content directly. It puts numerical values on MRI images of the brain to show how much myelin is present in a particular area compared to other areas of the image. A number 8, for instance, means that the myelin content at this point is only 8 percent of a maximum value of 100, which indicates a significant thinning of the myelin sheaths. Essentially, the darker the area and the smaller the number in the image, the more the myelin sheaths have been reduced. This information ought to enable doctors to better assess the severity and progression of MS.
Measuring signals within millionths of a second
However, it is difficult to image the myelin sheaths directly. That’s because the signals that the MRI triggers in the tissue are very short-lived; the signals that emanate from the myelin water last much longer. “Put simply, the hydrogen atoms in myelin tissue move less freely than those in myelin water. That means they generate much briefer signals, which disappear again after a few microseconds,” Weiger says, adding: “And bearing in mind a microsecond is a millionth of a second, that’s a very short time indeed.” A conventional MRI scanner can’t capture these fleeting signals because it doesn’t take the measurements fast enough.

To solve this problem, the researchers used a specially customised MRI head scanner that they have developed over the past ten years together with the companies Philips and Futura. This scanner is characterised by a particularly strong gradient in the magnetic field. “The greater the change in magnetic field strength generated by the three scanner coils, the faster information about the position of hydrogen atoms can be recorded,” Baadsvik says.
Generating such a strong gradient calls for a strong current and a sophisticated design. As the researchers scan only the head, the magnetic field is more contained and concentrated than with conventional devices. In addition, the system can quickly switch from transmitting radio waves to receiving signals; the researchers and their industry partners have developed a special circuit for this purpose.
The researchers have already successfully tested their MRI procedure on tissue samples from MS patients and on two healthy individuals. Next, they want to test it on MS patients themselves. Whether the new MRI head scanner will make its way into hospitals in the future now depends on the medical industry. “We’ve shown that our process works,” Weiger says. “Now it’s up to industry partners to implement it and bring it to market.”

An advanced human heart organoid system can be used to model embryonic heart development under pregestational diabetes-like conditions, researchers report February 8 in the journal Stem Cell Reports. The organoids recapitulate hallmarks of pregestational diabetes-induced congenital heart disease found in mice and humans. The findings also showed that endoplasmic reticulum (ER) stress and lipid imbalance are critical factors contributing to these disorders, which could be ameliorated with exposure to omega-3s.
“The new stem cell-based organoid technology employed will enable physiologically relevant studies in humans, allowing us to bypass animal models and obtain more information about relevant disease mechanisms, accelerating drug discovery and medical translation,” says senior study author Aitor Aguirre of Michigan State University.
Congenital heart disease is the most common type of congenital defect in humans. Pregestational diabetes — diabetes affecting the mother before and during the first trimester of pregnancy — is an important factor contributing to congenital heart disease and is present in a significant, growing population of diabetic female patients of reproductive age. Newborns from mothers with pregestational diabetes can have up to a 12-fold increased risk of congenital heart disease. Unfortunately, pregestational diabetes is hard to manage clinically due to the sensitivity of the developing embryo to glucose oscillations, and it represents a critical health problem for the mother and the fetus.
The limited access to human tissues for research of early-stage disease has resulted in an overreliance on animal models. But it remains unclear to what extent rodent models recapitulate abnormalities present in humans, given critical species differences in heart size, cardiac physiology, electrophysiology, and bioenergetics. In addition, rodent models and many in vitro cell models rely on aggressive diabetic conditions, leading to exaggerated features that may not be clinically relevant.
“Advances in biotechnology and bioengineering are enabling the creation of human mini-organs in vitro,” Aguirre says. “These mini-organs can currently be used to understand human disease much better without the drawbacks of animal models.”
In the new study, Aguirre and his team used an advanced heart organoid model derived from human pluripotent stem cells. This model recapitulates human heart development during the first trimester, including critical steps such as chamber formation, vascularization, cardiac tissue organization, and relevant cardiac cell types. To specifically model the effects of pregestational diabetes, the researchers modified culture conditions to accurately reflect reported physiological levels of glucose and insulin in patients.
The resulting pregestational diabetes heart organoids (PGDHOs) developed features observed in previous mouse and human studies. For example, the diabetic human heart organoids were larger, suggesting signs of cardiac hypertrophy — a first hallmark of maternal pregestational diabetes. This observation was confirmed by studying cardiomyocyte size. The PGDHOs also displayed arrythmias and a reduction in beat frequency, which has been observed in neonatal rats from diabetic mothers. In addition, single-cell transcriptomic analysis of PGDHOs revealed a reduction in cardiomyocyte numbers, a significant expansion of tissue on the outer surface of the heart, and the absence of a well-developed vasculature at early developmental stages.

The PGDHOs also exhibited increased accumulation of reactive oxygen species (ROS), revealing increased oxidative stress and mitochondrial swelling — also hallmarks of diabetic embryonic heart conditions. A significant portion of ROS was localized to the ER and could be impairing its function, leading to a condition known as ER stress. Moreover, the PGDHOs revealed a clear imbalance in very long chain fatty acids, particularly affecting omega-3 polyunsaturated fatty acids, which are mostly synthesized in the ER. Taken together, these results point to a major ER-induced lipid imbalance in PGDHOs. This imbalance is linked to the degradation of fatty acid desaturase 2 (FADS2) — a key lipid biosynthesis enzyme presents in the ER — by the IRE1-dependent mRNA decay (RIDD) pathway, which has been implicated in several other cardiac conditions.
In an attempt to remedy the effects of ER stress, the researchers tested several potentially therapeutic compounds on PGDHOs. A mixture of omega-3 fatty acids ameliorated diabetic features, while targeting inositol-requiring enzyme 1 (IRE1) reduced cardiomyocyte hypertrophy. All the compounds also restored FADS2 levels.
“The organoids still lack some features that could be important, such as external vascularization and outflow tract, and better chamber formation, so we might still be missing important aspects of congenital heart disease and diabetic cardiomyopathy,” Aguirre says. “On one hand, we want to partner with clinicians to establish the efficacy and safety of our findings in pregnant women. On the other hand, we want to apply our organoid model to other conditions affecting congenital heart disease so we can improve the lives of these children in the future.”
This research was supported by the National Institutes of Health, the National Science Foundation, the Michigan Diabetes Research Center, the University of Michigan, the American Heart Association and the Spectrum-MSU Alliance Foundation.