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About 55 million people worldwide are living with dementia, according to the World Health Organization. The most common form is Alzheimer’s disease, an incurable condition that causes brain function to deteriorate.
In addition to its physical effects, Alzheimer’s causes psychological, social and economic ramifications not only for the people living with the disease, but also for those who love and care for them. Because its symptoms worsen over time, it is important for both patients and their caregivers to prepare for the eventual need to increase the amount of support as the disease progresses.
To that end, researchers at The University of Texas at Arlington have created a novel learning-based framework that will help Alzheimer’s patients accurately pinpoint where they are within the disease-development spectrum. This will allow them to best predict the timing of the later stages, making it easier to plan for future care as the disease advances.
“For decades, a variety of predictive approaches have been proposed and evaluated in terms of the predictive capability for Alzheimer’s disease and its precursor, mild cognitive impairment,” said Dajiang Zhu, an associate professor in computer science and engineering at UTA. He is lead author on a new peer-reviewed paper published open access in Pharmacological Research. “Many of these earlier prediction tools overlooked the continuous nature of how Alzheimer’s disease develops and the transition stages of the disease.”
In work supported by more than $2 million in grants from the National Institutes of Health and the National Institute on Aging, Zhu’s Medical Imaging and Neuroscientific Discovery research lab and Li Wang, UTA associate professor in mathematics, developed a new learning-based embedding framework that codes the various stages of Alzheimer’s disease development in a process they call a “disease-embedding tree,” or DETree. Using this framework, the DETree can not only predict any of the five fine-grained clinical groups of Alzheimer’s disease development efficiently and accurately but can also provide more in-depth status information by projecting where within it the patient will be as the disease progresses.
To test their DETree framework, the researchers used data from 266 individuals with Alzheimer’s disease from the multicenter Alzheimer’s Disease Neuroimaging Initiative. The DETree strategy results were compared with other widely used methods for predicting Alzheimer’s disease progression, and the experiment was repeated several times using machine learning-methods to validate the technique.
“We know individuals living with Alzheimer’s disease often develop worsening symptoms at very different rates,” Zhu said. “We’re heartened that our new framework is more accurate than the other prediction models available, which we hope will help patients and their families better plan for the uncertainties of this complicated and devastating disease.”
He and his team believe that the DETree framework has the potential to help predict the progression of other diseases that have multiple clinical stages of development, such as Parkinson’s disease, Huntington’s disease, and Creutzfeldt-Jakob disease.

As people age or become ill, their immune systems can become exhausted and less capable of fighting off viruses such as the flu or COVID-19. In a new mouse study funded in part by the National Institutes of Health and published in Science Advances, researchers from the USC Stem Cell lab of Rong Lu describe how specific gene activity could potentially enhance immune cell production.
“Hematopoietic stem cells, or HSCs, produce blood and immune cells, but not all HSCs are equally productive,” said the study’s corresponding author Rong Lu, PhD, who is an associate professor of stem cell biology and regenerative medicine, biomedical engineering, medicine, and gerontology at USC, and a Leukemia & Lymphoma Society Scholar. “We wanted to understand the mechanism of why some stem cells produce more immune cells, while other stem cells produce fewer.”
With this goal in mind, first author Du Jiang, PhD, and his colleagues in the in the Lu Lab at the Keck School of Medicine of USC pioneered new techniques for understanding the quantitative association between immune cell production and gene expression in lab mice. The scientists labeled individual stem cells with genetic “barcodes” to track their immune cell production. They then correlated the barcode tracking with measurements of gene expression activity. They also developed innovative bioinformatics approaches to characterize their quantitative association.
By leveraging these technical advances, the scientists identified nearly 40 genes — including genes associated with diseases such as myelodysplastic syndrome, a type of cancer caused by abnormal blood-forming cells — that are related to immune cell production. They discovered associations between the activity of these genes and both the quantity and variety of immune cells produced. For example, certain genes are associated with the production of lymphoid cells, others with myeloid cells, and still others with a healthy balance of various immune cell types.
A few of the genes showed what the scientists described as a “constant association” with the production of lymphocytes only. In other words, at any level of lymphocyte output, gene expression was always associated with lymphocyte production.
A few other genes had a “discrete association” with the production of lymphocytes only. This means that gene activity was associated with lymphocyte production within a specific range of lymphocyte output levels.
Most commonly, genes would have either a “unimodal or multimodal” association with immune cell production. In these instances, which involved both lymphoid and myeloid cells, gene activity was only associated with immune cell production at either one or multiple specific levels of immune cell production.
“In this study, we show that most genes associated with immune cell production are associated only at specific levels of immune cell production,” said Jiang, who earned his PhD in the Lu Lab.”Our findings can inform strategies to optimize bone marrow transplantation — for example, by selecting donor bone marrow cells with gene activity associated with high and balanced levels of immune cell production.”
Additional authors include Adnan Y. Chowdhury, Anna Nogalska, Jorge Contreras, Yeachan Lee, Mary Vergel-Rodriguez, and Melissa Valenzuela from the Lu Lab.
The project was supported by federal funding from the National Institutes of Health (grants R00HL113104, R01HL138225, R01HL135292, R01HL135292-S1, R35HL150826, and R01AG080982) and the National Cancer Institute (grant P30CA014089). Additional support came from the Leukemia & Lymphoma Society (grant LLS-1370-20), California Institute for Regenerative Medicine, and the Hearst Foundations.

Recording the activity of large populations of single neurons in the brain over long periods of time is crucial to further our understanding of neural circuits, to enable novel medical device-based therapies and, in the future, for brain-computer interfaces requiring high-resolution electrophysiological information.
But today there is a tradeoff between how much high-resolution information an implanted device can measure and how long it can maintain recording or stimulation performances. Rigid, silicon implants with many sensors, can collect a lot of information but can’t stay in the body for very long. Flexible, smaller devices are less intrusive and can last longer in the brain but only provide a fraction of the available neural information.
Recently, an interdisciplinary team of researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), in collaboration with The University of Texas at Austin, MIT and Axoft, Inc., developed a soft implantable device with dozens of sensors that can record single-neuron activity in the brain stably for months.
The research was published in Nature Nanotechnology.
“We have developed brain-electronics interfaces with single-cell resolution that are more biologically compliant than traditional materials,” said Paul Le Floch, first author of the paper and former graduate student in the lab of Jia Liu, Assistant Professor of Bioengineering at SEAS. “This work has the potential to revolutionize the design of bioelectronics for neural recording and stimulation, and for brain-computer interfaces.”
Le Floch is currently the CEO of Axoft, Inc, a company founded in 2021 by Le Floch, Liu and Tianyang Ye, a former graduate student and postdoctoral fellow in the Park Group at Harvard. Harvard’s Office of Technology Development has protected the intellectual property associated with this research and licensed the technology to Axoft for further development.
To overcome the tradeoff between high-resolution data rate and longevity, the researchers turned to a group of materials known as fluorinated elastomers. Fluorinated materials, like Teflon, are resilient, stable in biofluids, have excellent long-term dielectic performance, and are compatible with standard microfabrication techniques.

The researchers integrated these fluorinated dielectric elastomers with stacks of soft microelectrodes — 64 sensors in total — to develop a long-lasting probe that is 10,000 times softer than conventional flexible probes made of materials engineering plastics, such as polyimide or parylene C.
The team demonstrated the device in vivo, recording neural information from the brain and spinal cords of mice over the course of several months.
“Our research highlights that, by carefully engineering various factors, it is feasible to design novel elastomers for long-term-stable neural interfaces,” said Liu, who is the corresponding author of the paper. “This study could expand the range of design possibilities for neural interfaces.”
The interdisciplinary research team also included SEAS Professors Katia Bertoldi, Boris Kozinsky and Zhigang Suo.
“Designing new neural probes and interfaces is a very interdisciplinary problem that requires expertise in biology, electrical engineering, materials science, mechanical and chemical engineering,” said Le Floch.
The research was co-authored by Siyuan Zhao, Ren Liu, Nicola Molinari, Eder Medina, Hao Shen, Zheliang Wang, Junsoo Kim, Hao Sheng, Sebastian Partarrieu, Wenbo Wang, Chanan Sessler, Guogao Zhang, Hyunsu Park, Xian Gong, Andrew Spencer, Jongha Lee, Tianyang Ye, Xin Tang, Xiao Wang and Nanshu Lu.
The work was supported by the National Science Foundation through the Harvard University Materials Research Science and Engineering Center Grant No. DMR-2011754.

He won two Pulitzer Prizes by transforming accounts of doctors at work into in-depth, narrative articles that read like dramatic short stories.Jon Franklin, an apostle of narrative short-story style journalism whose own work won the first Pulitzer Prizes awarded for feature writing and explanatory journalism, died on Sunday in Annapolis, Md. He was 82.His death, at a hospice, came less than two weeks after falling at his home, his wife, Lynn Franklin, said. He had also been treated for esophageal cancer for two years.An author, teacher, reporter and editor, Mr. Franklin championed the nonfiction style that was celebrated as New Journalism but that was actually vintage narrative storytelling, an approach that he insisted still adhere to the old-journalism standards of accuracy and objectivity.He imparted his thinking about the subject in “Writing for Story: Craft Secrets of Dramatic Nonfiction” (1986), which became a go-to how-to guide for literary-minded journalists.In 1979, Mr. Franklin won the first Pulitzer ever given for feature writing for his two-part series in The Baltimore Evening Sun titled “Mrs. Kelly’s Monster.”His vivid eyewitness account transported readers into an operating room where a surgeon’s agonizing struggle to save the life of a woman whose brain was being squeezed by a rogue tangle of blood vessels illuminated the marvels and margins of modern medicine.We 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? 

In the retinas of human eyes, the cones are photoreceptor cells responsible for color vision, daylight vision, and the perception of small details. As vision scientists from the Division of Experimental Retinal Therapies at the University of Pennsylvania School of Veterinary Medicine, Gustavo D. Aguirre and William A. Beltran have been working for decades to identify the basis of inherited retinal diseases. They previously showed they could recover missing cone function by reintroducing a copy of the normal gene in photoreceptor cells.
Both humans and dogs are affected by retinal disease, and a new study of daylight vision using a canine model offers a critical insight for evaluating “whether these cell replacements — where we are introducing cones into the retinas of these dogs — is a successful approach for restoring cone vision,” says Beltran, the Corinne R. and Henry Bower Endowed Professor of Ophthalmology.
He and Gustavo Aguirre teamed with researchers including cognitive neuroscientist Geoffrey K. Aguirre, a professor of neurology at the Perelman School of Medicine, bringing together knowledge on the retinal system and brain measurements. In dogs with three different kinds of naturally occurring retinal disease and in dogs with normal vision, the scientists used functional magnetic resonance imaging (fMRI) to assess brain responses to lights that stimulate only the cone cells.
The researchers found that fMRI can detect brain responses to daylight vision for black and white information as well as color information, and it can identify the area of the visual cortex that responds to stimulation of a region in the dog retina that is rich in cones and similar to the human fovea. They also found they can use fMRI to measure the relative degree of loss of daylight vision. Using this technique in animals with a retinal disease caused by a mutation in a gene called NPHP5, they demonstrated that gene augmentation therapy restored the response in the cortex to black and white stimulation. That makes this disease a promising one in which to study photoreceptor cell replacement as a treatment in the future.
Their findings were published in Translational Vision Science & Technology. The other co-authors are Huseyin O. Taskin, a former research specialist at Penn in the GKAguirre Lab and current graduate student at the University of Toronto, and Jacqueline Wivel, a veterinary technician.
“Canine models are useful for studying retinal diseases because they have a variety of different naturally occurring genetic disorders. The ultimate goal is to first demonstrate that these disorders can be treated in canines before translating it to human patients,” says Taskin, the first author. Gustavo Aguirre says, “The hope is that successful therapeutic approaches in people will then become available to veterinarians so that they can benefit man’s four-legged friend.”
Geoffrey Aguirre says, “The purpose of the study was to see, in different versions of these retinal diseases, how much information about daylight vision makes it to the visual system in these dogs.” This knowledge is particularly useful, he says, because figuring out whether a treatment for retinal disease has been effective requires knowing how much vision function was present prior to treatment.

Beltran says this paper shows that gene therapy can recover cone function because it looks at an animal model with no cone function and shows an improvement. He explains that, in the disease caused by the NPHP5 mutation, cones are present but not functional. Animals with this disease are born day-blind but initially have some night vision, though rods — photoreceptors that allow night vision — die over a period of months, making dogs fully blind within a year.
Previous research has measured responses to stimuli through electroretinography and visual behavior tests, which Beltran says can require weeks if not months of dog training. Geoffrey Aguirre says the use of fMRI in this study is significant because it is faster and easier than measuring behavior, and it is not invasive. Taskin also notes that neither visual behavior tests nor electroretinography provide certainty as to what happens in the visual cortex.
A prior study showed that retinal gene therapy in a type of blinding disorder called Leber congential amaurosis is associated with restoration of fMRI responses from the canine visual cortex, but the nature of that study meant that both rod and cone responses could have contributed to cortical activity. The new study furthers knowledge of retinal disease by specifically stimulating the cones.
Huseyin O. Taskin is a former research specialist in the Department of Neurology at the Perelman School of Medicine and a current doctoral candidate in medical sciences at the University of Toronto.
Jacqueline Wivel is a certified veterinary technician in the University of Pennsylvania School of Veterinary Medicine.
Gustavo D. Aguirre is professor of medical genetics and ophthalmology in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.
William A. Beltran is the Corinne R. and Henry Bower Endowed Professor of Ophthalmology and director of the Division of Experimental Retinal Therapies in Penn Vet’s Department of Clinical Sciences & Advanced Medicine.
Geoffrey K. Aguirre is professor of neurology, associate director of the Penn Center for Neuroscience and Society, and associate director of neurology residency in the Department of Neurology at Penn Medicine.
This study was supported by the National Eye Institute (grants R24-EY029890, RO1-EY006855, RO1-EY017549, and P30-EY001583), Fighting Blindness Canada Vision 20/20, The Foundation Fighting Blindness, and the Low Vision Research Award from the Research to Prevent Blindness / Lions Clubs 25 International Foundation.

A new review of available evidence led by researchers at the Harvard Pilgrim Health Care Institute suggests that female reproductive characteristics may be overlooked as risk factors that contribute to later metabolic dysfunction.
The review, “Reproductive risk factors across the female lifecourse and later metabolic health,” was published in the January 26 edition of Cell Metabolism.
Metabolic health is characterized by optimal blood glucose, lipids, blood pressure, and body fat. Alterations in these characteristics may lead to the development of type 2 diabetes or cardiovascular disease.
“Our review provides insights into potential underlying causes and risk factors for poorer metabolic function,” said lead author Amy R. Nichols PhD, MS, RD, a research fellow at the Harvard Pilgrim Health Care Institute and the Harvard T.H. Chan School of Public Health. “Current evidence linking certain female reproductive traits to chronic metabolic health and disease suggests that screening for reproductive risk factors across the lifecourse may be an initial step to aid prevention or treatment of chronic metabolic diseases.”
These reproductive risk factors include early age of first menstruation, menstrual irregularity, the development of polycystic ovary syndrome (PCOS), high weight change in pregnancy, abnormal blood sugar and lipid levels during pregnancy, and the severity and timing of menopausal symptoms. The authors note these traits may share underlying mechanisms leading to poorer metabolic health, including genetic influences, hormonal fluctuations, or body fat. Though acknowledging these reproductive milestones as risk factors is one step toward better understanding the development of metabolic dysfunction, the study teams says future research is needed to understand these complex relationships.
“Disentangling the relationship between risk factors and metabolic dysfunction is challenging,” said senior author Emily Oken MD, MPH, Harvard Medical School Professor and Chair of the Department of Population Medicine at the Harvard Pilgrim Health Care Institute. “Clinical evidence gathered in the health care setting across the female reproductive lifespan may be critical for patient education, implementing prevention strategies, and staving off disease onset.”

In a groundbreaking study published in Nature, South Korean researchers led by Director KOH Gou Young of the Center for Vascular Research within the Institute for Basic Science (IBS) have uncovered a distinctive network of lymphatic vessels at the back of the nose that plays a critical role in draining cerebrospinal fluid (CSF) from the brain. The study, sheds light on a previously unknown route for CSF outflow, potentially unlocking new avenues for understanding and treating neurodegenerative conditions.
In our brains, waste products generated as byproducts of metabolic activity are expelled through cerebrospinal fluid (CSF). Accumulation of waste in the brain, if not properly expelled, can damage nerve cells, leading to impaired cognitive function, dementia, and other neurodegenerative brain disorders. Hence, the regulation of CSF production, circulation, and drainage has long been a focus of scientific attention, especially in relation to age-related conditions like Alzheimer’s disease and other neurodegenerative diseases.
The brain produces around 500 mL of this fluid per day, which is drained from the subarachnoid space. Among the known drainage routes are lymphatic vessels around the cranial nerves and the upper region of the nasal cavity. Despite well-documented evidence of lymphatics aiding CSF clearance, identifying the exact anatomical connections between the subarachnoid space and extracranial lymphatics has posed a challenge due to their extremely complex structure.
Koh’s team tackled this problem using transgenic mice with lymphatic fluorescent markers, microsurgeries, and advanced imaging techniques. Their efforts revealed a detailed network of lymphatic vessels at the back of the nose that serves as a major hub for CSF outflow to deep cervical lymph nodes in the neck. These lymphatics were found to have distinct features, including unusually shaped valves and short lymphangions.
Lead researcher JIN Hokyung highlighted, “Our study identified the nasopharyngeal lymphatic plexus as a hub for CSF outflow. CSF from specific cranial regions drained through these lymphatics to deep cervical lymph nodes in the neck. This discovery could have significant implications for understanding and treating conditions related to impaired CSF drainage.”
The study also demonstrated that pharmacological activation of the deep cervical lymphatics enhanced CSF drainage in mice. The researchers were able to successfully modulate cervical lymphatics using phenylephrine (which activates α1-adrenergic receptors, causing smooth-muscle contraction) or sodium nitroprusside (which releases nitric oxide, inducing muscle relaxation and vessel dilation). Importantly, this feature was preserved during aging, even when the nasopharyngeal lymphatic plexus had shrunk and was functionally impaired.
YOON Jin-Hui, the co-first author of this study, notes, “The deep cervical lymphatics, which remain intact with aging, offer a potential target for therapeutic interventions aimed at improving CSF outflow in individuals with compromised brain health.”
This endeavor was not without its own challenges, however. Deep anesthesia and removal of neck musculature were required to expose the lymphatics in the mice. These delicate procedures themselves had problems altering the physiological dynamics of CSF drainage because cerebral blood flow and blood pulsing through the vasculature contribute to CSF circulation, which in turn influences CSF outflow. Also, while the imaging techniques used were informative, researchers believe more advanced methods for imaging live animals (such as synchrotron X-ray imaging) may reveal more features of the dynamics of CSF drainage under physiological conditions.
Director KOH Gou Young of the Center for Vascular Research stated, “We plan to verify all the findings from the mice in primates, including monkeys and humans. We aim to investigate in a reliable animal model whether activating the cervical lymphatic vessels through pharmacological or mechanical means can prevent the exacerbation of Alzheimer’s disease progression by improving CSF clearance.”
The results of this research have been published online on January 11th in the journal Nature (IF 69.504). It also has been published in print in the January 25th issue of Nature, featured as a cover titled “BRAIN DRAIN.”

A new statistical tool developed by researchers at the University of Chicago improves the ability to find genetic variants that cause disease. The tool, described in a new paper published January 26, 2024, in Nature Genetics, combines data from genome wide association studies (GWAS) and predictions of genetic expression to limit the number of false positives and more accurately identify causal genes and variants for a disease.
GWAS is a commonly used approach to try to identify genes associated with a range of human traits, including most common diseases. Researchers compare genome sequences of a large group of people with a specific disease, for example, with another set of sequences from healthy individuals. The differences identified in the disease group could point to genetic variants that increase risk for that disease and warrant further study.
Most human diseases are not caused by a single genetic variation, however. Instead, they are the result of a complex interaction of multiple genes, environmental factors, and host of other variables. As a result, GWAS often identifies many variants across many regions in the genome that are associated with a disease. The limitation of GWAS, however, is that it only identifies association, not causality. In a typical genomic region, many variants are highly correlated with each other, due to a phenomenon called linkage disequilibrium. This is because DNA is passed from one generation to next in entire blocks, not individual genes, so variants nearby each other tend to be correlated.
“You may have many genetic variants in a block that are all correlated with disease risk, but you don’t know which one is actually the causal variant,” said Xin He, PhD, Associate Professor of Human Genetics, and senior author of the new study. “That’s the fundamental challenge of GWAS, that is, how we go from association to causality.”
To make the problem even harder, most of the genetic variants are located in non-coding genomes, making their effects difficult to interpret. A common strategy to address these challenges is using gene expression levels. Expression quantitative trait loci, or eQTLs, are genetic variants associated with gene expression.
The rationale of using eQTL data is that if a variant associated with a disease is an eQTL of some gene X, then X is possibly the link between the variant and the disease. The problem with this reasoning, however, is that nearby variants and eQTLs of other genes can be correlated with the eQTL of the gene X while affecting the disease directly, leading to a false positive. Many methods have been developed to nominate risk genes from GWAS using eQTL data, but they all suffer from this fundamental problem of confounding by nearby associations. In fact, existing methods can generate false positive genes more than 50% of the time.
In the new study, Prof. He and Matthew Stephens, PhD, the Ralph W. Gerard Professor and Chair of the Departments of Statistics and Professor of Human Genetics, developed a new method called causal-Transcriptome-wide Association studies, or cTWAS, that uses advanced statistical techniques to reduce false positive rates. Instead of focusing on just one gene at a time, the new cTWAS model accounts for multiple genes and variants. Using a Bayesian multiple regression model, it can weed out confounding genes and variants.

“If you look at one at a time, you’ll have false positives, but if you look at all the nearby genes and variants together, you are much more likely to find the causal gene,” He said.
The paper demonstrates the utility of this new technique by studying genetics of LDL cholesterol levels. As one example, existing eQTL methods nominated a gene involved in DNA repair, but the new cTWAS approach pointed at a different variant in the target gene of statin, a common drug used to treat high cholesterol. In total, cTWAS identified 35 putative causal genes of LDL, more than half of which have not been previously reported. These results point to new biological pathways and potential treatment targets for LDL.
The cTWAS software is now available to download from He’s lab website. He hopes to continue working on it to extend its capabilities to incorporate other types of ‘omics data, such as splicing and epigenetics, as well as using eQTLs from multiple tissue types.
“The software will allow people to do analyses that connect genetic variations to phenotypes. That’s really the key challenge facing the entire field,” He said. “We now have a much better tool to make those connections.”

A valuable molecule sourced from the soapbark tree and used as a key ingredient in vaccines, has been replicated in an alternative plant host for the first time, opening unprecedented opportunities for the vaccine industry.
A research collaboration led by the John Innes Centre used the recently published genome sequence of the Chilean soapbark tree (Quillaja saponaria) to track down and map the elusive genes and enzymes in the complicated sequence of steps needed to produce the molecule QS-21.
Using transient expression techniques developed at the John Innes Centre, the team reconstituted the chemical pathway in a tobacco plant, demonstrating for the first time ‘free-from ‘tree’ production of this highly valued compound.
Professor Anne Osbourn FRS, group leader at the John Innes Centre said: “Our study opens unprecedented opportunities for bioengineering vaccine adjuvants. We can now investigate and improve these compounds to promote the human immune response to vaccines and produce QS-21 in a way which does not depend on extraction from the soapbark tree.”
Vaccine adjuvants are immunostimulants which prime the body’s response to the vaccine — and are a key ingredient of human vaccines for shingles, malaria, and others under development.
QS-21, a potent adjuvant, is sourced directly from the bark of the soapbark tree, raising concerns about the environmental sustainability of its supply.
For many years researchers and industrial partners have been looking for ways to produce the molecule in an alternative expression system such as yeast or tobacco plants. But the complex structure of the molecule and lack of knowledge about its biochemical pathway in the tree have so far prevented this.

Previously researchers in the group of Professor Osbourn had assembled the early part of the pathway which makes up the scaffold structure for QS-21. However, the search for the longer full pathway, the acyl chain which forms one crucial part of the molecule that stimulates immune cells, remained unfinished.
In a new study which appears in Nature Chemical Biology, researchers at the John Innes Centre used a range of gene discovery approaches to identify around 70 candidate genes and transferred them to tobacco plants.
By analyzing gene expression patterns and products, supported by the Metabolomic and Nuclear Magnetic Resonance (NMR) platforms at the John Innes Centre, they were able to narrow the search down to the final 20 genes and enzymes which make up the QS-21 pathway.
First author Dr Laetitia Martin said: “This is the first time QS-21 has been produced in a heterologous expression system. This means we can better understand how this molecule works and how we might address issues of scale and toxicity.
“What is so rewarding is that this molecule is used in vaccines and by being able to make it more sustainably my project has an impact on people’s lives. It’s amazing to think that something so scientifically rewarding can bring such good to society.”
“On a personal level this research was scientifically extremely rewarding. I am not a chemist so I could not have done this without the support of the John Innes Centre metabolomics platform and chemistry platform.”
The team have partnered with Plant Bioscience Limited PBL (Plant Bioscience Limited) Norwich Limited who are leading commercialization of this project.

Staying hydrated and consuming appropriate amounts of salt is essential for the survival of terrestrial animals, including humans. The human brain has several regions constituting neural circuits that regulate thirst and salt appetite, in intriguing ways.
Previous studies suggested that water or salt ingestion quickly suppresses thirst and salt appetite before the digestive system absorbs the ingested substances, indicating the presence of sensing and feedback mechanisms in digestive organs that help real-time thirst and salt appetite modulation in response to drinking and feeding. Unfortunately, despite extensive research on this subject, the details of these underlying mechanisms remained elusive.
To shed light on this matter, a research team from Japan has recently conducted an in-depth study on the parabrachial nucleus (PBN), the brain’s relay center for ingestion signals coming from digestive organs. Their latest paper, whose first author is Assistant Professor Takashi Matsuda from Tokyo Institute of Technology, was published in Cell Reports on January 23, 2024.
The researchers conducted a series of in vivo experiments using genetically engineered mice. They introduced optogenetic (and chemogenetic) modifications and in vivo calcium imaging techniques into these mice, enabling them to visualize and control the activation or inhibition of specific neurons in the lateral PBN (LPBN) using light (and chemicals). During the experiments, the researchers offered the mice — either in regular or water- or salt-depleted conditions — water and/or salt water, and monitored neural activities along with the corresponding drinking behaviors.
In this way, the team identified two distinct subpopulations of cholecystokinin mRNA-positive neurons in the LPBN, which underwent activation during water and salt intake. The neuronal population that responds to water intake projects from the LPBN to the median preoptic nucleus (MnPO), whereas the one that responds to salt intake projects to the ventral bed nucleus of the stria terminalis (vBNST). Interestingly, if the researchers artificially activated these neuronal populations through optogenetic (genetic control using light) experiments, the mice drank substantially less water and ingested less salt, even if they were previously water- or salt-deprived. Similarly, when the researchers chemically inhibited these neurons, the mice consumed more water and salt than usual.
Therefore, these neuronal populations in the LPBN are involved in feedback mechanisms that reduce thirst and salt appetite upon water or salt ingestion, possibly helping prevent excessive water or salt intake. These results, alongside their previous neurological studies, also reveal that MnPO and vBNST are the control centers for thirst and salt appetite, integrating promotion and suppression signals from several other brain regions. “Understanding brain mechanisms controlling water and salt intake behaviors is not only a significant discovery in the fields of neuroscience and physiology, but also contributes valuable insights to understand the mechanisms underlying diseases induced by excessive water and salt intake, such as water intoxication, polydipsia, and salt-sensitive hypertension,” remarks Dr. Matsuda.
Prof. Noda mentions, “Many neural mechanisms governing fluid homeostasis remain undiscovered. We still need to unravel how the signals for inducing and suppressing water and salt intake, accumulated in the MnPO and vBNST, are integrated and function to control intake behaviors.”