The biomarker, called “brain-derived tau,” or BD-tau, outperforms current blood diagnostic tests used to detect Alzheimer’s-related neurodegeneration clinically. It is specific to Alzheimer’s disease and correlates well with Alzheimer’s neurodegeneration biomarkers in the cerebrospinal fluid (CSF).

“At present, diagnosing Alzheimer’s disease requires neuroimaging,” said senior author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. “Those tests are expensive and take a long time to schedule, and a lot of patients, even in the U.S., don’t have access to MRI and PET scanners. Accessibility is a major issue.”

Currently, to diagnose Alzheimer’s disease, clinicians use guidelines set in 2011 by the National Institute on Aging and the Alzheimer’s Association. The guidelines, called the AT(N) Framework, require detection of three distinct components of Alzheimer’s pathology — the presence of amyloid plaques, tau tangles and neurodegeneration in the brain — either by imaging or by analyzing CSF samples.

Unfortunately, both approaches suffer from economical and practical limitations, dictating the need for development of convenient and reliable AT(N) biomarkers in blood samples, collection of which is minimally invasive and requires fewer resources. The development of simple tools detecting signs of Alzheimer’s in the blood without compromising on quality is an important step toward improved accessibility, said Karikari.

“The most important utility of blood biomarkers is to make people’s lives better and to improve clinical confidence and risk prediction in Alzheimer’s disease diagnosis,” Karikari said.

Current blood diagnostic methods can accurately detect abnormalities in plasma amyloid beta and the phosphorylated form of tau, hitting two of the three necessary checkmarks to confidently diagnose Alzheimer’s. But the biggest hurdle in applying the AT(N) Framework to blood samples lies in the difficulty of detecting markers of neurodegeneration that are specific to the brain and aren’t influenced by potentially misleading contaminants produced elsewhere in the body.

For example, blood levels of neurofilament light, a protein marker of nerve cell damage, become elevated in Alzheimer’s disease, Parkinson’s and other dementias, rendering it less useful when trying to differentiate Alzheimer’s disease from other neurodegenerative conditions. On the other hand, detecting total tau in the blood proved to be less informative than monitoring its levels in CSF.

By applying their knowledge of molecular biology and biochemistry of tau proteins in different tissues, such as the brain, Karikari and his team, including scientists at the University of Gothenburg, Sweden, developed a technique to selectively detect BD-tau while avoiding free-floating “big tau” proteins produced by cells outside the brain.

To do that, they designed a special antibody that selectively binds to BD-tau, making it easily detectible in the blood. They validated their assay across over 600 patient samples from five independent cohorts, including those from patients whose Alzheimer’s disease diagnosis was confirmed after their deaths, as well as from patients with memory deficiencies indicative of early-stage Alzheimer’s.

The tests showed that levels of BD-tau detected in blood samples of Alzheimer’s disease patients using the new assay matched with levels of tau in the CSF and reliably distinguished Alzheimer’s from other neurodegenerative diseases. Levels of BD-tau also correlated with the severity of amyloid plaques and tau tangles in the brain tissue confirmed via brain autopsy analyses.

Scientists hope that monitoring blood levels of BD-tau could improve clinical trial design and facilitate screening and enrollment of patients from populations that historically haven’t been included in research cohorts.

“There is a huge need for diversity in clinical research, not just by skin color but also by socioeconomic background,” said Karikari. “To develop better drugs, trials need to enroll people from varied backgrounds and not just those who live close to academic medical centers. A blood test is cheaper, safer and easier to administer, and it can improve clinical confidence in diagnosing Alzheimer’s and selecting participants for clinical trial and disease monitoring.”

Karikari and his team are planning to conduct large-scale clinical validation of blood BD-tau in a wide range of research groups, including those that recruit participants from diverse racial and ethnic backgrounds, from memory clinics, and from the community. Additionally, these studies will include older adults with no biological evidence of Alzheimer’s disease as well as those at different stages of the disease. These projects are crucial to ensure that the biomarker results are generalizable to people from all backgrounds, and will pave the way to making BD-tau commercially available for widespread clinical and prognostic use.

Additional authors of this study are Fernando Gonzalez-Ortiz, B.S., Przemys?aw Kac, B.S., Nicholas Ashton, Ph.D., and Henrik Zetterberg, M.D., Ph.D., of the University of Gothenburg, Sweden; Michael Turton, Ph.D., and Peter Harrison, Ph.D., of Bioventix Plc, Farnham, U.K.; Denis Smirnov, B.S., and Douglas Galasko, M.D., of the University of California, San Diego; Enrico Premi, M.D., Valentina Cantoni, Ph.D., Jasmine Rivolta, Ph.D., and Barbara Borroni, M.D., of the University of Brescia, Italy; and Roberta Ghidoni, Ph.D., Luisa Benussi, Ph.D., and Claudia Saraceno, Ph.D., of RCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

This research was supported by the Swedish Research Council (Vetenskåpradet; #2021-03244), the Alzheimer’s Association (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), the International Society for Neurochemistry’s Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), the Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), the Swedish Dementia Foundation (Demensförbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation and the Anna Lisa and Brother Björnsson’s Foundation, among other sources.

It has rosy pink petals and stems resembling milk glass, giving it a beautiful, otherworldly appearance. As it was first found around Kirishima in Kagoshima Prefecture, Japan, the new species has been named Monotropastrum kirishimense.

Originally, this new species was tentatively treated as a color variant of M. humile, known as M. humile f. roseum. Thus began an extensive and multifaceted 20-year study to determine how exactly these plants differed. Specimens were collected from throughout Japan and Taiwan, as well as Vietnam.

Results of various analyses revealed morphological differences, including the following; M. kirishimense flowers and ovaries are more rounded than those of M. humile, and its rootball is more obscured by the surrounding soil (in contrast to M. humile‘s protruding root tips). M. kirishimense individuals are shorter above ground (under 5cm) and longer below ground (over 10cm). The flowering season is different too; M. humile flowers bloom approximately 40 days earlier than M. kirishimense. As the two plant species have the same primary pollinator (the bumblebee Bombus diversus), this difference in flowering times can reduce heterospecific pollen deposition, helping to ensure conspecific mating, and thereby preventing them from producing hybrids.

There are several other possible reasons why M. kirishimense and M. humile may have evolved into separate species. One possibility is that they have become specialized in feeding on different fungi, which has led to reproductive isolation, or the inability to produce offspring together. This process is known as resource partitioning and is one of the major ways that species can evolve from a common ancestor. Genetic analysis of mycobionts revealed that M. kirishimense has a consistent, specialized association with a particular lineage of fungi, whereas M. humile is associated with different lineages. Therefore, this study suggests that M. kirishimense may have evolved into a new species by relying on a specific type of fungus. In fact, the phylogenetic tree (a ‘family tree’ of the evolutionary history of a group of organisms) of the plants themselves shows that the genetic characteristics of M. kirishimense and M. humile can be separated into two clades. Based on the researchers’ analysis of various characteristics, it has been revealed that M. kirishimense is distinct from M. humile in terms of its appearance, flowering patterns, evolutionary history, and ecological relationships. Therefore, the researchers concluded that it should be recognized as an independent species.

Overall, the research group not only revealed that M. kirishimense is a distinct species but also deepened understanding of plants in the Monotropastrum genus. Mycohetrotrophic plants are very vulnerable to extinction as they rely on specific ecosystems to survive and are usually found in old-growth forests. The newly recognized species, M. kirishimense, is rare and presumably endangered. Now that it has been identified as a new species, conservation efforts can be made to protect it. This study emphasizes the importance of combining various analysis methods, called integrative taxonomy, to fully understand and protect biodiversity. This work was conducted by a multi-institutional research group, including Professor Suetsugu (Graduate School of Science, Kobe University), Professor SUYAMA Yoshihisa (Graduate School of Agricultural Science, Tohoku University), and Dr. Tian-Chuan Hsu (Taiwan Forestry Research Institute). The paper was published online in Journal of Plant Research on November 30, 2022.

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In a study published in the Dec. 26 issue of Nature Communications, a research team led by Houston Methodist delivered islet cells and immunotherapy directly into a 3D printed device akin to a bioengineered pancreas, called the NICHE. The treatment restored healthy glucose levels and eliminated Type 1 diabetes symptoms in animal models for more than 150 days while avoiding severe adverse effects of anti-rejection therapy by administering immunosuppressive drugs only where the transplanted islet cells were located.

Type 1 diabetes is caused by an autoimmune reaction that destroys the cells in the pancreas that make insulin. It can also cause kidney failure. Daily insulin injections are the most conventional treatment but attaining tight control of glucose levels remains challenging and cumbersome for patients. Further, in more severe cases, patients may need pancreas and kidney transplants, or they may qualify for an islet cell transplant, where the islet cells of a deceased pancreas donor are harvested, processed and then transplanted into the Type 1 diabetes patient’s liver.

These transplants can help improve a patient’s symptoms; however, as with all organ transplants, one of the biggest challenges is the need for immunosuppressive drugs for the rest of their lives to avoid transplant rejection. Lifelong immunosuppression can lead to patients being vulnerable to infectious diseases and increases the risk of certain types of cancer.

The NICHE, created in the Department of Nanomedicine at Houston Methodist Research Institute, is a flat device placed under the skin comprised of a cell reservoir for the islets and a surrounding drug reservoir for localized immunosuppression therapy. It is the first platform to combine direct vascularization and local immunosuppression into a single, implantable device for allogeneic islet transplantation and long-term Type 1 diabetes management. Direct vascularization is fundamental for supplying nutrients and oxygen for maintaining the viability of transplanted islet cells.

“A key result of our research is that local immunosuppression for cell transplantation is effective,” said Alessandro Grattoni, Ph.D., corresponding author and chair of the Department of Nanomedicine at Houston Methodist Research Institute. “This device could change the paradigm of how patients are managed and can have massive impact on treatment efficacy and improvement of patients’ quality of life.”

The NICHE incorporates ports for the refilling of drugs as needed. The researchers refilled the drug reservoirs every 28 days, which is comparable to other long-acting drugs clinically available for migraine prevention or HIV treatment.

Grattoni’s team is working on scaling up the NICHE technology for clinical deployment, for which drug refilling may only be needed once every six months. The ability to refill the NICHE technology allows for long-term use in patients. Further, changes in drug formulations or concentration could extend refill intervals to once each year, aligning with routine physician visits.

Grattoni and his collaborators will expand this research over the next few years, with the end goal of testing the NICHE’s safety in humans in about three years. Grattoni’s nanomedicine lab at Houston Methodist focuses on implantable nanofluidics-based platforms for controlled and long-term drug delivery and cell transplantation to treat chronic diseases.

Grattoni’s collaborators on this study include Jesus Paez-Mayorga, Jocelyn Nikita Campa-Carranza, Simone Capuani, Nathanael Hernandez, Hsuan-Chen Liu, Corrine Ying Xuan Chua, Fernanda Paola Pons-Faudoa, Gulsah Malgir, Bella Alvarez, Jean A. Niles, Lissenya B. Argueta, Xian C. Li, Joan E. Nichols and A. Osama Gaber (Houston Methodist); Kathryn A. Shelton, Sarah Kezar and Pramod N. Nehete (MD Anderson Cancer Center); and Dora M. Berman, Melissa A. Willman, Camillo Ricordi and Norma S. Kenyon (University of Miami).

This research received funding support from Juvenile Diabetes Research Foundation (1-INO-2018-595-A-N), Vivian L. Smith Foundation, Houston Methodist Research Institute, Diabetes Research Institute and the National Institutes of Health (NIDDK R01DK132104).

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The research group included Assistant Professor TOGASHI Hideru of Kobe University’s Graduate School of Medicine and Dr. KATSUNUMA Sayaka of Hyogo Prefectural Kobe Children’s Hospital.

These research results were published online in Frontiers in Cell and Developmental Biology on December 8, 2022.

Main Points

• In the organ of Corti in the inner ear, there are two types of cells arranged in a checkerboard-like mosaic pattern; hair cells responsible for hearing and their support cells. However, the relationship between this checkerboard pattern and hearing function has long remained unclear.
• In mice in which the cells in the organ of Corti could not form into this checkerboard pattern, only the hair cells died (apoptosis), which resulted in deafness.
• For the first time in the world, it was understood that the checkerboard layout plays a fundamental structural role in preserving hair cells and their functionality as the arrangement prevents hair cells from adhering to each other.
• This mosaic pattern of cells has been observed in various sensory organs in many different kinds of animals. Understanding the mechanism behind how cell self-organization forms these mosaic patterns will help illuminate the functions of a variety of sensory organs and the mechanisms behind disorders.

Research Background

The inner ear cochlea is necessary for hearing sound, and located inside it is the organ of Corti (*1). When the organ of Corti is viewed from above under a microscope, two types of cells arranged in a precisely ordered layout resembling a chess or checkerboard can be seen. Hair cells that convey sound waves to the brain are separated by support cells, which prevent the hair cells from touching each other. Although it has been thought that this checkerboard arrangement is necessary for the organ of Corti to function properly, the relationship between this pattern and hearing function has long remained unclear.

This research group previously revealed that this inner ear checkerboard is formed by a cellular segregation mechanism that enables the hair cells and support cells to move into line correctly. Hair cells and support cells each express a different type of the cell adhesion molecule nectin. This results in a hair cell and a support cell adhering more strongly to each other than two hair cells or two support cells would. This property is what causes hair cells and support cells to be arranged in a checkerboard pattern. In a mouse model where one of these nectin molecules is not functional, the properties change and the checkerboard pattern cannot form correctly. In this study, the researchers used these mice to investigate the connection between the checkerboard arrangement of cells and hearing functionality.

Research Methodology

The research group compared regular (control) mice to mice with one type of nectin not functioning correctly (nectin-3 KO mouse, referred to as nectin KO mouse below). No difference between the mice was observed in the number of hair cells and support cells in the organ of Corti immediately after birth. However, there was a difference in how easily the two types of cell adhere to each other; in the nectin-3 KO mice hair cells adhere together (which does not normally happen) resulting in abnormalities in the checkerboard pattern. At this point, the researchers hypothesized that testing the hearing of these mice might reveal the relationship between hearing and the checkerboard pattern. They measured the hearing of over one month-old nectin KO mice using the auditory brainstem response (ABR) method (*2). This test revealed that the nectin KO mice were moderately deaf, demonstrating that this hearing loss was caused by the abnormalities in the inner ear.

The researchers then examined the organs of Corti of the nectin KO mice that underwent the ABR test and found that the number of hair cells had decreased by approximately half. Next they set out to find out why only the hair cells (and not the support cells) had disappeared. They discovered that after 2 weeks of age, hair cell apoptosis (*3) occurred. In addition, examination of the traces of apoptosis revealed that cell death occurred in many cells that had adhered to each other. This led the researchers to suppose that the hair cells adhering to each other (which does not normally happen) caused the apoptosis.

In the epithelial tissue, which also includes the organ of Corti, there are tight junctions between each cell. These tight junctions not only connect the cells, they also prevent various molecules (including ions) from passing between the cells. If the organ of Corti doesn’t have these tight junctions, hair cells cannot function properly, cells die and hearing loss occurs. In nectin KO mice, tight junctions were not formed properly in the places where hair cells adhered together. However, tight junctions did correctly form in between hair cells and support cells. As long as two hair cells were not adhered together, normal cell function remained. In other words, hair cell apoptosis was induced only in the places where hair cells were abnormally adhered to each other and tight junctions did not form correctly. These results revealed for the first time that the checkerboard pattern of hair cells and support cells found in the organ of Corti functions as a fundamental structure, which protects hair cells and their functionality, by preventing hair cells from becoming attached to each other.

Further Research

Nectin is the causal gene for Margarita Island ectodermal dysplasia (*4). In addition to a cleft lip or palate and intellectual disabilities, deafness has also been reported in some cases of this genetic disorder. Therefore, the results of the current study might provide a new explanation for some cases of deafness where the cause is unclear.

This study focused on hearing and demonstrated the physiological significance of the checkerboard-like mosaic pattern of cells in the organ of Corti. However other sensory cells that respond to outside stimuli and their respective supporter cells are also arranged in the same kind of alternating mosaic pattern. These mosaic patterns are found in sensory organs, such as the olfactory epithelium that is responsible for the sense of smell and the retina which is responsible for vision. The fact that these mosaic patterns are not only found in mammals but also in a variety of other organisms suggests that they are functionally important. The mosaic patterns in sensory tissues are created by self-organization due to the differences in adhesiveness between cells. Therefore, focusing research on cellular self-organization in sensory organs will increase our knowledge of the functions of sensory organs and advance our understanding of various related diseases.

Glossary

1. Organ of Corti: The sensory organ responsible for hearing. It is located inside the cochlea in the inner ear.

2. Auditory brainstem response (ABR): A method of recording the brain waves that are generated when sound is heard. ABR is not only used to test the hearing of newborn human babies, it can also be used on mice and other animals.

3. Apoptosis: A form of programmed cell death or cellular suicide that occurs in multicellular organisms.

4. Margarita Island ectodermal dysplasia: A genetic disorder caused by mutations in the nectin-1 gene. The main manifestation is a cleft lip or palate accompanied by intellectual disability.

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The discovery at the U.S. Department of Energy’s (DOE) Princeton Plasma Physics Laboratory (PPPL) could improve tackling a range of astrophysical puzzles such as star formation, the origin of large-scale magnetic fields in the universe, and the ability to predict eruptive space weather events that can disrupt cell phone service and black out power grids on Earth. Understanding the heating process also has implications for fusion research.

Breakthrough

“Our direct numerical simulation is the first to provide clear identification of this heating mechanism in 3D space,” said Chuanfei Dong, a physicist at PPPL and Princeton University who unmasked the process by conducting 200 million hours of computer time for the world’s largest simulation of its kind.”Current telescope and spacecraft instruments may not have high enough resolution to identify the process occurring at small scales,” said Dong, who details the breakthrough in the journal Science Advances.

The hidden ingredient is a process called magnetic reconnection that separates and violently reconnects magnetic fields in plasma, the soup of electrons and atomic nuclei that forms the solar atmosphere. Dong’s simulation revealed how rapid reconnection of the magnetic field lines turns the large-scale turbulent energy into small-sale internal energy. As a consequence the turbulent energy is efficiently converted to thermal energy at small scales, thus superheating the corona.

“Think of putting cream in coffee,” Dong said. “The drops of cream soon become whorls and slender curls. Similarly, magnetic fields form thin sheets of electric current that break up due to magnetic reconnection. This process facilitates the energy cascade from large-scale to small-scale, making the process more efficient in the turbulent solar corona than previously thought.”

When the reconnection process is slow while the turbulent cascade is fast, reconnection cannot affect the transfer of energy across scales, he said. But when the reconnection rate becomes fast enough to exceed the traditional cascade rate, reconnection can move the cascade toward small scales more efficiently.

It does this by breaking and rejoining the magnetic field lines to generate chains of small twisted lines called plasmoids. This changes the understanding of the turbulent energy cascade that has been widely accepted for more than half a century, the paper says. The new finding ties the energy transfer rate to how fast the plasmoids grow, enhancing the transfer of energy from large to small scales and strongly heating the corona at these scales.

The new discovery demonstrates a regime with an unprecedentedly large magnetic Reynolds number as in the solar corona. The large number characterizes the new high energy transfer rate of the turbulent cascade. “The higher the magnetic Reynolds number is, the more efficient the reconnection-driven energy transfer is,” said Dong, who is moving to Boston University to take up a faculty position.

200 million hours

“Chuanfei has carried out the world’s largest turbulence simulation of its kind that has taken over 200 million computer CPUs [central processing units] at the NASA Advanced Supercomputing (NAS) facility,” said PPPL physicist Amitava Bhattacharjee, a Princeton professor of astrophysical sciences who supervised the research. “This numerical experiment has produced undisputed evidence for the first time of a theoretically predicted mechanism for a previously undiscovered range of turbulent energy cascade controlled by the growth of the plasmoids.

“His paper in the high-impact journal Science Advances completes the computational program he began with his earlier 2D results published in Physical Review Letters. These papers form a coda to the impressive work that Chuanfei has done as a member of the Princeton Center for Heliophysics,” a joint Princeton and PPPL facility. “We are grateful for a PPPL LDRD [Laboratory Directed Research & Development] grant that facilitated this work, and to the NASA High-End Computing (HEC) program for its generous allocation of computer time.”

The impact of this finding in astrophysical systems across a range of scales can be explored with current and future spacecraft and telescopes. Unpacking the energy transfer process across scales will be crucial to solving key cosmic mysteries, the paper said.

Funding for the paper comes from the DOE Office of Science (FES) and NASA, with computer resources provided by the NASA HEC together with the National Energy Research Scientific Computing Center, a DOE Office of Science user facility, and the NSF-sponsored Computational and Information Systems Laboratory. Co-authors of the paper were researchers at PPPL, Princeton and Columbia Universities, and the NASA Ames Research Center.

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Plants perform photosynthesis to grow. In this process they use energy from sunlight, release oxygen, and produce carbohydrates, which are the basic food resource for all humans and almost all animals on earth. Under natural conditions, light availability can change rapidly in a very short time. One of the main reasons are clouds which provide light and shadow as they pass in front of the sun. Plant leaves and branches can also temporarily provide shade when they are moved by the wind. Plants cannot move from shade to sun when light is limited, and conversely, cannot evade from sun to shade when exposed to too much sunlight. They have to respond to changing light conditions in other ways.

Just like for humans, too much sunlight is harmful to plants. In particular, a rapid change between faint and intense light is problematic. Like the retina in our eyes, plants use molecules in their leaves to capture light particles. When light is low, these light traps are very efficient at catching as much of the low light as possible. If light conditions suddenly change, too much light energy might reach the plant. This energy can overload or damage the sensitive photosynthetic apparatus inside the plant cells. Accordingly, plants have to constantly adapt their photosynthetic activity to their environmental conditions in order to obtain maximum light yield on the one hand, but avoid being harmed by too much light on the other hand.

To date, plants in greenhouses and laboratories are grown almost exclusively under stable and uniform light conditions. Therefore, our understanding of how adaptation to changing light conditions works is very limited. In the worst case, this can lead to plants that are growing well in laboratories and greenhouses but suddenly perform much worse than expected when cultured in the field.

Regulation of photosynthesis under changing light conditions

The researchers around Ute Armbruster from the Max Planck Institute of Molecular Plant Physiology in Potsdam-Golm and David Kramer from the College of Natural Science at Michigan State University (USA) examined the model plant Arabidopsis thaliana for their study. Plants were grown under a wide variety of conditions including static, fluctuating and natural light. The study focused on two ion transport proteins called VCCN1 and KEA3 which play a key role in dynamically adjusting photosynthetic performance. It is known from earlier studies that VCCN1 activates sun protection if the light suddenly becomes too strong. When the light intensity decreases, the second protein KEA3 quickly breaks down this sun protection so that the plant can catch more light again. However, the two proteins VCCN1 and KEA3 have never been examined under realistic light conditions.

The researchers used an innovative new approach to measure photosynthesis in combination with a targeted use of gene knockouts — i.e. plants whose genes for VCCN1 and KEA3 have been switched off. They show that the activities of the proteins VCCN1 and KEA3 depend on the light conditions the plants were raised in. Following suggestions by the head of the Plant Cultivation Infrastructure Group, Dr. Karin Köhl, the researchers focused on two growth-related light factors in the analysis and were able to show that both the amount of light a plant receives, and the frequency of light fluctuations have a strong influence on the function of the two ion transporters. The protective function of VCCN1 is only important in plants previously grown under low light. On the other hand, KEA3 which abolishes protection, was even active in high light periods when the plants were grown under conditions with elevated light intensities.

Sun protection also depends on the degree of light fluctuations the plants are exposed to. When light conditions change significantly, plants produce the orange pigment zeaxanthin, which is also involved in sun protection. The production of this sunscreen is suppressed by KEA3 under high light conditions as well. “Our study shows that we should not look separately at the effect of growth light and the rapid responses to light fluctuations,” said study lead author Thekla von Bismarck and added: “The integration of multiple time scales and metabolic levels in an increasingly complex manner will be a major future challenge for crop research. This will provide key ideas to improve crop yields in the field.”

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Figuring out how germinal centers work is therefore crucial to understanding immunity and developing more effective vaccines. Now, a new study in Cell reveals why some germinal centers persist for months rather than weeks, providing insights that could inform future vaccine design.

Old bottle, new wine

Germinal centers form in the body’s lymphatic tissues shortly after vaccination or infection. Once inside a germinal center, B cells undergo rapid mutations and, through a process of natural selection, only B cells with antibodies that most effectively bind to their target antigens survive. These superior B cells then become either plasma cells, antibody factories that secrete copious amounts of antibodies into serum, or memory B cells, which patrol the body for signs of return of the pathogen they evolved to fight.

“The goal of the germinal center is to generate high-affinity plasma cells and memory B cells, that it then exports” says Renan V.H. de Carvalho, a postdoctoral fellow in the laboratory of Gabriel D. Victora at The Rockefeller University.

In mice, most germinal centers shut down after a few weeks, having accomplished their goal of producing high-affinity B cells. But those that form in response to certain respiratory infections, including the flu, can stay in business for more than six months, roughly a quarter of a mouse’s normal lifespan. De Carvalho and his colleagues wanted to understand why these germinal centers are so long-lived, and what precisely goes on inside them.

For the study, the researchers first infected mice with influenza and SARS-CoV-2 viruses, waited for them to form germinal centers, and then sequenced the antibody genes of B cells harvested from those centers over the course of 24 weeks. Much to their surprise they found that, rather than continuously evolving at a steady clip, antibody optimization peaked after 12 weeks and then apparently regressed, even as the center remained active. This puzzling drop-off was due to the continuous introduction of unevolved “naïve” B cells into the germinal centers, researchers later found.

As weeks turned into months, a more complete picture began to form: the founder B cells that had initially seeded the long-lived germinal centers were being gradually replaced by naïve ones, so that only a tiny fraction of late germinal centers were made of the descendants of the B cells that started them.

Old-school vs new-school

These new recruits did not behave like the original B cells in the germinal center. Subsequent experiments showed that, while the naïve B cells also underwent evolution inside the germinal centers, they did not produce antibodies that could bind to flu or SARS-CoV2 antigens.

“We used to think of infection-induced germinal centers as a single reaction targeting antigens from a particular pathogen,” de Carvalho says. “Apparently it’s not, at least in the case of these long-lived germinal centers.”

But the few original B cells that remained on site were enough to produce efficient immunity against the initial pathogen. When the researchers re-exposed the mice to flu antigens 3 months after they were first infected — effectively mimicking a repeat infection or booster shot — they demonstrated that many of the memory B cells which began pumping out antibodies were descended from the few founder cells that lingered in germinal centers for many months, and not their naïve replacements.

“Even though they constitute a small fraction of the total number of cells later on, the founder cells that stay in the germinal center for a long time are still doing their job,” de Carvalho says. But just how well those founder B cells do their jobs, and whether naïve recruits cramp their style and reduce their efficacy, remains to be seen. Future studies from the Victora lab will address this question.

Meanwhile, the findings already have implications for our general understanding about how germinal centers operate. Understanding the dynamic between founder and naïve B cells could help researchers leverage long-lived germinal centers to produce more effective antibodies against dangerous respiratory viruses, like the flu and SARS-CoV-2.

“The invasion of ongoing germinal center structures by sequential waves of B cells may turn out to be an important factor in predicting germinal center outcomes, possibly well beyond this particular influenza model,” Victora says, “and might give us some insight into how to coax germinal centers to produce the antibodies we need them to.”