There is nothing new about humans and all other vertebrates having evolved from fish. The conventional understanding has been that certain fish shimmied landwards roughly 370 million years ago as primitive, lizard-like animals known as tetrapods. According to this understanding, our fish ancestors came out from water to land by converting their fins to limbs and breathing under water to air-breathing.

However, limbs and lungs are not innovations that appeared as recent as once believed. Our common fish ancestor that lived 50 million years before the tetrapod first came ashore already carried the genetic codes for limb-like forms and air breathing needed for landing. These genetic codes are still present in humans and a group of primitive fishes.

This has been demonstrated by recent genomic research conducted by University of Copenhagen and their partners. The new research reports that the evolution of these ancestral genetic codes might have contributed to the vertebrate water-to-land transition, which changes the traditional view of the sequence and timeline of this big evolutionary jump. The study has been published in the scientific journal Cell.

“The water-to-land transition is a major milestone in our evolutionary history. The key to understanding how this transition happened is to reveal when and how the lungs and limbs evolved. We are now able to demonstrate that the genetic basis underlying these biological functions occurred much earlier before the first animals came ashore,” stated by professor and lead author Guojie Zhang, from Villum Centre for Biodiversity Genomics, at the University of Copenhagen’s Department of Biology.

A group of ancient living fishes might hold the key to explain how the tetrapod ultimately could grow limbs and breathe on air. The group of fishes includes the bichir that lives in shallow freshwater habitats in Africa. These fishes differ from most other extant bony fishes by carrying traits that our early fish ancestors might have had over 420 million years ago. And the same traits are also present in for example humans. Through a genomic sequencing the researchers found that the genes needed for the development of lungs and limbs have already appeared in these primitive species.

Our synovial joint evolved from fish ancestor

Using pectoral fins with a locomotor function like limbs, the bichir can move about on land in a similar way to the tetrapod. Researchers have for some years believed that pectoral fins in bichir represent the fins that our early fish ancestors had.

The new genome mapping shows that the joint which connects the socalled metapterygium bone with the radial bones in the pectoral fin in the bichir is homologous to synovial joints in humans — the joints that connect upper arm and forearm bones. The DNA sequence that controls the formation of our synovial joints already existed in the common ancestors of bonefish and is still present in these primitive fishes and in terrestrial vertebrates. At some point, this DNA sequence and the synovial joint was lost in all of the common bony fishes — the socalled teleosts.

“This genetic code and the joint allows our bones move freely, which explains why the bichir can move around on land,” says Guojie Zhang.

First lungs, then swim bladder

Moreover, the bichir and a few other primitive fishes have a pair of lungs that anatomically resembles ours. The new study reveals that the lungs in both bichir and alligator gar also function in a similar manner and express same set of genes as human lungs.

At the same time, the study demonstrates that the tissue of the lung and swim bladder of most extant fishes are very similar in gene expression, confirming they are homologous organs as predicted by Darwin. But while Darwin suggested that swim bladders converted to lungs, the study suggests it is more likely that swim bladders evolved from lungs. The research suggests that our early bony fish ancestors had primitive functional lungs. Through evolution, one branch of fish preserved the lung functions that are more adapted to air breathing and ultimately led to the evolution of tetrapods. The other branch of fishes modified the lung structure and evolved with swim bladders, leading the evolution of teleosts. The swim bladders allow these fishes to maintain buoyancy and perceive pressure, thus better survive under water.

“The study enlightens us with regards to where our body organs came from and how their functions are decoded in the genome. Thus, some of the functions related to lung and limbs did not evolve at the time when the water-to-land transition occurred, but are encoded by some ancient gene regulatory mechanisms that were already present in our fish ancestor far before landing. It is interesting that these genetic codes are still present in these ‘living-fossil” fishes, which offer us the opportunity to trace back the root of these genes,” concludes Guojie Zhang.

FACT BOX 1: Not just limbs and lungs, but also the heart

Primitive fish and humans also share a common and critical function in the cardio-respiratory system: The conus arteriosus, a structure in the right ventricle of our heart which might allow the heart to efficiently deliver the oxygen to the whole body, and which is also found in the bichir. However, the vast majority of bony fish have lost this structure. The researchers discovered a genetic element that appears to control the development of the conus arteriosus. Transgenic experiments with mice showed that when researchers removed this genetic element, the mutated mice died due to thinner, smaller right ventricles, which lead to congenital heart defects and compromised heart function.

FACT BOX 2:

• The vast majority of extant fish species belong to the ray-finned fishes, a subclass of bony fish. These are typically fish with gills, fins and a swim bladder.
• The terrestrial group of vertebrates are known as tetrapod. The tetrapod includes all vertebrates that descended from the first animals adapted to a life on land by developing four limbs and lungs, i.e., all mammals, birds, reptiles and amphibians.
• The researchers’ theory is that the air-breathing ability in these primitive fishes allowed them to survive the second mass extinction roughly 375-360 million years ago. At that time, oxygen depletion in Earth’s oceans caused a majority of species to be wiped out. Lungs allowed some fish to survive on land.
• The study has been published in the scientific journal Cell. The research team also contributed to another paper which reported the genome for another primitive fish, the lungfish. The genome is the biggest vertebrate genome decoded so far. This paper was published in Cell at the same time.
• The research is supported by the Villum Foundation, among others.

“Physical discipline and cognitive deprivation are well-established risks to child development. However, it is rare that these experiences are examined in relation to each other,” said lead author Carmel Salhi, ScD, an Assistant Professor at the Department of Health Sciences, Northeastern University, Boston, MA, USA. “Our study allowed us to explore how these experiences co-occur in childhood internationally and whether they relate to different aspects of child development.

“This is important as recent research in neuroscience suggests that experiences, which provoke fear, have different effects on a child’s neurodevelopment than cognitive deprivation.”

A sample of 29,792 children between the ages of 3 — 6 years old and their caregivers, across 17 countries completed measures of physical discipline, cognitive deprivation and risk of developmental delay. Factors used to determine physical discipline included spanking or slapping on the arm, hand, or leg. Cognitive deprivation included not counting or reading with a child over the past 3 days and the absence of books in the home.

“To see if this framework has the potential to inform policy and public health interventions, we conducted the first large-scale epidemiological study using this conceptual framework,” Dr. Salhi added.

Physical discipline was associated with 50 percent higher odds for risk of socioemotional delay, at least 2.5 times higher than the risk of any of the experiences of cognitive deprivation. Not counting or not reading with the child were associated with 47 percent and 62 percent higher odds, respectively, for risk of cognitive delay. Physical discipline did not confer any risk of cognitive delay.

These findings suggest that the distinction between fear and deprivation in child development, established in clinical neuroscience, is important to public health research and interventions. Furthermore, a large body of evidence links both physical discipline and experiences of cognitive deprivation with poverty and social marginalization. Taken together, this suggests that redistributive policies that alleviate socioeconomic strain can have demonstrably positive effects across a range of child developmental outcomes within a population.

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The study, published Feb. 5 in Cell, reveals a new twist in the complex relationship between humans and their associated microbes, and points the way toward novel therapies that could help combat a rising tide of drug-resistant pathogens.

The new discovery stemmed from work on inflammatory bowel disease, which often causes patients to carry larger than normal populations of fungi in their guts. These patients often develop strong antibody responses against mannan, a molecule common to a wide range of fungal species. However, Dr. Iliyan Iliev, associate professor of immunology in medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, noticed that healthy controls in these studies also had some level of anti-fungal antibodies. “There was no actual evidence for fungal infections in the healthy individuals that we examined, so we started thinking about the possible function of those antibodies,” said Dr. Iliev, who is senior author on the study and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.

The team developed a platform that allowed them to determine which gut fungi are targeted by antibodies in the blood of individual patients. They detected a strong response against the yeast Candida albicans. Turning to experiments in mice, Dr. Iliev and Itai Doron, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate in the lab and lead author on the study, found that colonizing the animals’ guts with Candida albicans caused them to develop antibodies against the fungus in their bloodstreams, even though they didn’t develop blood-borne fungal infections. Instead, the animals’ immune cells appeared to transport fungal antigens to the spleen, stimulating the production of circulating antibodies in the bloodstream. “Those fungi just educate that immune response,” Dr. Iliev said.

In patients with suppressed immune systems, such as organ transplant recipients and some cancer patients, fungi in the gut can invade the bloodstream and cause life-threatening infections. Dr. Iliev and his colleagues mimicked this process by treating mice with immunosuppressive drugs. When a Candida species colonizes the gut of these mice, the fungus moves into the bloodstream, causing a fatal infection. Treating the mice with purified anti-fungal antibodies from donor animals protected the immunosuppressed mice from these infections. The same strategy worked against infection with either Candida albicans or the emerging pathogenic yeast Candida auris, which has become a major cause of fungal disease in immunosuppressed patients and the elderly in recent years.

Collaborating with researchers at INSERM in Paris, France, the Weill Cornell Medicine team also looked at serum from patients with mutations in a gene called CARD9. This mutation affects a critical adapter protein in the immune system, leaving the affected individuals susceptible to severe fungal infections. Dr. Iliev’s team found that the serum of these patients lacked the anti-fungal antibodies normally seen in serum of patients without this mutation. Experiments in mice confirmed an essential and specific role for CARD9 in priming the production of anti-fungal antibodies.

Graphic depicting relationship between fungi in gut, antibody levels and CARD gene Relationship between gut fungi, anti-fungal antibodies, CARD9 gene, and fungal immunity. Image courtesy of the Iliev lab.

The results suggest that normal intestinal fungi such as Candida albicans may function as a kind of intestinal vaccine against fungal infection in healthy people, by inducing the production of bloodborne antibodies that can target multiple species of potentially pathogenic fungi. When those fungi do enter the bloodstream, the antibodies bind them and target them for destruction by cells of the immune system. In patients with suppressed immunity, the anti-fungal antibodies may decline, leaving them vulnerable to fungal infection. New therapies that involve either stimulating the production of anti-fungal antibodies, or injecting such purified antibodies directly into patients’ bloodstreams, could potentially help combat these increasingly common infections.

If that approach works, it would be a welcome development. “Many fungal infections in immunosuppressed patients and elderly patients are happening by translocation of pathogenic Candida species from the gastrointestinal tract, and the survival rates upon systemic spreading are alarmingly low,” said Dr. Iliev.

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In a study published Feb. 3 in Cell Host and Microbe, the investigators showed that patients with Crohn’s disease have an overabundance of a type of gut bacteria called adherent-invasive Escherichia coli (AIEC), which promotes inflammation in the intestine. Their experiments revealed that a metabolite produced by the bacteria interacts with immune system cells in the lining of the intestine, triggering inflammation. Interfering with this process, by either reducing the bacteria’s food supply or eliminating a key enzyme in the process relieved gut inflammation in a mouse model of Crohn’s disease.

“The study reveals a therapeutically targetable weak point in the bacteria,” said senior author Dr. Randy Longman, associate professor of medicine in the Division of Gastroenterology and Hepatology and the Director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.

To find this “Achilles heel,” Dr. Longman and his colleagues, including Drs. Ellen Scherl and Chun-Jun Guo at Weill Cornell Medicine and collaborators Dr. Gretchen Diehl at Memorial Sloan Kettering and Dr. Kenneth Simpson at Cornell’s Ithaca campus, targeted a process the AIEC bacteria uses to convert a byproduct of sugar fermentation in the gut to grow. Specifically, the AIEC uses 1,2-propanediol, a byproduct of the breakdown of a type of sugar called fucose that is found in the lining of the intestines. When the AIEC converts 1,2-propanediol, it produces propionate, which the study showed interacts with a type of immune system cell called mononuclear phagocytes that are also found in the lining of the gut. This sets off a cascade of inflammation.

Next, the investigators genetically engineered AIEC bacteria to lack a key enzyme in this process called propanediol dehydratase. Without propanediol dehydratase, the bacteria do not set off a cascade of inflammation in a mouse model of Crohn’s disease. Reducing the available supply of fucose in the animal’s gut also reduced inflammation.

“Changing one metabolic pathway in one type of bacteria can have a big impact on intestinal inflammation,” said the study’s co-lead author Dr. Monica Viladomiu, a post-doctoral associate in medicine in the Division of Gastroenterology and Hepatology and in the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. Maeva Metz, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate in Dr. Longman’s laboratory, is also co-lead author.

The discovery could lead to better treatments for Crohn’s disease, a type of inflammatory bowel disease that affects more than 4 million people worldwide. Currently, patients with Crohn’s disease are often treated with antibiotics, which can kill both beneficial and harmful bacteria causing unwanted side effects. But treatments that precisely target the inflammatory cascade discovered by Dr. Longman and colleagues might help reduce inflammation while preserving beneficial bacteria.

“If we can develop small molecule drugs that inhibit propanediol dehydratase or use dietary modifications to reduce the availability of fucose, we may be able to reduce intestinal inflammation in patients with Crohn’s disease with fewer side effects,” said Dr. Longman, who is also a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease.

One of the next steps for the team will be testing potential treatments. They also plan to study the potential role of an enzyme called fucosyltransferase 2 in protecting the gut against this inflammatory cascade. Dr. Longman explained that many patients with Crohn’s disease have mutations in the gene that encodes this enzyme, rendering it nonfunctional.

“From a clinical perspective, that’s interesting because it may help us stratify people for whom one intervention or another maybe more useful,” Dr. Longman said.

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“The prominence and early onset of retinal degeneration in JNCL makes it likely that cellular processes that are compromised in JNCL are critical for health and function of the retina,” said Ruchira Signh, Ph.D., an associate professor in the Department of Ophthalmology and Center for Visual Science and lead author of the study which appears in the journal Communications Biology. “It is important to understand how vision loss is triggered in this disease, what is primary and what is secondary, and this will allow us to develop new therapeutic strategies.”

Batten disease is caused by a mutation in the CLN3 gene, which is found on chromosome 16. Most children suffering from JNCL have a missing part in the gene which inhibits the production of certain proteins. Rapidly progressive vision loss can start in children as young as 4 and eventually develop learning and behavior problems, slow cognitive decline, seizures, and loss of motor control. Most patients with the disease die between the ages of 15 and 30.

It has been well established that vision loss in JNCL is due to degeneration of the light-sensing tissue in the retina. The vision loss associated with JNCL can precede other neurological symptoms by many years in some instances, which often leads to patients being misdiagnosed with other more common retinal degenerations. However, one of the barriers to studying vision loss in Batten disease is that mouse models of CLN3 gene mutation do not produce the retinal degeneration or vision loss found in humans. Additionally, examination of eye tissue after death reveals extensive degeneration of retinal cells which does not allow researchers to understand the precise mechanisms that lead to vision loss.

URMC is a hub for Batten disease research. The Medical Center is home to the University of Rochester Batten Center (URBC), one of the nation’s premier centers dedicated to the study and treatment of this condition. The URBC is led by pediatric neurologist Jonathon Mink, M.D., Ph.D., who is a co-author of the study. Batten disease is also one of the key research projects that will be undertaken by the National Institute of Child Health and Human Development-supported University of Rochester Intellectual and Development Diseases Research Center.

To study Batten disease in patient’s own cells, the research team reengineered skin cells from patients and unaffected family members to create human-induced pluripotent stem cells. These cells, in turn, were used to create retinal cells which possessed the CLN3 mutation. Using this new human cell model of the disease, the new study shows for the first time that proper function of CLN3 is necessary for retinal pigment epithelium cell structure, the cell layer in the retina that nourishes light sensing photoreceptor cells in the retina and is critical for their survival and function and thereby vision.

Singh points out that understanding how RPE cell dysfunction contributes to photoreceptor cell loss in Batten disease is important first step, and it will enable researchers to target specific cell type in the eye using potential future gene therapies, cell transplantation, and drug-based interventions.

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Tail wagging the dog

Doing force microscopy by ‘vibrating the table under the finger’ may look like making the entire procedure a whole lot more complicated. In a sense it does. But mastering the complexity of this inverted approach comes with great payoff. The new method promises to push the sensitivity of force microscopy to its fundamental limit, beyond what can be expected from further improvements of the conventional ‘finger tapping’ approach.

The key to the superior sensitivity is the choice of substrate. The ‘table’ in the experiments of Eichler, Degen and their co- workers is a perforated membrane made of silicon nitride, a mere 41 nm in thickness. Collaborators of the ETH physicists, the group of Albert Schliesser at the University of Copenhagen in Denmark, have established these low- mass membranes as outstanding nanomechanical resonators with extreme ‘quality factors’. That is, that once the membrane is tipped on, it vibrates millions of times, or more, before coming to rest. Given these exquisite mechanical properties, it becomes advantageous to vibrate the ‘table’ rather than the ‘finger’. At least in principle.

New concept put to practice

Translating this theoretical promise into experimental capability is the objective of an ongoing project between the groups of Degen and Schliesser, with theory support from Dr. Ramasubramanian Chitra and Prof. Oded Zilberberg of the Institute for Theoretical Physics at ETH Zurich. As a milestone on that journey, the experimental teams have now demonstrated that the concept of membrane- based scanning force microscopy works in a real device.

In particular, they showed that neither loading the membrane with samples nor bringing the tip to within a distance of a few nanometres compromises the exceptional mechanical properties of the membrane. However, once the tip approaches the sample even closer, the frequency or amplitude of the membrane changes. To be able to measure these changes, the membrane features not only an island where tip and sample interact, but also a second one — mechanically coupled to the first — from where a laser beam can be partially reflected, to provide a sensitive optical interferometer.

Quantum is the limit

Putting this setup to work, the team successfully resolved gold nanoparticles and tobacco mosaic viruses. These images serve as a proof of principle for the novel microscopy concept, but they do not yet push the capabilities into new territory. But the destination is just there. The researchers plan to combine their novel approach with a technique known as magnetic resonance force microscopy (MRFM), to enable magnetic resonance imaging (MRI) with a resolution of single atoms, thus providing unique insight, for example, into viruses.

Atomic-scale MRI would be another breakthrough in imaging, combining ultimate spatial resolution with highly specific physical and chemical information about the atoms imaged. For the realization of that vision, a sensitivity close to the fundamental limit given by quantum mechanics is needed. The team is confident that they can realise such a ‘quantum-limited’ force sensor, through further advances in both membrane engineering and measurement methodology. With the demonstration that membrane-based scanning force microscopy is possible, the ambitious goal has now come one big step closer.

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The study, published today (5 February 2021) in Science Advances, sought to understand why neuroblastomas range in severity, with some easy to treat and others having relatively low five-year survival rates. The fact that all neuroblastomas arise from sympathoblasts makes them an attractive drug target, because these cells exist only in the tumour after the child is born.

Neuroblastoma is a rare cancer that generally affects children under five years old. It begins in the abdomen, usually in the adrenal glands — hormone-producing glands above the kidneys. Neuroblastoma is remarkable in that its severity can vary greatly between individuals. In some children the cancer will disappear without treatment, whereas in others the cancer is relentless. The five-year survival rate for neuroblastoma is one of the lowest of all childhood cancers*.

This varied outlook prompted the researchers to ask whether the range of severity could be caused by neuroblastomas arising from different cell types at different stages of the child’s development in the womb. This was made possible by the advent of single cell mRNA sequencing, a high-resolution technology that can identify different cell types present in a tissue according to the genes expressed by individual cells.

In this study, gene expression of 19,723 cancer cells was analysed and compared to a reference of 57,972 developmental adrenal cells in the hope of identifying the cell types from which neuroblastomas arise and to find novel treatment targets.

Dr Jan Molenaar, a senior author of the study from the Princess Máxima Center for Pediatric Oncology in the Netherlands, said: “What is most striking about our findings is that despite the great diversity of clinical behaviour of neuroblastoma, there is an overarching neuroblastoma cell type that is found in all patients. The identification of sympathoblasts as the root of all neuroblastoma is an important step towards understanding how the disease develops and, hopefully, how we can treat it.”

Currently, many cancer treatments cause serious side effects for the patient. But in recent years, technological advances have sped up drug development by allowing researchers to identify differences between the biological processes, such as the expression of a particular gene, within healthy human cells and those within cancerous ones. These differences can be exploited to attack cancer cells without affecting the patient’s healthy cells.

The presence of sympathoblasts, a developmental cell type not normally found in children after they are born, makes it a promising drug target for the treatment of neuroblastoma.

Dr Karin Straathof, a senior author of the study from Great Ormond Street Hospital, said: “Neuroblastoma is an unusual cancer in that some tumours resolve without intervention, yet the disease still has one of the lowest five-year survival rates of any childhood cancer. This study fills important gaps in our knowledge of what neuroblastoma cells are and revealed novel treatment targets. My hope is that new, less intrusive therapies can be developed by targeting sympathoblasts, a developmental cell type that exists only in neuroblastoma tumours after a child is born.”

As well as facilitating the discovery of sympathoblasts as the root of neuroblastoma, the single-cell reference map of the developmental adrenal gland will also contribute to the Human Cell Atlas project**. The project aims to create comprehensive reference maps of all types of human cells — the fundamental units of life — as a basis for understanding human health and diagnosing, monitoring, and treating disease.

Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute and Cambridge University Hospitals, said: “Our study shows the power of looking at individual childhood cancer cells in revealing not just one, but a plethora of novel treatment ideas. This raises the exciting prospect that a single cell atlas of all types of paediatric tumours may transform our understanding of childhood cancer.”

But until now, no optical coating had ever been developed that could simultaneously reflect and transmit the same wavelength, or color.

In a paper in Nature Nanotechnology, researchers at the University of Rochester and Case Western Reserve University describe a new class of optical coatings, so-called Fano Resonance Optical Coatings (FROCs), that can be used on filters to reflect and transmit colors of remarkable purity.

In addition, the coating can be made to fully reflect only a very narrow wavelength range.

“The narrowness of the reflected light is important because we want to have a very precise control of the wavelength,” says corresponding author Chunlei Guo, professor at Rochester’s Institute of Optics. “Before our technology, the only coating that could do this was a multilayered dielectric mirror, that is much thicker, suffers from a strong angular dependence, and is far more expensive to make. Thus, our coating can be a low-cost and high-performance alternative.”

The researchers envision a few applications for the new technology. For example, they show how FROCs could be used to separate thermal and photovoltaic bands of the solar spectrum. Such capability could improve the effectiveness of devices that use hybrid thermal-electric power generation as a solar energy option. “Directing only the useful band of the solar spectrum to a photovoltaic cell prevents its overheating,” says Guo.

The technology could also lead to a six-fold increase in the life of a photovoltaic cell. And the rest of the spectrum “is absorbed as thermal energy, which could be used in other ways, including energy storage for night-time, electricity generation, solar-driven water sanitation, or heating up a supply of water,” Guo says.

“These optical coatings can clearly do a lot of things that other coatings cannot do,” Guo adds. But as with other new discoveries, “it will take a little bit of time for us or other labs to further study this and come up with more applications.

“Even when the laser was invented, people were initially confused about what to do with it. It was a novelty looking for an application.”

Guo’s lab, the High-Intensity Femtosecond Laser Laboratory, is noted for its pioneering work in using femtosecond lasers to etch unique properties into metal surfaces.

The FROC project resulted from a desire to explore “parallel” ways to create unique surfaces that do not involve laser etching. “Some applications are easier with laser, but others are easier without them,” Guo says.

Fano resonance, named after the physicist Ugo Fano, is a widespread wave scattering phenomenon first observed as a fundamental principle of atomic physics involving electrons. Later, researchers discovered that the same phenomenon can also be observed in optical systems. “But this involved very complex designs,” Guo says.

Guo and his colleagues found a simpler way to take advantage of Fano resonance in their optical coatings.

They applied a thin, 15 nanometer-thick film of germanium to a metal surface, creating a surface capable absorbing a broad band of wavelengths. They combined that with a cavity that supports a narrowband resonance. The coupled cavities exhibit Fano resonance that is capable of reflecting a very narrow band of light.

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