Monthly Archives: June 2021

Genetics

Rapid Genetic Testing May Have Spared This Baby From Death – MedPage Today

For an infant with seizures, every passing hour risks more harm to the newborn's brain.

That's why this story from Rady Children's Hospital in San Diego is so inspiring, not just for parents and their children, but for doctors and geneticists.

It shows the huge progress since the start of the Human Genome Project 30 years ago, not only in faster sequencing of 3.2 billion base pairs, but the ability to convert that information into a diagnosis. This case, which was published in the New England Journal of Medicine, is one that was easy and inexpensive to treat.

The ordeal began one Sunday night in October 2020 when a frightened couple took their 41-day-old child to Rady's emergency department (ED) because he wouldn't stop crying. The same thing happened to their newborn daughter 10 years earlier, before genetic testing was as advanced. The sister deteriorated rapidly and died before her first birthday. Would her brother have the same dire course?

'This Is Why I Chose Genetics'

"This [baby] is exactly the reason I chose biogenetics," said Anna-Kaisa Niemi, MD, who is both a Rady neonatologist and metabolic geneticist. "You always try to find the defect and the diagnosis and if you do, you're able to start treatment fast. But it's never happened this fast before."

Late that October night, a head CT showed worrisome changes and an MRI revealed concerning white patterns in the infant's basal ganglia. The ED team transferred the baby to the hospital's NICU. When Niemi arrived Monday morning, the child was still crying.

"It wasn't a hungry cry, or 'my diapers are dirty' cry, or even 'I have a broken bone' cry. It was non-stop, inconsolable crying, like something is very wrong in the brain," Niemi told MedPage Today. "I don't want to say scary, but it was very alarming to me. I knew we needed to figure it out right away."

A physical exam revealed downward eye deviation, and the parents disclosed they are first cousins, more hints for a possible genetic abnormality. An electroencephalogram identified brain seizures.

Mallory Owen, MBChB, a pediatric neurologist who then was working with the affiliated Rady Children's Institute for Genomic Medicine (RCIGM), described what happened next.

"We got a call from the [hospital] medical director who said we have a baby in the NICU who I think might really benefit from having this research protocol, 'ultra-ultra' rapid whole genome sequencing," said Owen.

There are some 1,500 genetic diseases associated with epileptic encephalopathy with similar or identical symptoms but very different treatments, Owen said.

To attempt to figure out which one it could be, a blood sample was drawn by 4 p.m. Monday and sequencing began at 7:23 p.m. It was completed by 6:30 a.m. Tuesday, according to a timeline prepared by Owen, lead author of the case report.

By 7:24 a.m. Tuesday, the in-house sequencing process was aided by Rady's partners, Illumina, which has developed DNA PCR-Free Prep, and Alexion Pharmaceuticals, whose scientists helped narrow the list of variants to match the infant's symptoms.

One in a Million

The result, 10 minutes later, revealed the boy had autosomal recessive thiamine metabolism dysfunction, syndrome 2, (THMD2) a defect in the mechanism responsible for transporting thiamine from the blood to the brain. But lucky for him, oral supplements of two over-the-counter vitamins, thiamine and biotin, resolved the problem.

THMD2 is extremely rare, occurring in an estimated one-in-a-million babies, according to the institute's medical director, David Dimmock, MD. It's a two base-pair frameshift, which Owen described as like a line of text in which the last two letters of one word are shifted into the next word, "and suddenly all the words don't make sense because the spaces between the words are in the wrong places."

It is likely that because the mutation is homozygous, the child inherited one copy from his mom and one from his dad, who each had the same mutation because they are related, she said.

By 12:13 p.m. Tuesday, vitamin tablets were crushed, added to liquid in appropriate dosage and administered to the infant through a feeding tube. Six hours later, his crying, seizures and irritability had resolved and as of June 14, have not returned. "The baby looked completely different," said Niemi. "It's unbelievable how fast (the vitamins) worked."

Time will tell if the baby, now 9 months old, will have permanent damage from his first 5 weeks of life. Owen acknowledged some signs of delayed development that could resolve in time, though it's too soon to tell. "No baby with this particular disease has been treated this early," she said.

But without this diagnosis, Owen is confident the boy would follow the path of his sister, who had the same seizures and "basically made no developmental progress from 2 months of age to the time of her death."

RCIGM had been working on developing a way to sequence the entire genome faster for 6 years. At commercial labs nationally, standard whole-genome sequencing can take weeks to identify a culprit sequence variant.

'Ultra-Ultra-Rapid' Sequencing

Like several other genetic projects around the globe, the institute has developed faster techniques: a "rapid" method that takes less than a week and an "ultra-rapid" protocol that averages between 30 and 50 hours. Still experimental, however, is this 13.5-hour process, nicknamed "ultra-ultra-rapid" by the team.

Time is of the essence in newborns, and a week or two delay can be fatal. During that time, the clinician has already administered ineffective treatments that may even have caused harm. "There could already be permanent brain damage, and when that happens, it's irreversible," Owen said.

Marc Williams, MD, president of the American College of Medical Genetics and Genomics, who heard about the case on social media, called Rady's latest sequencing speed "transformative," potentially saving many children from conditions such as intellectual disability or cerebral palsy.

For most hospitals today, if a clinician orders a sequence for a child with a suspected abnormality, it would be sent to an outside laboratory and take anywhere from 1 to 3 weeks to get back, and even then, may not give enough specific information.

"One could argue the difference between 50 hours or 30 hours or 13 hours isn't all that big of a deal," he told MedPage Today. But the bigger deal, he said, is now we have "a child who has a chance at a normal outcome, as opposed to either death or severe disability if we did things the way we've always done them."

Asked if there is a kind of race going on among geneticists to see who can beat the clock, Williams said Rady's team keeps trying to beat itself. "They're pushing the limit to show how fast we can do this, in some ways, like a sprinter who sets a world record, but now says I think I can go faster."

The institute now does sequencing for a network of 60 other children's hospitals in the U.S. and Canada. Since last October, it has performed ultra-ultra-rapid sequencing on two other babies and got a diagnosis for one of them, a rare mitochondrial disease. That case is being written up for publication.

Does Rady see itself as the go-to institute for hospitals with patients suspected of having treatable genetic conditions?

Mallory said that becoming a "center of excellence" for whole genome sequencing is one of its aims, especially for NICU babies. But, she said, "rapid sequencing needs to be something that is not led by a single center. It's a huge project, with huge massive data requirements, and really should be pushed forward by a large assortment of institutions, of which Rady is one."

Rady's ultra-ultra-rapid sequencing is still in the research phase. It was funded by numerous federal grants to its president/CEO, Stephen Kingsmore, MBChB, DSc, and did not cost the family.

Currently, the Rady institute's cost is around $10,000 for standard sequencing, although this varies case by case. When it's ready and has received required approvals, the ultra-ultra-rapid will cost much more.

That's why bills were recently introduced in the U.S. Senate and in the California legislature to cover the cost.

Sen. Susan Collins (R-Maine), introduced S. 2022, the Ending the Diagnostic Odyssey Act, which would give states the option of providing federal matching funds for whole genome sequencing for Medicaid-eligible children with conditions that are suspected of having a genetic cause.

In California, state Assemblymember Brian Maienschein, whose district includes Rady Children's, has introduced AB 114, the Rare Disease Sequencing for Critically Ill Infants Act, which would improve access to rapid whole genome sequencing for Medi-Cal beneficiaries.

Cheryl Clark has been a medical & science journalist for more than three decades.

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Rapid Genetic Testing May Have Spared This Baby From Death - MedPage Today

Genetics

Genetic Mutation Reveals Surprising Role of Bioelectricity in Early Brain Formation – SciTechDaily

In polymicrogyria, the cortex of the brain has many irregular, small folds (gyria) and disorganization of its layers, caused by mutations in one of several genes. Many affected children have severe developmental delay, intellectual disabilities, and epilepsy, Credit: Richard Smith/Sebastian Stankiewicz, Boston Childrens Hospital

A mutation in four children with polymicrogyria illuminates the role of bioelectricity in early brain development.

In polymicrogyria, the cortex of the brain has many irregular, small folds (gyria) and disorganization of its layers. Many affected children have severe developmental delay, intellectual disabilities, and epilepsy, and many need to use a wheelchair. Mutations in several different genes can cause this overfolding of the brain condition.

Studying four patients with polymicrogyria, Richard Smith, PhD, identified mutations in a gene that caused him to do a double-take. His curiosity drove him to investigate the role of this gene, called ATP1A3, in the developing brain.

ATP1A3 is critical to many cell biological processes, says Smith, an investigator theDivision of Genetics and GenomicsatBoston Childrens Hospital. Its one of the most important genes we have in our brains.

ATP1A3 encodes a protein that makes up part of a cellular pump. It moves sodium and potassium ions across the cell membrane, allowing our cells to maintain differing concentrations of charged ions on either side, similar to a battery. This difference enables electrical currents to flow into or out of cells, drivingaction potentialsin neurons and other essential cell functions.

For me it was very compelling to understand how these pump proteins, and the flow of ions, contribute to core mechanisms in brain development, says Smith, an electrophysiologist by training. We got a lot of great biological insights by studying these four patients.

When and where in the typical developing brain is ATP1A3 turned on? To answer this question, Smith, with senior investigatorChristopher Walsh, MD, PhDand colleagues at multiple other sites, obtained donated human tissues from several hospital tissue banks and the NIH NeuroBiobank. The investigators analyzed samples from two times in early brain development: at around 20 weeks gestation, when the fetal cortex, initially smooth, starts to fold, and in infants soon after birth.

Using single-cell RNA sequencing (DropSeq) in collaboration withMarta Florio, PhD, at Harvard Medical School, they looked for expression (turning on) of ATP1A3 in about 125,000 individual neurons from 11 areas of the prenatal cortex. They also profiled about 52,000 neurons from the infants, sampling four areas of the cortex.

Overall, ATP1A3 expression levels were highest in the prefrontal cortex at both time points, and highest in the most active, frequently-firing neurons in the cortex. In the fetal cortex, ATP1A3 expression was particularly high in the subplate, a layer that disappears later in development. Electrical activity in the subplate is thought to be a hub of signaling driving synapse formation, neuron migration, and other brain developmental processes.

In the infants, we found increased expression of the gene in interneurons, which are inhibitory, says Smith. We think that ATP1A3 mutations may disrupt the balance of excitation and inhibition in the brain, which could contribute to epilepsy in other ATP1A3-related conditions.

The work, published inPNAS, underscores how research in rare diseases can yield fundamental insights in biology in this case, how the brain develops its contours and organizational pattern. It provides a map for future studies of how mutations in ATP1A3 cause the brain to form abnormally.

When we first published this as a preprint, we had a lot of people reach out to us with patients with overlapping phenotypes, so it is very exciting to better understand this disease, says Smith.

The findings may also inform scientists understanding of other known ATP1A3-related disorders. While the patients with polymicrogyria had severe mutations causing loss of function of the gene, milder mutations cause a spectrum of later-onset neurologic diseases including alternating hemiplegia of childhood, which causes bouts of temporary paralysis; amovement disorderknown as rapid onset dystonia parkinsonism; and childhood-onset schizophrenia. These later-onset disorders may be more amenable to therapeutic intervention.

Polymicrogyria is at the extreme end of severity, but we think that ATP1A3-related disorders in the middle of this spectrum could have early pathogenic roots that could possibly be treated before they become more severe, says Smith.

He adds that ifnewborn DNA sequencingbecomes common, it could offer a window of opportunity for treating ATP1A3 related disorders before they manifest clinically.

As for polymicrogyria, a structural malformation is trickier to reverse, but infant brains are amazingly plastic and capable of reorganizing, says Smith. So if you could lessen the epilepsy-related damage from the earliest point, you might be able to improve quality of life.

Reference: Early role for a Na+,K+-ATPase (ATP1A3) in brain development by Richard S. Smith, Marta Florio, Shyam K. Akula, Jennifer E. Neil, Yidi Wang, R. Sean Hill, Melissa Goldman, Christopher D. Mullally, Nora Reed, Luis Bello-Espinosa, Laura Flores-Sarnat, Fabiola Paoli Monteiro, Casella B. Erasmo, Filippo Pinto e Vairo, Eva Morava, A. James Barkovich, Joseph Gonzalez-Heydrich, Catherine A. Brownstein, Steven A. McCarroll and Christopher A. Walsh, 14 June 2021, Proceedings of the National Academy of Sciences.DOI: 10.1073/pnas.2023333118

Smith is supported by the NIH National Institute of Neurological Disorders and Stroke and the Tommy Fuss Foundation. Walsh is a HHMI Investigator, and receives funding from the Paul Allen Discovery Foundation and the NIH.

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Genetic Mutation Reveals Surprising Role of Bioelectricity in Early Brain Formation - SciTechDaily

Cell Biology

Cell Biology Test Kits Market to Show Incredible Growth by 2027 The Manomet Current – The Manomet Current

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Segmentation on the Basis of Type:Bacteria Test Kits Protein Test Kits Others

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In-depth Cell Biology Test Kits Market Report: Intended AudienceCell Biology Test Kits manufacturersDownstream vendors and end-usersTraders, distributors, and resellers of Cell Biology Test KitsCell Biology Test Kits industry associations and research organizationsProduct managers, Cell Biology Test Kits industry administrator, C-level executives of the industriesMarket Research and consulting firms

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Cell Biology Test Kits Market to Show Incredible Growth by 2027 The Manomet Current - The Manomet Current

Cell Biology

Cell Biology Test Kits Market COVID -19 Impact | Growth, Analysis, Opportunities and Forecast To 2028 by Growing Players: Thermo Fisher Scientific,…

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Cell Biology Test Kits Market COVID -19 Impact | Growth, Analysis, Opportunities and Forecast To 2028 by Growing Players: Thermo Fisher Scientific,...

Cell Biology

Presence of certain stem cells linked to nongenetic resistance mechanisms of cancer cells – News-Medical.Net

Cancer cells can develop resistance to therapy through both genetic and non-genetic mechanisms. But it is unclear how and why one of these routes to resistance prevails. Understanding this 'choice' by the cancer cells may help us devise better therapeutic strategies. Now, the team of Prof. Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology) shows that the presence of certain stem cells correlates with the development of nongenetic resistance mechanisms. Their study is published in the prestigious journal Cancer Cell.

Even though cancer therapy has made great strides in the last few years, resistance remains a major problem. When cancer cells develop resistance against the drugs targeting them, they can continue to spread, even when the patient is going through therapy.

Until recently, it was thought that this resistance arises exclusively through mutations - genetic alterations - in the cancer cells. However, new studies have suggested that resistance against cancer drugs can also arise via non-genetic mechanisms that change the expression of certain genes without altering the DNA sequence.

Prof. Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology): "The importance of nongenetic reprogramming as a driver of therapy resistance is not yet widely accepted in the field. Although my group has demonstrated that drug tolerance can be driven by nongenetic mechanisms, strong evidence that resistance can be acquired in absence of a genetic cause is still lacking."

In their study, the team of Prof. Marine firmly establishes that nongenetic mechanisms contribute to resistance to therapy in melanoma. The key question has become: "How do cancer cells 'choose' between the different routes to resistance?"

Surprisingly, the team demonstrates that the road to resistance is predetermined and not randomly selected. They show that the presence of a specific group of cells, neural crest stem cells, leads to non-genetic rather than genetic drug resistance in melanoma. A possible reason for this is that these neural crest stem cells exhibit 'epigenetic plasticity', which means that these cells have an increased ability to select which genes they express and how much. These cells literally reprogram themselves to evade the therapeutic pressure.

The researchers also identified the signaling pathway that drives the emergence of the neural crest stem cells and promotes their survival. This signaling pathway depends crucially on the protein Focal Adhesion Kinase (or FAK). By blocking the activity of this protein, the team was able to drastically reduce the occurrence of non-genetic drug resistance in patient-derived xenografts - tumor cells from human patients that were implanted in mice.

This combination of new basic insights into tumor cell biology and recently discovered non-genetic resistance mechanisms to cancer drugs has far-reaching clinical consequences.

Florian Rambow, senior postdoc who contributed to the study, explains:

These findings have several important clinical implications. Not only did we show a viable way to suppress non-genetic resistance, but we also demonstrated that the presence of specific cells dictates which resistance mechanism is likely to occur. This observation is the key to predicting potential resistance routes in patients and developing personalized therapies."

Source:

Journal reference:

Marin-Bejar, O., et al. (2021) Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell. doi.org/10.1016/j.ccell.2021.05.015.

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Presence of certain stem cells linked to nongenetic resistance mechanisms of cancer cells - News-Medical.Net

Cell Biology

The Future Of Synthetic Biology and The Companies Using These Technologies – BioSpace

The market of synthetic biology is estimated to worth 11 billion by 2028. The increasing demands by biotechnological and pharmaceutical companies have greatly contributed to the growth of its market.

Well look at what synthetic biology is all about and the latest trends of this technology.

RELATED: Current Trends in Synthetic Biology

Synthetic biology is defined as the design and fabrication of biological systems and components that do not exist in the real world thru editing alteration of the deoxyribonucleic acid (DNA). At the same time, it is referred to as the redesign and fabrication of existing biological systems and DNA.

With this, we can re-engineer DNA sequences of anything and re-assemble them to new genomes.

It means we can eventually create synthetic things such as a flower changing color, sterile mosquitos, create fuel or perfume by programming microbes, or plants that glow, among others.

However, the downside of this is that it could harm us if used or engineered the wrong way. Synthetic biology can potentially be a threat if we create a harmful virus that can wipe out humanity.

The opportunities for the growth of this new technology are endless, such as manufacturing good chemicals from agricultural waste, discovering petroleum substitutes, and replicating rubber tires.

As this type of technology is starting to grow, companies that focus on synthetic biology are starting to grow. Some companies sell synthetic DNAs, and some do the building themselves.

Companies that sell synthetic DNAs:

Companies that build DNAs for multiple purposes such as healthcare, biofuels, and bioproducts:

Amyris, Inc.

Codexis, Inc.

Genencor International, Inc.(A Division of Danisco)

Life Science Technologies

Qteros

CODA Genomics, Inc.

Modular Genetics, Inc.

Verdezyne, Inc.

DSM

Myriant Technologies LLC

Gevo, Inc.

LS9, Inc.

OPX Biotechnologies

Solazyme, Inc.

Synthetic Genomics, Inc.

RELATED: De-Bottlenecking Molecular Biology

Scientists can now produce small molecules with the use of synthetic biology. The new products are commonly used for drug development.

AstraZeneca Pharmaceuticals LPand has been using this technology for therapeutics. They have produced drugs that can be taken orally or through the cell membranes.

Amgenalso uses small molecules for drugs. These drugs can only treat some diseases because they can penetrate cell walls to target specific cells.

Numerous other laboratories are now resulting in this kind of discovery. However, there are some downsides to it. Even though they can design and manufacture new kinds of molecules, the process can be tedious and have a long trial and error process.

It is because it is difficult to engineer new microbes that nature didnt intend. It may be a long process overall, but it can be rewarding what the final product can do.

It is slowly taking shape, but scientists are now using synthetic biology to create a new technology that could treat cancer patients.

In addition to transformational improvements in healthcare, patients can now enjoy chimeric antigen receptor (CAR) technology which attacks cancer cells. This technology engineers the T-cells (immune cells) of a patient to recognizes the cancer cells and eliminates them.

Some of the companies that use T-cell therapy include Kite Pharma, REGENXBIO, Autolus, American Gene Technologies, and Arcellx Inc..

Kite Pharma has its Yescarta, which is used for CAR T cell therapy. It is used as therapy for some non-Hodgkin lymphoma (NHL) and is approved by the Food and Drug Administration (FDA).

REGENXBIO has its ZOLGENSMA, a treatment for spinal muscular atrophy (SMA) for children below two years.

Autolus focuses on solid tumors and hematological cancer treatments and is now developing treatments for CAR T cell therapy.

American Gene Technologies is developing a cure for HIV-positive patients by using their cells from T cells to disable diseases and build immunity.

Lastly, Arcelix is in its early stages of development for CAR T-Cell therapy.

In relation to the creation of chimeric antigen receptors, scientists are also engineering viruses to treat inherited diseases like Severe Combined Immune Deficiency (SCID) or epidermolysis bullosa.

This technology is possible by using a patients stem cell to replicate and create new cells to replace the mutated genes that cause diseases.

St. Jude Research Hospital managed to develop a genetically engineered virus to treat SCID on young children. They created a lentivector, a virus delivered to the genes to fix certain medical conditions without activating any genes that may cause cancer.

Computational protein design builds proteins from scratch (de novo design) and makes calculated variants of protein structures and variants (protein design).

Researchers build new enzymes that have never been seen and not common to nature using amino acids and co-factors that are not part of the standard macromolecular toolkit.

One company that uses this technology is Ginkgo Bioworks, which uses computer automation to create new organisms.

Arzeda is another company developing new enzymes from scratch to develop the production of rare sugars and natural sweeteners.

Cellular agriculture is replicating the way food is produced by animals without the need to have animals. Researchers are looking at how the by-products of animals we consume are made and done through tissue engineering and biotechnology.

Some examples of these are creating milk just like how a cow would produce them or creating eggs just like how chickens would produce them. This includes the creation of lab foods such as meat and fish.

One of the companies that use this technology is New Harvest. As mentioned above, this company is responsible for creating milk and eggs from cells instead of getting them from animals.

Another one is Meatable, which uses cellular agriculture for creating cell-based meats.

The future of synthetic biology is vast because of all the opportunities this technology can make.

From the development of pharmaceutical products to answer humanitys problems to producing agricultural products for our daily consumption, the possibilities are endless. They could lead to a very successful future for humankind.

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The Future Of Synthetic Biology and The Companies Using These Technologies - BioSpace

Cell Biology

New Super-resolution Microscopy Method Approaches the Atomic Scale – Weill Cornell Medicine Newsroom

Click on the image to view a video about the paper.

Scientists at Weill Cornell Medicine have developed a computational technique that greatly increases the resolution of atomic force microscopy, a specialized type of microscope that feels the atoms at a surface. The method reveals atomic-level details on proteins and other biological structures under normal physiological conditions, opening a new window on cell biology, virology and other microscopic processes.

In a study, published June 16 in Nature, the investigators describe the new technique, which is based on a strategy used to improve resolution in light microscopy.

To study proteins and other biomolecules at high resolution, investigators have long relied on two techniques: X-ray crystallography and cryo-electron microscopy. While both methods can determine molecular structures down to the resolution of individual atoms, they do so on molecules that are either scaffolded into crystals or frozen at ultra-cold temperatures, possibly altering them from their normal physiological shapes. Atomic force microscopy (AFM) can analyze biological molecules under normal physiological conditions, but the resulting images have been blurry and low resolution.

"Atomic force microscopy can easily resolve atoms in physics, on solid surfaces of silicates and on semiconductors, so it means that in principle the machine has the precision to do that," said senior author Dr. Simon Scheuring, professor of physiology and biophysics in anesthesiology at Weill Cornell Medicine. The technique is a bit like if you were to take a pen and scan over the Rocky Mountains, so that you get a topographic map of the object. In reality, our pen is a needle that is sharp down to a few atoms and the objects are single protein molecules."

However, biological molecules have many small parts that wiggle, blurring their AFM images. To address that problem, Dr. Scheuring and his colleagues adapted a concept from light microscopy called super-resolution microscopy. "Theoretically it wasn't possible by optical microscopy to resolve two fluorescent molecules that were closer together than half the wavelength of the light, he said. However, by stimulating the adjacent molecules to fluoresce at different times, microscopists can analyze the spread of each molecule and pinpoint their locations with high precision.

Instead of stimulating fluorescence, Dr. Scheuring's team noted that the natural fluctuations of biological molecules recorded over the course of AFM scans yield similar spreads of positional data. First author Dr. George Heath, who was a postdoctoral associate at Weill Cornell Medicine at the time of the study and is now a faculty member at the University of Leeds, engaged in cycles of experiments and computational simulations to understand the AFM imaging process in greater detail and extract the maximum of information from the atomic interactions between tip and sample.

Using a method like super-resolution analysis, they were able to extract much higher resolution images of the moving molecules. Continuing the topographic analogy, Dr. Scheuring explained that "if the rocks (i.e., atoms) wiggle a little bit up and down, you can detect this one, then that one, and then you average all detections over time and you receive high-resolution information."

Because previous AFM studies have routinely collected the necessary data, the new technique can be applied retroactively to the blurry images the field has generated for decades. As an example, the new paper includes an analysis of an AFM scan of an aquaporin membrane protein, originally acquired during Dr. Scheuring's doctoral thesis. The reanalysis generated a much sharper image that matches X-ray crystallography structures of the molecule closely. "You basically get quasi-atomic resolution on these surfaces now," said Dr. Scheuring. To showcase the power of the method, the authors provide new high-resolution data on annexin, a protein involved in cell membrane repair, and on a proton-chloride antiporter of which they also report structural changes related to its functional.

Besides allowing researchers to study biological molecules under physiologically relevant conditions, the new method has other advantages. For example, X-ray crystallography and cryo-electron microscopy rely on averaging data from large numbers of molecules, but AFM can generate images of single molecules. "Instead of having observations of hundreds of molecules, we observe one molecule a hundred times and calculate a high-resolution map," said Dr. Scheuring.

Imaging individual molecules as they carry out their functions could open entirely new types of analysis. "Let's say you have a [viral] spike protein that's in one conformation and then it gets activated and goes into another conformation, said Dr. Scheuring. You would in principle be able to calculate a high-resolution map from that same molecule as it transits from one conformation to the next, not from thousands of molecules in one or the other conformation." Such high-resolution single molecule data could provide more detailed information and avoid the potentially misleading results that can occur when averaging data from many molecules. Furthermore, the map might reveal new strategies for precisely redirecting or interrupting such processes.

Additional study co-authors include Drs. Ekaterina Kots, Shifra Lansky, George Khelashvili, and Harel Weinstein from the Department of Physiology and Biophysics at Weill Cornell Medicine and Dr. Janice Robertson from the Department of Biochemistry and Molecular Biophysics at Washington University.

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New Super-resolution Microscopy Method Approaches the Atomic Scale - Weill Cornell Medicine Newsroom

Cell Biology

Post-doctoral Fellow, School of Biomedical Sciences job with THE UNIVERSITY OF HONG KONG | 257563 – Times Higher Education (THE)

Work type: Full-timeDepartment: School of Biomedical Sciences (22600)Categories: Academic-related Staff

Applications are invited for appointment asPost-doctoral Fellow (several posts) in the School of Biomedical Sciences (Ref.: 504335), to commence as soon as possible for one year, with the possibility of renewal subject to satisfactory performance.

Applicants should have a Ph.D. degree preferably in Biomedical/Biological Sciences, Cell Biology, or a related discipline. Preference will be given to those with research experience in at least two of the areas including stem cells, regenerative medicine, cancer, heart disease, liver disease, animal models, immunology, embryology, genomics, genome-editing or drug screening. Applicants should have a good command of written and spoken English, strong communication skills, and a demonstrated track record of publishing academic research papers. They should also be self-motivated, innovative, and able to work well in an interdisciplinary team. The appointees are expected to contribute to a translational research programme in stem cell biology, and conduct research projects in a multidisciplinary team of clinicians and scientists. Working outside campus may be required. Enquiries about the posts should be sent to Professor Liu Pengtao atpliu88@hku.hk.

A highly competitive salary commensurate with qualifications and experience will be offered, in addition to annual leave and medical benefits.

The University only accepts online applications for the above posts. Applicants should apply online and upload an up-to-date C.V. Review of applications will start from July 1, 2021 and continue until September 30, 2021, or until the posts are filled, whichever is earlier.

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Post-doctoral Fellow, School of Biomedical Sciences job with THE UNIVERSITY OF HONG KONG | 257563 - Times Higher Education (THE)

Cell Biology

Could Regenerative Biology Work in Humans? – Harvard Magazine

Chop a three-banded panther worm in half, and the head and tail will swirl around as if nothing had happened. Even more astonishing, a few days later, the halves will grow to become two complete and almost indistinguishable worms.

Loeb associate professor of the natural sciences Mansi Srivastava has studied this process of healing and regeneration for more than a decade. Together with members of her research group, she has been working to uncover the molecular and cellular mechanisms underlying whole-body regeneration, and tracing their evolutionary history. Understanding both these aspects of regeneration, she believes, could aid in efforts to develop the field of human regenerative medicine.

Srivastava chose to study the three-banded panther worm because this tiny, carnivorous Bermuda native is especially adept at whole-body regeneration: able to heal and then recreate an entire organism from even a small fragment of its body. Moreover, the species is sufficiently similar to planarians, worms widely studied in the field of regeneration biology, that scientists can make comparisons between the two species, whose last common ancestor lived 550 million years ago. If there are similarities in the molecular mechanisms they use to regenerate, Srivastava explains, identifying and investigating these shared elements could lead to an understanding of the fundamental principles controlling this feat.

An advance in this direction came in 2019 when her research group reported the discovery of a pioneer factor, a molecular agent responsible for initiating the cascade of genetic signals necessary for regeneration. In the moments after an injury, she explains, cells around the damaged site sound an alarm by generating proteins that activate the choreography of regeneration. But what intracellular factor causes the genes encoding those proteins to switch on? How does an incomplete animal know what is missing, and how to recreate it? Who or what decides how to proceed?

Her team probed these questions using a technique known as ATACseq that allowed them to zoom in on the structure of chromatinthe packaging material of cellular DNA. They focused on regions of the chromatin structure that opened up soon after amputation. These sites marked genes likely activated in response to injury. By analyzing the commonalities among multiple regions of open chromatin across many cells found near the damage site, Srivastava and colleagues were able to identify one such decision-maker, or factor responsible for the observed changes in the products of these activated genes. Known as EGR, the protein proved crucial for regeneration: when the researchers turned off its production, many of the genes that should have been switched on werentand the worm never regenerated.

This work provided a broad look, Srivastava says, at the early steps following amputation. Her team is currently developing a more detailed picture of these molecular events. To do so, they have applied the same analysis of the chromatin structure to individual cells of the worm. By looking at chromatin changes within single cells, they hope to learn exactly how the process that directs regeneration unfolds.

By tagging a single potentially pluripotent cell (above, at far left) with a red fluorescent protein, researchers can watch as it divides, eventually becoming a complete worm.

Courtesy of Mansi Srivastava

At the same time, Srivastava has turned her attention to the raw material the worms use to regenerate tissues, a form of adult stem cell called a neoblast. In response to amputation, these typically dormant cells wake up and undergo rapid bursts of division. A sort of cellular alchemy ensues, she explains: like embryonic stem cells, which are active during development, the neoblasts turn into neurons, muscles, skin, whatever you need. This ability to become any cell type, known as pluripotency, is a well-described feature of embryonic stem cells. But panther worms are somehow able to maintain pluripotency of neoblasts into adulthood.

By investigating the cellular origins of the worms embryonic and adult pluripotent stem cells, and characterizing the differences and similarities between the two, Srivastava hopes to learn how neoblasts persist and reawaken, and why human and other mammalian stem cells are limited in their regenerative capacities.

Using ultraviolet light to tag cells of interest and follow them during their life cycle, her team has made significant progress toward identifying the cellular lineage that gives rise to stem cells during the worms early development. We now want to use that same approach in adults, she says, to understand how the worms make and then maintain a neoblast, to keep it hanging out, happily pluripotent, in its body. I dont think my work is going to help anyone grow a limb five years from now, she adds, but I do think it could lead to an understanding of pluripotency, and how genomes are regulated during regeneration. That could lead to breakthroughs in the nascent field of human regenerative medicine.

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Could Regenerative Biology Work in Humans? - Harvard Magazine

Cell Biology

3D Cell Culture Market Size, Share, Worth, Latest Trend, Research Insights, Overview & Industry Forecast till 2027 The Manomet Current – The…

Global 3D Cell Culture Market

3D Cell Culture is defined as a practice of growing biological cells and allow them to interact with their surroundings in all three dimensions. This technique enables the cells to grow in their natural environment in an in vivo condition. Numerous techniques are used to carry out culturing of cells in all the three dimensions. 3-dimension cell culture is a man-made environment. Cells grown in 3-dimension cell culture with similar properties of cells found inside living organisms in terms of cellular characteristics & behavior.

As three-dimension cell cultures can mimic the structure, activity, as well as microenvironment of the in-vivo tissues, this technique has varied applications in the fields of regenerative medicine, drug screening, stem cell therapies, cancer research & cell biology. The extracellular matrix in three-dimension cell cultures alows cellcell communication by direct contact as in in-vivo environment by secreting cytokines & trophic factors. These factors are changed in a 2D environment which can significantly affect the cellcell communication, which in turn can alter the cell morphology & proliferation. As 2-Dimesion cultures cannot recapitulate the architecture & complex cellular matrices as in 3-Dimension cultures, this technique is gaining popularity in healthcare research industry. Also, 3D cell cultures can offer results with improved efficiency & reduce the cost of overall research and development process.

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The cancer and stem cell segment is anticipated to grow at the highest CAGR over the forecast period. On the basis of application, the 3D cell culture market is categorized into drug discovery & toxicology testing, cancer & stem cell research, and tissue engineering & regenerative medicine. The cancer and stem cell research segment hold the largest revenue share of the market and is projected to register the highest CAGR during this forecast period. The increase in prevalence of cancer and significant funding for cancer research are major prominent factors driving the growth of this application segment.

Lack of consistency in products is anticipated hamper growth of the global 3D cell culture market. The lack of consistency between wells & batches of cell culture are the other major challenges in the adoption of 3D cell culture. In addition, matrices made from animal tissues may contain unwanted growth factors & viruses, which could negatively affect the cell culture productivity &reproducibility.

Impact of COVID-19

The COVID-19 crisis has resulted in nationwide lockdowns, thereby impacting every industry, Likewise, market is also affected by the pandemic. The 3D cell culture industry is facing various challenges to cope up with the demand & supply of 3D cell culture components due to the COVID-19 crisis. Furthermore, inconsistent &interrupted supply chain activities and availability of human resources are projected to impact the market growth. Moreover, surge in research practices for developing novel therapies against COVID-19 (Coronavirus) is serving as a huge opportunity for the key market players. Research associated with stem cell therapies and regenerative medicine has shown promising results for treating the COVID-19, this is anticipated to compensate the deleterious impact caused by lockdowns across the globe. Thus, the overall COVID-19 impact is expected to remain moderate for the prominent players in the global 3D cell culture market.

Market Segmentation

The Global 3D Cell Culture Market is categorized into product including Scaffold-based 3D Cell Cultures, (Solid Scaffolds, Hydrogels/ECM Analogs, and Micropatterned Surfaces), Scaffold-free 3D Cell Cultures (Low Attachment Plates, Hanging Drop Plates, 3D Bioreactors, 3D Petri Dishes), Microfluidics-based 3D Cell Cultures , and Magnetic & Bioprinted 3D Cell Cultures, by application market is segmented into Cancer & Stem Cell Research, Drug Discovery & Toxicology Testing, and Tissue Engineering & Regenerative Medicine. Further, market is segmented into end user such as Pharmaceutical & Biotechnology Companies, Research Institutes, Cosmetics Industry, and Others.

Also, the Global 3D Cell Culture Marketis segmented into five regionssuch as North America, Latin America, Europe, Asia Pacific, and Middle East & Africa.

Regional Analysis

North America led the market share in the year 2020 & accounted for the highest revenue share throughout the forecast period. Due to availability of private & government funding for the development of advanced 3D cell culture models, high healthcare spending, and the presence of a large number of universities & research organizations investigating various stem cell-based approaches. For instance, in December 2020, researchers from Mayo Clinic & Terasaki Institute, U.S., had developed visible hydrogels which can be used for the monitoring & control of hemorrhage. However, the Asia Pacific region is estimated to be the fastest-growing market due to the increase investments by various international companies in the emerging economies of this region.

Market Key Players

Various key players are listed in this report such as Thermo Fisher Scientific, Inc., Merck KGaA, PromoCell GmbH, Corning, Inc., Greiner Bio One International GmbH, 3D Biomatrix,Lonza, Tecan Trading AG, 3D Biotek LLC, Global Cell Solutions, Inc., InSphero, etc.

Market Taxonomy

By Product

By Application

By End User

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3D Cell Culture Market Size, Share, Worth, Latest Trend, Research Insights, Overview & Industry Forecast till 2027 The Manomet Current - The...