Category Archives: Cell Biology

Cell Biology

This Entrepreneur Is Changing the Face Of Cancer Treatment In India – Entrepreneur

Dr. Manjiri Bakre is the founder of OncoStem Diagnostics, a Bengaluru-based start-up that has developed a test to help women with a certain kind of breast cancer be diagnosed and given the right kind of treatment.

February22, 20206 min read

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Breast cancer is the most common cancer in women in India. Accounting for 25-32 per cent of all cancers in women, the mortality rate post-treatment is 60 per cent, compared to as much as 89 per cent in the United States. The numbers, to put it simply, are disappointing and an entrepreneur based in Bengaluru is trying to change that.

Dr. Manjiri Bakre, who has a postgraduate doctoral degree in cell biology, is the founder and chief executive officer of OncoStem Diagnostics, a start-up that has developed a test to help women with a certain kind of breast cancer be diagnosed and given the right kind of treatment.

One of her earliest encounters with breast cancer was when a friend during her PhD years was diagnosed with the same. Bakre says the friend felt the tumor herself, went to the doctor and since it was diagnosed early, got it removed. Thereafter, as did everyone, that friend went on her post doctoral fellowship, which was in Israel.

Thats when the cancer relapsed, and spread to multiple organs. It was so sudden; we really tried to help her by sending her for various therapies, even non-traditional ones but nothing helped, she says.

The sudden demise of this friend got Bakre thinking about why, despite early detection, so many patients like her are unable to survive.

If the tumor is five centimeters or ten centimeters large and has spread to nearby organs, then you understand that the patient has a limited lifespan but when the tumors are small and detected early, typically, such patients should be doing well.

While Bakre was thinking about those whys and working on a solution, a company in the US had come up with a similar test.

However, the biggest differences between patients there and in India is that the former are mostly postmenopausal women and because they have much better insurance schemes with regular, annual checkups, the tumors are also very small when first detected.

When the patient is elderly and diagnosed with a smaller tumor, the biology is different; our patients are younger and and we don't have great programmes of insurance, she says.

Compared to those in the west, Indian women are also more likely to have triple negative breast cancer, which is considered to be a more aggressive type.

Breast cancers are classified based on biomarkers that are proteins present on the tumor cells. If a patients tumor has three proteins: estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, they are called triple positive patients while their absence makes one a triple negative patient.

The hormone receptors are really key determinants of how the disease will progress; in the universe of breast cancer patients, if the patient's tumor has hormone receptors they do well, says Bakre.

OncoStems first and currently only test is for hormone receptorpositive patients. This test is only valid for early stage breast cancer patients, that is, for those at stage one and two.

With the tests, patients are certified into low recurrence or high recurrence categories and the treatments are done accordingly.

Majority of Indian patients are getting treated with chemotherapy, even in early stage hormone receptor positive cancer, which is supposed to be a less aggressive form of the disease. To really save the excessive chemotherapy, we decided to develop a test which would suit our population,

The idea was to cut down on chemotherapy,as the side effects are often enormous.

Another point where the company is different from others, according to her, is that theirs is a protein-based test while the others are gene-based. The company has a machine learning-based algorithm which gives the risk of cancer recurrence. Bakre claims the test is 95 per cent accurate.

The biomarker analysis process is patented while in her own terms, the ML-based algorithm is a trade secret.

Bakre incorporated the company in 2011 but it took six-seven years to develop the test and eventually go to market.

A major reason for such a long process was that they needed to do a five-year follow up. The patient base in India is huge but the system isnt organized enough to keep the follow ups going.

How the company managed to sustain over the period of time when they were developing the test and not making any revenue was through investor money. In the very early days, they received $1 million in seed funding from Artiman Ventures, an early stage Silicon Valley-based venture capital fund.

The biggest challenge, however, has been to work with hospitals, she says. Given that there are multiple layers to convince and explain the test to, it takes a lot of time and that's something investors are unable to understand. She feels a lack of clarity in terms of guidelines is also an issue that elongates processes.

On VC funding still not going much into the healthcare space, Bakre says, entrepreneurship is like bringing up a child; at every stage you have different issues, you cannot be like I have given you seed funding and thats enough, you have to think of the entrepreneur in the next stage.

Bakre feels that their kind of work requires a lot of patience from the side of the investors and a lot more than what many of the now well-known tech start-ups began with.

Our kind of work is not like you can buy a laptop and start working out of a coworking space, she jokes.

In 2017, the company raised $6 million in a Series A round led by Sequoia Capital.

Currently, the test is prescribed by 180 doctors across India and the company works with 15 hospitals, of which 12 are in India.

Bakre says the company is looking to touch the lives of about 1000 patients in the next one year and build from there. According to her, the way to reach the masses is through insurance schemes such as Pradhan Mantri Jan Arogya Yojana.

Because the majority of the chemotherapy costs for cancer patients are given by the government and so if 70 per cent don't need, it is saving about INR 750 crore per year, just on the cost of chemotherapy.

The test costs INR 60,000 to one patient and the strategy of working with government hospitals, and treating low-income patients is to provide discounts as the volumes go up.

If the numbers go up, our costs will come down, and then we can work on reducing the price of the test, says Bakre.

In terms of new offerings, OncoStem is now working on developing a test for triple negative patients as well as something for patients of ovarian cancer.

The ultimate goal, though, she says, is to work with pharmaceutical companies and help develop treatments for the patients being diagnosed.

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This Entrepreneur Is Changing the Face Of Cancer Treatment In India - Entrepreneur

Cell Biology

Researchers map the cellular diversity of entire salivary gland tumors – News-Medical.net

What goes on inside and between individual cells during the very earliest stages of tumor development? Single cell sequencing technologies and a mouse model have enabled researchers to comprehensively map the cellular diversity of whole salivary gland tumors and trace the path of cancer stem cells.

Two research teams from the Max Delbrck Center for Molecular Medicine and their collaborators have produced a detailed cell atlas of an entire salivary gland tumor in a mouse model, mapping individual cells throughout the tumor and its surrounding tissue. The "single cell" approach, recently described in Nature Communications, has provided key insights about cellular composition changes through the earliest stages of cancer development.

A solid tumor is not, as many might assume, a lump of cells that are all the same. Rather it is mix of many different cell types, including a variety of stromal and immune cells besides the actual tumor cells.

"Conventional methods in molecular biology often consider a sample as a whole, which fails to recognize the complexity within it," said Dr. Samantha Praktiknjo, senior scientist and first author from MDC's Systems Biology of Gene Regulatory Elements Lab headed by Professor Nikolaus Rajewsky at the Berlin Institute for Medical Systems Biology (BIMSB). Developing a detailed understanding of the different cells within a tumor and how they interact could help identify more effective treatment strategies.

The team used single-cell RNA sequencing technologies developed in the Rajewsky lab and novel epitope profiling to produce the cell atlas, and identified the cells that were specific to the tumor by leveraging the reproducibility and the large sample size of their data.

The latter was possible by using a mouse model, developed in MDC's Signal Transduction in Development and Cancer Lab headed by Professor Walter Birchmeier, which harbors designed mutations that induce a salivary gland squamous cell carcinoma. This system provides a consistent supply of genetically similar tumors to sequence from the earliest stages of development, which is nearly impossible with human patients.

"In a patient, the tumor is already developed and you cannot go back and rewind time and look at how it started," said Dr. Benedikt Obermayer, a co-first author now at the Berlin Institute of Health (BIH). "Here, we have a model that is so controlled, we can watch it happen." And Dr. Qionghua Zhu, the third first author and a former postdoc at the Birchmeier Lab, added: "To fight cancer effectively, we need to find the driver mutations. This method gives us clues about the evolution trajectories of a tumor."

Sequencing technologies have advanced so that it is now possible to quickly and affordably sequence the RNA inside single cells, one at a time, as well as the proteins on the surfaces of cells in the tissues. While other methods grind up the tissue and identify what genes and molecules are present in the mix, the single cell approach precisely identifies how many of each type of cell is present, and which genes and molecules are associated with which cell.

For this study, the researchers sequenced more than 26,000 individual salivary gland cells from mice with tumors and healthy mice. They used computational models to analyze the huge amount of data and identify each individual cell and sort them into groups - such as stromal cells, immune cells, saliva producing cells, cancer cells - based on the hundreds of genes expressed and molecules present.

The single cell approach revealed something that surprised the researchers: "When I saw the data, I thought, where is the tumor?" Obermayer said. The population of cancer stem cells in the tumor was extremely small - less than one percent of all profiled cells in the tissue. Due to their low abundance, investigation of these cells still heavily depends on assumptions about surface markers and is often performed in cell culture-based systems. Here, the authors were able to identify the cancer stem cells directly from the solid tumor samples with their single cell approach.

Furthermore, the team was able to predict the progression of the different cell types through different stages of tumor development. Their model suggests that the cancer stem cells emerge from cancerous basal cells, then develop into another subtype before ultimately becoming a population of cells similar to luminal cells, a cell type present in normal, healthy salivary glands.

This progression supports the idea that when something goes awry in the basal cells of this solid tumor model, they are triggered to turn into cancer stem cells, which can then become a different type of cell. "What I found fascinating was clearly seeing the order of signals and events, transitioning from the progenitor to the progeny populations of the cancer stem cells," Praktiknjo said.

Further research is required to verify that individual cells are transforming through these stages, and explore the cellular and molecular interactions driving tumor growth. The team anticipates the approach they've demonstrated here can be applied to other cancer types as well.

To me the main conceptual insight is that we can apply ideas from single-cell based developmental biology to reconstruct molecular progression of tumorigenesis."

Professor Nikolaus Rajewsky, Head of MDC's Systems Biology of Gene Regulatory Elements Lab and scientific director of the BIMSB

Source:

Journal reference:

Praktiknjo, S.D., et al. (2020) Tracing tumorigenesis in a solid tumor model at single-cell resolution. Nature Communications. doi.org/10.1038/s41467-020-14777-0.

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Researchers map the cellular diversity of entire salivary gland tumors - News-Medical.net

Cell Biology

How the monkeyflower gets its spots – UC Berkeley

The yellow monkeyflowers distinctive red spots serve as landing pads for bees and other pollinators, helping them access the sweet nectar inside. A new study reveals the genetic programming that creates these attractive patterns. (Image by PollyDot via PixaBay)

The intricate spotted patterns dappling the bright blooms of the monkeyflower plant may be a delight to humans, but they also serve a key function for the plant. These patterns act as bee landing pads, attracting nearby pollinators to the flower and signaling the best approach to access the sweet nectar inside.

They are like runway landing lights, helping the bees orient so they come in right side up instead of upside down, said Benjamin Blackman, assistant professor of plant and molecular biology at the University of California, Berkeley.

See the companion press release at UConn Today

In a new paper, Blackman and his group at UC Berkeley, in collaboration with Yaowu Yuan and his group at the University of Connecticut, reveal for the first time the genetic programming that helps the monkeyflower and likely other patterned flowers achieve their spotted glory. The study was published online today (Thursday, Feb. 20) in the journal Current Biology.

While we know a good deal about how hue is specified in flower petals whether it is red or orange or blue, for instance we dont know a lot about how those pigments are then painted into patterns on petals during development to give rise to these spots and stripes that are often critical for interacting with pollinators, Blackman said. Our lab, in collaboration with others, has developed the genetic tools to be able to identify the genes related to these patterns and perturb them so that we can confirm whats actually going on.

In the study, the research team used CRISPR-Cas9 gene editing to recreate the yellow monkeyflower patterns found in nature. On the left, a wild-type monkeyflower exhibits the typical spotted pattern. In the middle, a heterozygote with one normal RTO gene and one damaged RTO gene exhibits blotchier spots. And on the right, homozygote with two copies of the damaged RTO gene is all red, with no spots. (UC Berkeley photo by Srinidhi Holalu)

The positions of petals spots arent mapped out ahead of time, like submarines in a game of battleship, Blackman said. Instead, scientists have long theorized that they could come about through the workings of an activator-repressor system, following what is known as a reaction-diffusion model, in which an activator molecule stimulates a cell to produce the red-colored pigment that produces a spot. At the same time, a repressor molecule is expressed and sent to neighboring cells to instruct them not to produce the red pigment.

The results are small, dispersed bunches of red cells surrounded by cells that keep the background yellow color.

By tweaking the parameters how strongly a cell turns on an inhibitor, how strongly the inhibitor can inhibit the activator, how quickly it moves between cells it can lead to big spots, small spots, striped patterns, really interesting periodic patterns, Blackman said.

In the study, UC Berkeley postdoctoral researcher Srinidhi Holalu and research associate Erin Patterson identified two natural varieties of the yellow monkeyflower one type with the typical red spots in the throat of the flower and a second type with an all-red throat appearing in multiple natural populations in California and Oregon, including at the UC Davis McLaughlin Reserve. In parallel, UConn postdoctoral researcher Baoqing Ding worked with a very similar plant with fully red-throated flowers found when surveying a population of Lewiss monkeyflower that had induced DNA mutations.

When the scientists presented bees in the lab with the two types of monkeyflowers, they preferred the red tongue variety to the spotted variety, though the red tongue variety is less common in nature. (UC Berkeley video by Erin Patterson and Anna Greenlee)

In a previous study, the Yuan lab had found that a gene called NEGAN (nectar guide anthocyanin) acts as an activator in the monkeyflower petals, signaling the cells to produce the red pigment. Through detailed genomic analysis in both monkeyflower species, the two groups were able to pinpoint that a gene called RTO, short for red tongue, acts as the inhibitor.

The red-throated forms of the monkeyflower have defective RTO inhibitor genes, resulting in a characteristic all-red throat, rather than red spots. To confirm their findings, Holalu used the CRISPR-Cas9 gene editing system to knock out the RTO gene in spotted variants of the flower. The result was flowers with a flashy red throat. Further experiments revealed how the functional form of the RTO protein moves to neighboring cells and represses NEGAN to prevent the spread of pigmentation beyond the local spots. This study is the first reported use of CRISPR-Cas9 editing to research the biology of monkeyflowers.

The team also collaborated with Michael Blinov at the UConn School of Medicine to develop a mathematical model to explain how different self-organized patterns might arise from this genetic system.

This work is the simplest demonstration of the reaction-diffusion theory of how patterns arise in biological systems, said Yaowu Yuan, associate professor of ecology and evolutionary biology at UConn. We are closer to understanding how these patterns arise throughout nature.

Monkeyflower plants with the RTO gene knocked out by CRISPR-Cas9 gene editing produce one big patch where all flowers exhibit a fully red throat, in contrast to wild fields where red-tongued flowers appear in small dispersed spots (UC Berkeley photo by Srinidhi Holalu)

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How the monkeyflower gets its spots - UC Berkeley

Cell Biology

Stem cells and the heartthe road ahead – Science Magazine

Heart disease is the primary cause of death worldwide, principally because the heart has minimal ability to regenerate muscle tissue. Myocardial infarction (heart attack) caused by coronary artery disease leads to heart muscle loss and replacement with scar tissue, and the heart's pumping ability is permanently reduced. Breakthroughs in stem cell biology in the 1990s and 2000s led to the hypothesis that heart muscle cells (cardiomyocytes) could be regenerated by transplanting stem cells or their derivatives. It has been 18 years since the first clinical trials of stem cell therapy for heart repair were initiated (1), mostly using adult cells. Although cell therapy is feasible and largely safe, randomized, controlled trials in patients show little consistent benefit from any of the treatments with adult-derived cells (2). In the meantime, pluripotent stem cells have produced bona fide heart muscle regeneration in animal studies and are emerging as leading candidates for human heart regeneration.

In retrospect, the lack of efficacy in these adult cell trials might have been predicted. The most common cell type delivered has been bone marrow mononuclear cells, but other transplanted cell types include bone marrow mesenchymal stromal cells and skeletal muscle myoblasts, and a few studies have used putative progenitors isolated from the adult heart itself. Although each of these adult cell types was originally postulated to differentiate directly into cardiomyocytes, none of them actually do. Indeed, with the exception of skeletal muscle myoblasts, none of these cell types survive more than a few days in the injured heart (see the figure). Unfortunately, the studies using bone marrow and adult resident cardiac progenitor cells were based on a large body of fraudulent work (3), which has led to the retraction of >30 publications. This has left clinical investigators wondering whether their trials should continue, given the lack of scientific foundation and the low but measurable risk of bleeding, stroke, and infection.

Additionally, investigators have struggled to explain the beneficial effects of adult cell therapy in preclinical animal models. Because none of these injected cell types survive and engraft in meaningful numbers or directly generate new myocardium, the mechanism has always been somewhat mysterious. Most research has focused on paracrine-mediated activation of endogenous repair mechanisms or preventing additional death of cardiomyocytes. Multiple protein factors, exosomes (small extracellular vesicles), and microRNAs have been proposed as the paracrine effectors, and an acute immunomodulatory effect has recently been suggested to underlie the benefits of adult cell therapy (4). Regardless, if cell engraftment or survival is not required, the durability of the therapy and need for actual cells versus their paracrine effectors is unclear.

Of particular importance to clinical translation is whether cell therapy is additive to optimal medical therapy. This remains unclear because almost all preclinical studies do not use standard medical treatment for myocardial infarction. Given the uncertainties about efficacy and concerns over the veracity of much of the underlying data, whether agencies should continue funding clinical trials using adult cells to treat heart disease should be assessed. Perhaps it is time for proponents of adult cardiac cell therapy to reconsider the approach.

Pluripotent stem cells (PSCs) include embryonic stem cells (ESCs) and their reprogrammed cousins, induced pluripotent stem cells (iPSCs). In contrast to adult cells, PSCs can divide indefinitely and differentiate into virtually every cell type in the human body, including cardiomyocytes. These remarkable attributes also make ESCs and iPSCs more challenging to control. Through painstaking development, cell expansion and differentiation protocols have advanced such that batches of 1 billion to 10 billion pharmaceutical-grade cardiomyocytes, at >90% purity, can be generated.

Preclinical studies indicate that PSC-cardiomyocytes can remuscularize infarcted regions of the heart (see the figure). The new myocardium persists for at least 3 months (the longest time studied), and physiological studies indicate that it beats in synchrony with host myocardium. The new myocardium results in substantial improvement in cardiac function in multiple animal models, including nonhuman primates (5). Although the mechanism of action is still under study, there is evidence that these cells directly support the heart's pumping function, in addition to providing paracrine factors. These findings are in line with the original hope for stem cell therapyto regenerate lost tissue and restore organ function. Additional effects, such as mechanically buttressing the injured heart wall, may also contribute.

Breakthroughs in cancer immunotherapy have led to the adoption of cell therapies using patient-derived (autologous) T cells that are genetically modified to express chimeric antigen receptors (CARs) that recognize cancer cell antigens. CAR T cells are the first U.S. Food and Drug Administration (FDA)approved, gene-modified cellular pharmaceutical (6). The clinical and commercial success of autologous CAR T cell transplant to treat B cell malignancies has opened doors for other complex cell therapies, including PSC derivatives. There is now a regulatory path to the clinic, private-sector funding is attracted to this field, and clinical investigators in other areas are encouraged to embrace this technology. Indeed, the first transplants of human ESC-derived cardiac progenitors, surgically delivered as a patch onto the heart's surface, have been carried out (7). In the coming years, multiple attempts to use PSC-derived cardiomyocytes to repair the human heart are likely.

What might the first human trials look like? These studies will probably employ an allogeneic (non-self), off-the-shelf, cryopreserved cell product. Although the discovery of iPSCs raised hopes for widespread use of autologous stem cell therapies, the current technology and regulatory requirements likely make this approach too costly for something as common as heart disease, although this could change as technology and regulations evolve. Given that it would take at least 6 months to generate a therapeutic dose of iPSC-derived cardiomyocytes, such cells could only be applied to patients whose infarcts are in the chronic phase where scarring (fibrosis) and ventricular remodeling are complete. Preclinical data indicate that chronic infarcts benefit less from cardiomyocyte transplantation than do those with active wound-healing processes.

Adult cells from bone marrow or the adult heart secrete beneficial paracrine factors but do not engraft in the infarcted heart. Pluripotent stem cells give rise to cardiomyocytes that engraft long term in animal models, beat in synchrony with the heart, and secrete beneficial paracrine factors. Long-term cardiomyocyte engraftment partially regenerates injured heart, which is hypothesized to bring clinical benefits.

The need for allogeneic cells raises the question of how to prevent immune rejection, both from innate immune responses in the acute phase of transplantation or from adaptive immune responses that develop more slowly through the detection of non-self antigens presented by major histocompatibility complexes (MHCs). A current strategy is the collection of iPSCs from patients who have homozygous MHC loci, which results in exponentially more MHC matches with the general population. However, studies in macaque monkeys suggest that MHC matching will be insufficient. In a macaque model of brain injury, immunosuppression was required to prevent rejection of MHC-matched iPSC-derived neurons (8). Similarly, MHC matching reduced the immunogenicity of iPSC-derived cardiomyocytes transplanted subcutaneously or into the hearts of rhesus macaques, but immunosuppressive drugs were still required to prevent rejection (9).

Numerous immune gene editing approaches have been proposed to circumvent rejection, including preventing MHC class I and II molecule expression, overexpressing immunomodulatory cell-surface factors, such CD47 and human leukocyte antigen E (HLA-E) and HLA-G (two human MHC molecules that promote maternal-fetal immune tolerance), or engineering cells to produce immunosuppressants such as programmed cell death ligand 1 (PDL1) and cytotoxic T lymphocyteassociated antigen 4 (CTLA4) (10). These approaches singly or in combination seem to reduce adaptive immune responses in vitro and in mouse models. Overexpressing HLA-G or CD47 also blunts the innate natural killer cellmediated response that results from deleting MHC class I genes (11). However, these manipulations are not without theoretical risks. It could be difficult to clear viral infections from an immunostealthy patch of tissue, and possible tumors resulting from engraftment of PSCs might be difficult to clear immunologically.

Ventricular arrhythmias have emerged as the major toxicity of cardiomyocyte cell therapy. Initial studies in small animals showed no arrhythmic complications (probably because their heart rates are too fast), but in large animals with human-like heart rates, arrhythmias were consistently observed (5, 12). Stereotypically, these arrhythmias arise a few days after transplantation, peak within a few weeks, and subside after 4 to 6 weeks. The arrhythmias were well tolerated in macaques (5) but were lethal in a subset of pigs (12). Electrophysiological studies indicate that these arrhythmias originate in graft regions from a source that behaves like an ectopic pacemaker. Understanding the mechanism of these arrhythmias and developing solutions are major areas of research. There is particular interest in the hypothesis that the immaturity of PSC-cardiomyocytes contributes to these arrhythmias, and that their maturation in situ caused arrhythmias to subside.

A successful therapy for heart regeneration also requires understanding the host side of the equation. PSC-derived cardiomyocytes engraft despite transplantation into injured myocardium that is ischemic with poor blood flow. Although vessels eventually grow in from the host tissue, normal perfusion is not restored. Achieving a robust arterial input will be key to restoring function, which may require cotransplanting other cell populations or tissue engineering approaches (13, 14). Most PSC-mediated cardiac cell therapy studies have been performed in the subacute window, equivalent to 2 to 4 weeks after myocardial infarction in humans. At this point, there has been insufficient time for a substantial fibrotic response. Fibrosis has multiple deleterious features, including mechanically stiffening the tissue and creating zones of electrical insulation that can cause arrhythmias. Extending this therapy to other clinical situations, such as chronic heart failure, will require additional approaches that address the preexisting fibrosis. Cell therapy may again provide an answer because CAR T cells targeted to cardiac fibroblasts reduced fibrosis (15).

Developing a human cardiomyocyte therapy for heart regeneration will push the limits of cell manufacturing. Each patient will likely require a dose of 1 billion to 10 billion cells. Given the widespread nature of ischemic heart disease, 105 to 106 patients a year are likely to need treatment, which translates to 1014 to 1016 cardiomyocytes per year. Growing cells at this scale will require introduction of next generation bioreactors, development of lower-cost media, construction of large-scale cryopreservation and banking systems, and establishment of a robust supply chain compatible with clinical-grade manufacturing practices.

Beyond PSC-cardiomyocytes, other promising approaches include reactivating cardiomyocyte division and reprogramming fibroblasts to form new cardiomyocytes. However, these approaches are at an earlier stage of development, and currently, PSC-derived cardiomyocyte therapy is the only approach that results in large and lasting new muscle grafts. The hurdles to this treatment are known, and likely addressable, thus multiple clinical trials are anticipated.

Acknowledgments: C.E.M. and W.R.M. are scientific founders of and equity holders in Sana Biotechnology. C.E.M. is an employee of Sana Biotechnology. W.R.M. is a consultant for Sana Biotechnology. C.E.M. and W.R.M. hold issued and pending patents in the field of stem cell and regenerative biology.

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Stem cells and the heartthe road ahead - Science Magazine

Cell Biology

Discovery of a new nano-structure that lies at the center of our cellular skeleton – Tech Explorist

Every single animal cell has an organelle called a centrosome, which is fundamental to the organization of their cell skeleton. The centrosome plays major jobs, particularly during cell division, where it permits the equivalent sharing of genetic data between two daughter cells.

At the point when the cells quit isolating, the centrioles, cylindrical structures made out of microtubules at the base of the centrosome, move to the plasma membrane and permit the development of essential and cell cilia, which are utilized separately for the exchange of data and the genesis of movement.

While performing these pivotal biological functions, centrioles are along these lines exposed to numerous physical powers, which they must resist.

Scientists from the University of Geneva (UNIGE) have discovered an internal structure at the center of these nano-cylinders, a real cellular scaffolding that maintains the physical integrity of this organelle.

They have discovered a new nano-structure that lies at the center of our cellular skeleton. This discovery will allow understanding better how the cell maintains its architecture as well as the pathologies associated with dysfunctions of this structure.

Paul Guichard, Professor in the Department of Cell Biology of the Faculty of Science at UNIGE, said,Centrioles, formed by microtubules, are components of the cell skeleton. They have a canonical organization defined by nine triplets of microtubules that must be maintained as a structural unit to resist the various forces they face during their cellular functions.

For this study, scientists used an internal scaffolding for this organelle using high-powered electron microscopes, in collaboration with researchers at the University of Basel and the Helmholtz Campus in Neuherberg, Germany.

Maeva Le Guennec, a UNIGE researcher and first author of the study, said,This study allowed to analyze centrioles of four different species and to demonstrate that this inner scaffold is present systematically.

Virginie Hamel, a researcher at the Department of Cell Biology and co-leader of the study, said,We then investigated which centriolar proteins were located in this new structure. To do so, we used an innovative super-resolution method, called expansion microscopy, which makes it possible to inflate cells without deforming them to observe their internal organization. Thus, we were able to identify four proteins that are located at the level of this inner scaffold.

Virginie Hamel noted,We realized that the four proteins we identified are associated with pathologies related to retinal degeneration.

Paul Guichard said,The loss of retinal photoreceptors is possibly due to a failure to maintain the microtubule doublets present in these specialized cells. We now intend to discover the possible link between such a structural maintenance defect and retinal disorders, to pave the way for a better understanding of this pathology.

This study is published in the journal Science Advances.

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Discovery of a new nano-structure that lies at the center of our cellular skeleton - Tech Explorist

Cell Biology

Record number of faculty appointed as distinguished professors in honor of IU’s Bicentennial Year – IU Newsroom

Indiana University trustees have approved the appointment of 15 faculty members as distinguished professors, IU's highest academic title for its most outstanding and renowned scholars and researchers. This is the largest number of new distinguished professors to be appointed in the university's history.

The record number is being recognized in honor of IU's Bicentennial Year and to highlight the remarkable research, scholarship and creative accomplishments of IU's past and present faculty as well as their public impact over the past 200 years.

"Faculty honored with the title of distinguished professor -- a title reserved for only the most highly acclaimed and accomplished IU faculty -- truly are among the finest scholars and researchers in the world," IU President Michael A. McRobbie said. "This prestigious appointment celebrates those who have earned national and international recognition and who have strengthened and transformed their fields of study through their research, scholarship, innovation and creative contributions to the world. They were chosen from the largest and best pool of candidates in IU's history.

"Our students and our campuses benefit enormously from the superb academic achievements, engagement and academic integrity of the faculty who have earned appointment as IU distinguished professor and who have been central to the reputation for excellence that IU enjoys as it begins its third century."

Distinguished Professor Symposia in Bloomington and Indianapolis to honor the 15 new distinguished professors will be announced in the coming weeks. Below are brief biographies of the appointees:

Lisa B. Amsler is the Keller-Runden Professor of Public Service in the O'Neill School of Public and Environmental Affairs. Her research examines dispute systems design and the legal infrastructure for collaboration, dispute resolution and public participation in governance. She has co-edited three books and authored more than 70 articles, monographs and book chapters. She joined the IU faculty in 1989 after practicing labor and employment law.

Lynda Bonewald is a professor of anatomy and cell biology and of orthopedic surgery in the School of Medicine. She is the founding director of the Indiana Center for Musculoskeletal Health, which has more than 100 members from 36 departments on four campuses. She has been continually funded by National Institutes of Health for more than 30 years and is responsible for tools used by researchers globally to determine osteocyte biology and function.

Ann Elsner is a professor in the School of Optometry. Her research led to the discovery that infrared light can image the retina, and she has studied a range of retinal pathologies with a focus on diabetic retinopathy, age-related macular degeneration and normal aging of the eye.

Loren Field is a professor of medicine, of physiology and biophysics, and of pediatrics in the School of Medicine. Field and his IU colleagues were the first to show that relatively simple genetic modifications can induce mammalian heart cells to regenerate. His current research is focused on identifying genes and molecules that promote heart muscle regeneration by coaxing healthy cells to proliferate. The success of this research would offer the potential for seriously ill patients whose tissue has been damaged by heart attack to "re-grow" their own hearts.

Charles Geyh is the John F. Kimberling Chair and professor in the Maurer School of Law. His scholarship focuses on the operation of state and federal courts in relation to the political branches of government and the legal profession. His work on judicial independence, accountability, administration and ethics has appeared in more than 20 articles, book chapters and reports.

David Giedroc is a Lilly Chemistry Alumni Professor and director of the Graduate Training Program in Quantitative and Chemical Biology in the College of Arts and Sciences' Department of Biology. His research interests include the biophysical chemistry of infectious disease. Giedroc is a fellow of the American Association for the Advancement of Science and the Royal Society of Chemistry.

Jeffrey Gould is a Rudy Professor of History in the College of Arts and Sciences' Department of History. He is a groundbreaking historian, writer and filmmaker whose work has transformed scholarship on social movements in Nicaragua and El Salvador. He helped build the Center for Latin American and Caribbean Studies into one of the leading research centers of its kind. He's authored several books and articles, and several have been published in Spanish.

Roger Innes is a Class of 1954 Professor of Biology in the College of Arts and Sciences' Department of Biology. His lab work primarily focuses on understanding the genetic and biochemical basis of disease resistance in plants. He's investigating how plants are able to recognize pathogens and actively respond. The research is funded by two grants from the NIH and has recently been featured in the European journal International Innovation.

Filippo Menczer is a professor of informatics and computer science in the Luddy School of Informatics, Computing and Engineering. His research, supported by the National Science Foundation, Department of Defense, McDonnell Foundation and Democracy Fund, focuses on web and data science, social network analysis, social computation, web mining and modeling of complex information networks. His work on the spread of information and misinformation on social media has been covered by many national and international news outlets.

Mark Messier is a Rudy Professor of Physics in the College of Arts and Sciences' Department of Physics. His research focuses on the experimental study of neutrinos, which are among the most abundant particles in the universe. He is a member of the Deep Underground Neutrino Experiment, which is made up of more than 1,000 collaborators from 190 institutions in over 30 countries. DUNE advances work in each of the key areas of physics research.

Osamu James Nakagawa is the Ruth N. Halls Professor and professor of photography and studio art in the Eskenazi School of Art, Architecture + Design. His photography has been published, reviewed and exhibited internationally. He has permanent collections on display at several museums, including the Metropolitan Museum of Art in New York, the International Museum of Photography at the George Eastman House, the Tokyo Metropolitan Museum of Photography and the Museum of Contemporary Photography in Chicago.

G. David Roodman is the Kenneth Wiseman Professor of Medicine in the School of Medicine. His research focuses on osteoclasts and osteoblast activity in both normal and pathological states, including Paget's disease and multiple myeloma. Roodman's lab pioneered the development of long-term marrow culture techniques to study osteoclast differentiation and activity.

Chandan Sen is the J. Stanley Battersby Chair and professor of surgery at the School of Medicine. He and a team of more than 30 scientists study how to tap into the power of regenerative medicine and engineering to heal burns, develop new therapies for diabetic complications, treat injured soldiers and even regrow damaged and diseased tissue. Sen has published more than 300 articles and is cited more than 900 times a year in literature.

Marietta Simpson is a Rudy Professor of Music in the Jacobs School of Music. She is one of the most sought-after mezzo-sopranos and is greatly admired for the rich beauty of her deeply expressive voice. Simpson has performed with many of the world's great conductors and has performed with all the major orchestras in the U.S. and most of those in Europe.

David Williams is the Harry G. Day Chair and Professor of Chemistry in the College of Arts and Sciences' Department of Chemistry. He is an internationally recognized scientist in the field of organic chemistry. His research is focused on the synthesis of biologically active natural products and the development of new reaction methods. He serves on a number of advisory boards, including for the NI H. Williams is a fellow of the American Association for the Advancement of Science.

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Record number of faculty appointed as distinguished professors in honor of IU's Bicentennial Year - IU Newsroom

Cell Biology

Cyclacel (CYCC) to Report Q4 Earnings: What’s in the Cards? – Yahoo Finance

Cyclacel Pharmaceuticals, Inc. CYCC is scheduled to release fourth-quarter 2019 results on Feb 26.

The companys surprise history has been impressive so far. The trailing four-quarter earnings beat is 16.56%, on average. In the third quarter, Cyclacel delivered a positive earnings surprise of 35.29%.

Shares of Cyclacel have lost 7.9% in the past year compared with theindustrysdecline of 2%.

Lets see how things are shaping up for the quarter to be reported.

Key Developments in Q4

Cyclacel is a biopharmaceutical company developing innovative medicines based on cancer cell biology. As the company does not have any marketed products in its portfolio, we expect it to provide updates on its pipeline during the fourth-quarter earnings call.

In December 2020, the company announced study design and preliminary data from two of the phase I studies, evaluating a combination of CYC065, a CDK2/9 inhibitor, and Venclexta(venetoclax), which is a BCL2 inhibitor, to treat patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL), respectively. We expect updates on this during the fourth-quarter earnings announcement.

The company is evaluating CYC140 in patients with advanced leukemias. CYC140 is a small molecule, selective polo-like-kinase 1 (PLK1) inhibitor that has demonstrated potent and selective target inhibition and high activity in xenograft models of human cancer. We expect the company to provide updates on the study during the fourth quarter earnings announcement.

The company isevaluating an oral regimen of sapacitabine in combination with venetoclax in patients with relapsed or refractory AML/MDS in a phase I/II study. We expect the company to provide an update on this study.

What Our Model Indicates

Our proven model does not conclusively predict an earnings beat for Cyclacel this season. The combination of a positiveEarnings ESPand a Zacks Rank #1 (Strong Buy), 2 (Buy) or 3 (Hold) increases the odds of an earnings beat. But that is not the case here, as you will see below.

Earnings ESP:Cyclacel has an Earnings ESP of 0.00%, as both the Zacks Consensus Estimate and the Most Accurate Estimate are pegged at a loss of 12 cents. You can uncover the best stocks to buy or sell before theyre reported with ourEarnings ESP Filter.

Zacks Rank:The company carries a Zacks Rank #3. You can seethe complete list of todays Zacks #1 Rank stocks here.

Cyclacel Pharmaceuticals, Inc. Price and EPS Surprise

Cyclacel Pharmaceuticals, Inc. Price and EPS Surprise

Cyclacel Pharmaceuticals, Inc. price-eps-surprise | Cyclacel Pharmaceuticals, Inc. Quote

Stocks That Warrant a Look

Here are a few healthcare stocks worth considering, as our model shows that these have the right mix of elements to beat estimates this time around.

Vericel Corporation VCEL has an Earnings ESP of +11.29% and a Zacks Rank #1. The company is scheduled to release fourth-quarter results on Feb 25.

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Cyclacel (CYCC) to Report Q4 Earnings: What's in the Cards? - Yahoo Finance

Cell Biology

LumaCyte Expands into Europe Tackling Expansive Vaccine and Cell and Gene Therapy Markets – BioSpace

The vaccine and cell and gene therapy biomanufacturing sectors are growing at an accelerated rate with the US and Europe driving a significant segment of this growth. European biopharma and CDMO scientists often ask if we have representation in the region as they search for innovative tools to alleviate their production and QC bottlenecks; we can now finally say yes to this important question," says Dr. Sean Hart, LumaCytes Chief Executive Officer. In support of these efforts, LumaCyte has hired analytical instrumentation veteran, Christof Hasse, PhD to manage sales and service as part of its European expansion. At LumaCyte, were obsessed with delivering exceptional customer service, so having Laser Force Cytology (LFC) experts who understand our customers unique needs, and are located in the same region, is critical to delivering the highest level of service, says Rene Hart, LumaCyte President and Chief Business Officer. We are excited to have Christof on board as he brings LumaCytes transformative Laser Force Cytology to the hands of European researchers and production scientists.

About LumaCyte

LumaCyte is an advanced research and bioanalytics instrumentation company headquartered in Charlottesville, VA. LumaCyte produces label-free, single cell analysis and sorting instrumentation where the use of antibody or genetic labeling is not required for cellular analysis. This revolutionary technology utilizes Laser Force Cytology (LFC) to measure optical and fluidic forces within a microfluidic channel to identify and measure the intrinsic cellular properties of each cell. The multivariate nature of the data has enabled a host of Big Data strategies and cloud computing capabilities that drive advanced analytics, allowing a deeper understanding of cell based biological systems. Applications of LumaCyte's label-free platform technology include viral infectivity for vaccine development and manufacturing, cell and gene therapy, cancer biology R&D, CAR T cell immunotherapy, adventitious agent testing (AAT), iPSCs, infectious disease, and pre-clinical drug discovery, in addition to multiple applications across the biomanufacturing sector for quality control and process optimization.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200220005263/en/

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LumaCyte Expands into Europe Tackling Expansive Vaccine and Cell and Gene Therapy Markets - BioSpace

Cell Biology

We need to take steps toward building a consensus definition of biological aging – STAT

Ive been committed to understanding the biology of aging since I was a teenager, and my education and career took aim at this problem from many angles. One aspect that still perplexes me is that there isnt a good, easily communicable answer to this simple question: What is biological aging?

When it comes to biological aging research or, to use a fancier term, translational geroscience, scientists finally have a pretty good understanding of the major components of aging. But theres no consensus definition of it that consolidates the existing framework.

Why do we need such a definition of biological aging? A good definition can grab the essential characteristics of an entity and put them to good use. Two examples illustrate this.

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Here is an example from medicine, published this month in Nature: Cancer is a catch-all term used to denote a set of diseases characterized by autonomous expansion and spread of a somatic clone. That is a more exact way of saying, Cancer is a disease caused by uncontrolled division of abnormal cells. This definition captures the universal mechanism behind all cancers. As such, it also offers therapeutic options. No matter how diverse cancers get, keeping them under one umbrella is easier compared to the broad-spectrum of biological aging.

A definition from mathematics is also instructive: The derivative of a function is the measure of the rate of change of the value of the function dependent on changes in the input. It is a solid definition as it offers a procedure to compute the extreme values of a function.

Here are three consecutive steps empirical, philosophical, and computational that can be taken to create a good definition of biological aging:

The empirical step involves collecting what is already out there. Over the years, researchers have invented their own idiosyncratic definitions of biological aging, though these generally miss parts of the story.

Scientists often start papers with a summary referring to the consensus knowledge in the field and then ask the particular question they want to address and highlight the results. These summaries, which often contain definitions, are important educational windows into science, used by mainstream media to publicize results and form relevant narratives.

To illustrate the empirical step, I extracted four definitions from scientific papers exploring different aspects of aging that reveal the conceptual mess around defining biological aging.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death came from a 2013 paper in the journal Cell by Carlos Lpez-Otn and colleagues.

Aging underlies progressive changes in organ functions and is the primary risk factor for a large number of human diseases was the definition in a 2019 report in Nature Medicine by Benoit Lehallier and colleagues.

Aging is a progressive decline in functional integrity and homeostasis, culminating in death was used in a 2019 review of the genetics of aging in Cell by Param Priya Singh and colleagues.

Finally, a 2020 paper in Nature Medicine on personal markers of aging by Sara Ahadi and colleagues offered this: Aging is a universal process of physiological and molecular changes that are strongly associated with susceptibility to disease and ultimately death.

I analyzed several components of these definitions of biological aging, as indicated by the column headers in the table below, and identified some recurring themes. The final column indicates logical connections between these components.

This analysis offers two lessons, one negative and one positive. The negative lesson is that some definitions have hardly any overlap, as seen in I and II its apples and oranges. The positive lesson is that the recurring themes suggest the possibility of creating a core definition for biological aging using a bottom-up, empirical approach by analyzing many attempted definitions.

However, I dont believe that such a process would be sufficient.

The myriad definitions of biological aging help identify some necessary components of it. But an aggregated mash-up wont guarantee a formally correct and useful definition. Identifying the content itself is not enough, especially when dealing with such a complex and lifelong process. Just because we have found most of the puzzle pieces does not mean we can put the puzzle together without a clue to its shape.

This is where the philosophical step comes into the picture. Here, biologists will benefit from recruiting people trained to come up with a formal definition: philosophers, mathematicians, computer scientists, and the like.

The philosophical step involves identifying a list of criteria that a consensus definition of biological aging should meet. I believe that such a definition should meet at least these five criteria:

Completing the empirical and philosophical steps would yield a good starting point for a well-formed definition that captures the essentials of biological aging.

A consensus definition that meets both content and formal criteria, achieved through the empirical and philosophical steps, might help stabilize not just scientific consensus but consensus on public policy. Here the main issues are the relationship between biological aging and disease; and regulatory, clinical, and social aspects of healthy longevity. But a completed computational step will give us actual tools, helping the biomedical technology that advances healthy lifespans.

Applicability is perhaps the most important feature of a good definition, and this where the computational step comes in. The definition should suggest future experiments and, even more important, lend itself to computability so a formal model of biological aging can be built from it. Such a model can be used to simulate and compute biological aging scores based on input data and assess the effects of planned or real interventions to slow or stop negative aging processes.

Biomedical researchers now have a solid core of knowledge on biological aging, but do not have a working consensus definition to consolidate and represent this core knowledge and capture this so far elusive life process. The lack of an unambiguous and computable formal consensus definition of biological aging severely limits the applicability of this core knowledge to design comprehensive interventions to slow or stop negative aging processes.

A confident answer to the question What is biological aging? in humans will help us ensure that complexity does not hide any magical mysteries. Controlling that complexity to maximize a healthy lifespan wouldnt need a magic wand, either.

Attila Csordas is a longevity biologist and philosopher and the founding director of AgeCurve Limited, based in Cambridge, U.K.

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We need to take steps toward building a consensus definition of biological aging - STAT

Cell Biology

Penn announces seven 2020 Thouron Award winners – Penn: Office of University Communications

Four University of Pennsylvania seniors and three recent alumni have won a Thouron Award to pursue graduate studies in the United Kingdom. Each scholarship winner receives tuition for as long as two years, as well as travel and living stipends, to earn a graduate degree there.

Established in 1960 and supported with gifts by the late John Thouron and his wife, Esther du Pont Thouron, the Thouron Award is a graduate exchange program between Penn and U.K. universities that aims to improve understanding and relations between the two countries.

Penns seven 2020 Thouron Scholars are:

Daniel Brennan

Senior Daniel Brennan, of Miami, is a varsity oarsmen for Penns lightweight crew team majoring in history and political science, with concentrations in military history and political theory in the School of Arts and Sciences. As a United States Marine and past moderator of the Universitys Philomathean Society, he is an advocate for greater civil-military awareness. Brennan works on national security policy as a Student Fellow at the Perry World House and is writing his honors thesis on the development of counterinsurgency strategy during the Cuban War of Independence. He is a Benjamin Franklin Scholar and has worked on anti-hunger issues both as a Fox Leadership Fellow with the Catholic Archdiocese of Philadelphia and by organizing his crew teams meal-packing events. In the U.K., he plans to pursue a masters degree in military history.

Braden Cordivari

Braden Cordivari, of Elverson, Pennsylvania, is a 2018 graduate of the College of Arts and Sciences. He received his bachelors degree in classical studies and anthropology with a minor in archaeological science. Since 2015, he has continued to work at Penns excavations at the ancient Iron Age city of Gordion in Turkey. He spent the 2018-19 academic year as a John Williams White Fellow at the American School of Classical Studies at Athens completing a program of intensive study of Greek archaeology and history. His research interests include human/environment relationships in the past and the study of craft production through science-based methods. Cordivari plans to pursue a masters degree in archaeological science at the University of Cambridge.

Gregory Forkin

Gregory Forkin, of Philadelphia, is a 2019 graduate with a bachelors degree in mathematics, physics, and biology and a minor in chemistry. He was a University Scholar and a member of Phi Beta Kappa. Currently, he is conducting research in neuroscience under Professor Vijay Balasubramanian and is a teaching assistant in the Math Department in the School of Arts and Sciences. Forkin plans to pursue a masters degree in pure mathematics at the University of Cambridge.

Natasha Menon

Senior Natasha Menon, of Scottsdale, Arizona, is pursuing a major in philosophy, politics, and economics with a concentration in distributive justice and a minor in legal studies and history in the School of Arts and Sciences. Menon serves as president of the Undergraduate Assembly, through which she works to elevate the voices of marginalized communities on campus to effect change. She is also a Civic Scholar, and has volunteered at Moder Patshala, a Bangladeshi immigrant services center in Philadelphia, for three years. Menon plans to pursue a masters degree in international migration and public policy at the London School of Economics. Upon returning to the U.S., she hopes to pursue a law degree and engage in public service in Arizona.

Robert Subtirelu

Senior Robert Subtirelu, from Ronkonkoma, New York, is majoring in the biological basis of behavior and minoring in chemistry in the School of Arts and Sciences. A recipient of the 2019 Clinical and Translational Research Award, he has conducted research with the Perelman School of Medicines Department of Neurosurgery to investigate post-traumatic epilepsy. He works as a teaching assistant, volunteers with Wissahickon Hospice, and remains an active member of Penns Medical Emergency Response Team. He also founded and coordinated the activities of a not-for-profit organization that has established educational and nutritional programs internationally. Subtirelu plans to pursue a masters degree in clinical and therapeutic neuroscience at the University of Oxford.

Zachary Whitlock

Senior Zachary Whitlock, of Washington, D.C., is in the Vagelos Integrated Program in Energy Researchjoint-degree program, majoring in materials science and engineering in the School of Engineering and Applied Science and in earth science in the School of Arts and Sciences. Whitlock has workedon biomimetic functional materialswith Penn Engineerings Shu Yang Laboratory and internationally at the French Alternative Energies and Atomic Energy Commission. More recently, he worked at the intersection of industrial materials and environmental impact on the Kleinman Center for Energy Policy-funded project Fossil Fuels, the Building Industry, and Human Health. He is a 2020 Kleinman Undergraduate Fellow and Supported Student at the Water Center at Penn. He is planning to pursue a masters degree in environmental systems engineering at University College London and ultimately hopes to contribute to the sustainability and impact mitigation of projects reliant on ecosystem services.

Maia Yoshida

Maia Yoshida, of Madison, New Jersey, received her bachelors degree in 2018 in molecular and cell biology with a minor in fine arts. She is now a researcher in a bioengineering lab, engineering immune cells to better fight cancers. While at Penn, she researched the molecular mechanisms involved in neurodegenerative diseases and was a teaching assistant for a fine arts course on biological design. She also taught elementary school science at the Penn Alexander School in West Philadelphia. As the president of Global Brigades at Penn, she led fundraising efforts for sustainable development projects in Honduras. Yoshida plans to pursue a masters degree in STEM Education at Kings College London.

TheCenter for Undergraduate Research and Fellowshipsserves as Penns primary information hub and support office for students and alumni applying for major grants and fellowships, including the Thouron Award.

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Penn announces seven 2020 Thouron Award winners - Penn: Office of University Communications