Category Archives: Cell Biology

April 6, 2023

A study published in Cell Stem Cell looks at the generation of embryo-like structures from monkey embryonic stem cells.

Prof Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering, California Institute of Technology; and Professor of Mammalian Development and Stem Cell Biology, University of Cambridge, said:

This is an exciting development building on work from our own and other labs showing the importance of establishing interactions between embryonic and extra-embryonic stem cells to establish models of the mammalian embryo at pre-and early post-implantation stages. The excitement of this study is not only that embryos generated from monkey stem cells provide a close model for human embryos, but monkeys are also experimentally tractable.

The authors follow approaches that have been previously used to direct embryonic stem cells into a naive state, and then use treatments that allow the nave monkey ES cells to form extra-embryonic cell types. Together these cells assemble into blastoids, structures resembling blastocysts, that are able to develop in vitro into structures with a striking resemblance to the embryonic disc at gastrulation, both in morphology and gene expression. The blastoids also appear to implant into foster monkey mothers but, in common with similar structures in the mouse, development appears restricted.

This study is a hugely encouraging development in the study of primate embryo models.

The paper is excellent and an important step forward but still the stem cell derived embryos have a limited developmental potential, as the authors state themselves. Nevertheless, it is an important step in the very exciting field of enormous potential for understanding how the embryo develops and why so many pregnancies fail.

Prof Roger Sturmey, Professor of Reproductive Medicine, Hull York Medical School, University of Hull, said:

The work by Li and colleagues is an impressive technical achievement that has demonstrated the possibility that embryonic stem cells from a primate can be persuaded to form structures that mirror many features of early embryos.

Similar achievements have already been reported in other species, however this work assesses the primate embryo-like structures in detail and gives new insights into how the cell lineages families of cells that constitute the early embryo can be generated from stem cells.

Remarkably, when cultured in a laboatory, the embryo-like structures are able to replicate a number of key developmental features, most notably the formation of cells that resemble the primordial germ cells the cells that can produce gametes as well as the formation of a structure similar to the so-called primitive streak. When transferred into a recipient macaque uterus, these embryo-like structures were able to generate components of a pregnancy response, but were unable to develop, indicating that while these structures do share many features with competent embryos, there are still aspects of early development that differ between competent embryos and stem-cell derived models, preventing full development.

The work by Li and colleagues will offer important new tools in our understanding of the earliest stages of embryo development, but also highlight the need for guidance in this area, something that scientists in the UK are actively working on.

Prof Alfonso Martinez Arias, ICREA Senior Research Professor, Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), said:

This is a timely study.

About half of human pregnancies fail during the proliferation of the zygote and the implantation of the blastocyst. Understanding the causes of this failure rate will impact human fertility and IVF success. In part to address this need, over the last few years, a number of Embryonic Stem (ES) cell models of early mammalian development have been created in the lab. Amidst these, mouse and human blastoids mimic mammalian blastocysts and as such can play an important role in understanding the process of implantation. Blastoids have been derived from mouse and human ES cells.

For these studies to go forward there is a need to develop a proper test for the function of the blastocyst: its implantation into the uterus. In the case of mouse blastoids this can be tested by implanting them into females. However, there is no such a test for human blastoids since, for obvious reasons, it is not possible to implant them into a human uterus. And yet there is a need to develop a system to study these structures in humans. Mouse reproductive biology and implantation are very different from human, which means that while an excellent system to find principles, the mouse is not useful for the specifics of this process; and this is what matters. It is this vacuum of a system to study human implantation and peri-implantation development that is addressed in the present study.

Following protocols established for human blastoids, macaque blastoids are made from nave stem cells and their potential is tested in two ways. One, by culturing them in vitro up to gastrulation stages and the other, by placing them in the uterus of a macaque foster mother. The idea behind this system is that it has reduced ethical barriers compared to human and therefore might provide an experimental system to test the potential of blastoids fully and, in the long term, to study infertility. The work is well conducted and the result is clear: although at the level of single cells macaque blastoids bear a strong resemblance to blastocysts, they do not behave as blastocysts. Although they implant and initiate gastrulation, they do not reach the end of this process. In vitro, blastoids cultured to form an epiblast and to undergo gastrulation, display progressive problems over time and, though they reach early stages of gastrulation, it is difficult to see in their data how faithful they are to an early gastrula. In one important experiment they implant some of these into female macaques and follow their progress with ultrasound. It appears as if they might perform well in the early stages of implantation, and the release of progesterone is a sign that something has gone well, but then, they disappear after about a week.

So, the important result of this work is that we are not close to generating blastoids that can be recognised as blastocysts by the mother. Definitely an important proof of principle but the lesson is that there is work to do.

An important difference between a blastoid and a blatocyst is their origin. The blastocyst in the egg, the blastoid in the ES cells. There might be elements in the oocyte that are important for the viability of the blastocysts and that will not be provided by the ES cells. Furthermore, if about 50% of conceptions fail at implantation, it is difficult to gauge whether the failure of the high level goal of the experiment (long term development in the womb) is due to defects in the blastoid system or whether the failure mirrors the natural situation; eight experimental subjects, the numbers of the experiment, are not sufficient to make a judgement. Only more experiments will decide and the one reported here, within well established ethical footprints, is definitely one to watch.

Dr Darius Widera, Associate Professor in Stem Cell Biology and Regenerative Medicine, University of Reading, said:

This is an interesting study that demonstrates the successful generation of embryo-like structures from monkey embryonic stem cells. These structures resembled natural early embryonic structures and could generate cell types of all three germ layers. Although similar studies have been conducted using human stem cells, this is the first report showing that (in this case, monkey) embryo-like structures can induce signs of pregnancy if transplanted into females. Therefore, the method could be used as a model of primate and human development and potentially provide new insights into certain factors that contribute to miscarriages in humans.

However, the study has some limitations. Only 3 out of 8 embryo-like structures were successfully implanted into female monkeys, and none of these persisted for more than one week. Thus, the structures do not have full developmental potential.

In addition, the ethical implications of embryonic stem cell research in monkeys are complex. Primates are intelligent, social animals with complex cognitive and emotional lives. Therefore, it is important to carefully consider both the potential benefits and the ethical impact of primate embryonic stem cell research.

Prof Robin Lovell-Badge FRS FMedSci, Group Leader, Francis Crick Institute, said:

The paper by Jie Li et al is another demonstration of the remarkable ability of pluripotent stem cells, in this case embryonic stem cells derived from early Macaque (non-human primate) embryos, to self-organise and begin a process of embryo formation in culture that mirrors that of normal Macaque embryos. However, the paper also shows that these stem cell-based embryo models are not entirely normal they could be implanted in female macaques, appear to initiate a pregnancy, but then fail soon after.

The authors were able to culture these stem cell-based embryo models, which they refer to as blastoids, through to gastrulation stages, equivalent to post-implantation embryos developing in a uterus, with good signs of development of all the main extraembryonic and embryonic tissues, where the latter included ectoderm, mesoderm and endoderm organised in a similar fashion to normal embryos. They could also demonstrate the presence of primordial germ cell-like cells and cells that are early progenitors of the blood system. These stages would be equivalent to those of human embryos at about 16 -18 days of development, beyond the 14 day limit (or the beginning of gastrulation) which is the maximum period normal human embryos are allowed to be cultured by law in the UK and some other countries.

It has been shown by others that human pluripotent stem cells can also be used to form blastoids, but to date such cultures have been stopped prior to gastrulation, but the paper by Li et al suggests that they could indeed be taken beyond this and provide valuable information about these early stages of human development that are otherwise very difficult to obtain. The data from the Macaque embryos and blastoid cultures may also help to understand aspects of human development, but without direct comparisons this will always be tentative, given how much mammalian embryos can vary at these stages.

These embryo models are referred to as integrated stem cell-based embryo models because they include extraembryonic tissues that normally give rise to the placenta and yolk sac that in a normal conceptus would permit implantation into the uterus and support the development of the embryo proper. So how much like a real embryo are these Macaque blastoids and could they implant and develop much further in a uterus? Although all the detailed comparisons presented in the paper of gene expression in the various cell types between normal Macaque embryos and the embryo models suggests that they can be very similar, the proportion of the blastoids reaching advanced stages was very low, indicating that most are not normal, and those that did still showed some differences. Moreover, while some could implant, begin to develop some complexity, and induce a typical response in the host uterus and lead to production of the typical pregnancy hormones, chorionic gonadotrophin and progesterone, the embryos all failed before gastrulation. This suggests that they failed to form fully functional extraembryonic tissues that could adequately support the embryo and that these could not give rise to a placenta, which would be essential for more complex development. It is likely that the same would be true for human integrated stem cell-based embryo models, although it would be unethical and illegal (in the UK) to attempt to implant these into a woman.

It seems likely that the culture methods for these integrated stem cell-based embryo models will be improved, and who knows it may eventually be possible to have them implant and develop normally, but the failure of this to happen as reported in this paper will give regulators some breathing space to develop appropriate rules for the culture of such human models, notably whether they can be taken beyond the equivalent of gastrulation stages, which would be of immense importance in helping to understand not just normal development of the human embryo, but what so often goes wrong and leads to embryo failure and congenital disorders.

Cynomolgus monkey embryo model captures gastrulation and early pregnancy by Jie Li et al. was published in Cell Stem Cell at 16:00 UK time on Thursday 6 April 2023.

DOI: 10.1016/j.stem.2023.03.009

Declared interests

Prof Magdalena Zernicka-Goetz: I have no conflict of interest to declare.

Prof Roger Sturmey: None.

Prof Alfonso Martinez Arias: I have no conflict of interests.

Dr Darius Widera: I have no conflict of interest to declare.

Prof Robin Lovell-Badge: I have no conflicts of interest to declare, except I do serve on the HFEAs Scientific and Clinical Advances Advisory Committee and I am a member of their Legislative Reform Advisory Group.

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Cell Biology

UCF Bone Researcher Receives National Recognition – UCF

April 8, 2023 medical

As a child, Melanie Coathup enjoyed solving puzzles and had a deep fascination with science. Now an internationally recognized biomedical engineer, Coathup has been inducted to the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows one of the highest professional distinctions accorded to a medical and biological engineer.

As head of the Biionix Cluster at UCF and professor of medicine, Coathups work focuses on orthopedic innovation developing new technologies and therapeutics to rebuild and repair bone tissues lost due to aging, cancer therapy, degenerative diseases such as osteoporosis, or exposure to environments like space orbit.

Being recognized by AIMBE for my research is so phenomenal, its difficult to fully capture with words. I am ecstatic, excited and inspired for the future, she says. Carrying out research is a humbling experience, as there are always ups and downs and often with more challenges than successes. Its been an immense pleasure to work with my amazing post-docs and students over the years to create this body of research.

Coathup was elected by her peers and members of the College of Fellows for pioneering research in developing biomaterials for orthopedics and providing International leadership in translational medicine. She was honored at a formal induction ceremony in Arlington, VA on March 27 one of 140 inductees to the College of Fellows Class of 2023.

AIMBE Fellows represent the top two percent of medical and biological engineers who have made outstanding contributions to engineering and medicine through research, practice, or education. Three are Nobel Prize laureates, and 11have received the Presidential Medal of Science and/or Technology and Innovation.

Associate Dean and Director of the Burnett School of Biomedical Sciences Griff Parks congratulated Coathup on her induction.

This award highlights both the outstanding research that is ongoing in her lab, as well as her long term commitment to training the next generation of biomedical scientists in areas of high impact to human health, he says.

Coathups research has led to new implant designs to replace bone lost to cancer, and the development of a new kind of synthetic bone material to help patients with skeletal injuries regenerate their tissue for a speedier recovery.

I have always had a deep fascination with medical science, she says. One of my earliest memories as a child was reading books on science along with a (failed) attempt to read and learn the entire medical dictionary.

Through the Biionix Cluster, Coathup leads amultidisciplinary team of researchers working to develop innovative materials, processes and interfaces for advanced medical implants, tissue regeneration, prostheses and other future high-tech products.

Before joining UCF, Coathup was a professor and researcher at University College Londons Institute of Orthopaedics and Musculoskeletal Science, serving as head of the Centre for Cell and Tissue Research. Born in the U.K., Dr. Coathup completed undergraduate studies in medical cell biology at the University of Liverpool, U.K. before furthering her knowledge with a Ph.D. in orthopedic implant fixation. A first-generation graduate, she is passionate about encouraging and inspiring future generations of scientists, particularly young women and was previously honored by UCF in March 2019 for Womens History Month.

Three weeks ago, I learned that a 6-year-old girl in Wales named Lilly who was researching me for a class project wouldnt believe that I was a doctor working in STEM, Coathup says. This was because she is a girl. She told her teacher that she had made a mistake and that I couldnt be a doctor. To Lilly, and all young girls, I want you to know that you can do it. Allow yourself to dream, and follow your beliefs, passion, and heart, and with hard work, you can achieve all. I look forward to celebrating your future successes.

Cell Biology

PhenomeX to Participate in American Association of Cancer … – BioSpace

April 8, 2023 medical

EMERYVILLE, Calif., April 7, 2023 /PRNewswire/ -- PhenomeX Inc. (Nasdaq: CELL), the functional cell biology company, today announcedits participation at the American Association of Cancer Research (AACR) Annual Meeting 2023 being held from April 14-19 at the Orange County Convention Center in Orlando, Fla. AACR brings together scientists, clinicians, other health care professionals, survivors, patients, and advocates to share the latest advances in cancer science and medicine through this year's meeting theme of "Advancing the Frontiers of Cancer Science and Medicine."

At the conference, PhenomeX, the new company recently formed through the combination of Isoplexis and Berkeley Lights, will showcase its IsoSpark and Beacon optofluidic platform technologies and workflows in booth #3444. Attendees will have a chance to explore demonstrations of the technologies and learn more about how PhenomeX's applications can provide unparalleled insights into cell function along the continuum of scientific discovery, bioprocessing, translational, and clinical research.

In addition, the AACR Annual Meeting covers the latest advances in cancer through a variety of poster and speaker presentations. This year, PhenomeX technologies are highlighted in nine poster presentations ranging from Polyfunctional Profiles and Cytokine Secretion Activity of Transgenic TCR-T cells and Anti-Cancer Macrophage-Based Cell Therapy to the Identification of Myeloma-Specific T Cell Receptors by Functional Single Cell Interaction Analyses.Some of the presenting abstracts include:

About PhenomeX Inc.

PhenomeX is empowering scientists to leverage the full potential of each cell and drive the next era of functional cell biology that will advance human health. We enable scientists to reveal the most complete insights on cell function and obtain a full view of the behavior of each cell. Our unique suite of proven high-throughput tools and services offer unparalleled resolution and speed, accelerating the insights that are key to advancing discoveries that can profoundly improve the prevention and treatment of disease. Our award-winning platforms are used by researchers across the globe, including those at the top 15 global pharmaceutical companies and approximately 85% of leading U.S. comprehensive cancer centers.

Forward-Looking Statements

To the extent that statements contained in this press release are not descriptions of historical facts regarding PhenomeX or its products, they are forward-looking statements reflecting the current beliefs and expectations of management. Such forward-looking statements involve substantial known and unknown risks and uncertainties that relate to future events, and actual results and product performance could differ significantly from those expressed or implied by the forward-looking statements. PhenomeX undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties relating to the Company's growth and continual evolution see the statements in the "Risk Factors" sections, and elsewhere, in our filings with the U.S. Securities and Exchange Commission.

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Cell Biology

Inland Empire stem-cell therapy gets $2.9 million booster – UC Riverside

April 8, 2023 medical

A new UC Riverside training program will help undergraduates transition into regenerative medicine careers, infusing the Inland Empire wraith expertise in cutting-edge trauma and disease treatments.

Guadalupe Ruiz,RAMP diversity and outreach director, left, and Huinan Hannah Liu, bioengineering professor and RAMP principal investigator. (Stan Lim/UCR)

The Research Training and Mentorship Program to Inspire Diverse Undergraduates toward Regenerative Medicine Careers, or RAMP, has received $2.9 million to work with multiple groups of students over the next five years. The grant comes from the California Institute for Regenerative Medicine, the states stem cell agency.

The overall goal of the program is to develop therapies for cells and tissues damaged by injury, trauma, or disease, including brain cells. Laboratory work will include tissue engineering but also research into techniques where the body uses its own biological systems, sometimes with help of engineered materials to rebuild tissues and organs.

UCR already had parts of a stem-cell career training pipeline in place. The university hosts STRIDE, a program offering local high school students opportunities to participate in laboratory research projects. In addition, the TRANSCEND program, directed by UCR molecular biology professor Prue Talbot, helps increase the number and diversity of Ph.D. and postdoctoral scientists trained in stem cell biology.

The missing link was undergraduates, said Huinan Hannah Liu, UCR bioengineering professor and RAMP principal investigator. RAMP is a linker molecule between those two programs.Interested undergrads are encouraged to apply.

Liu got involved with the program because her laboratory works on ways to improve cellular nutrient delivery and waste transport. A lot of metabolic waste in a cell impedes regeneration, Liu said. Nothing thrives in an environment full of waste.

Sometimes called the body's master cells, stem cells develop into blood, brain, bones, and all of the body's organs. They have the potential to repair, restore, replace, and regenerate cells. (luismmolina/iStock/Getty)

Her focus mirrors the first of three sub-specialties from which RAMP students will be able to choose. Faculty from UCRs Marlan and Rosemary Bourns College of Engineering will work with students to engineer materials that serve as scaffolds for growing cells and tissues.

Students can also choose to work with faculty from the College of Natural and Agricultural Sciences, who have expertise in cell biology. They understand the biological mechanisms behind tissue development, and the pathology of different disease stages, Liu said. Their collaboration with engineering faculty will be critical.

Faculty from UCRs School of Medicine will also work with students on ways to differentiate stem cells toward various cell types, and research the mechanisms of how cells and tissues function in the body. They can determine, for example, whether the body will accept an engineered cell, Liu said.

Moving forward, Liu is hopeful that RAMP will attract more clinical faculty, who can help do studies to test whether engineered materials, cells and tissues are safe before translating the work to human subjects.

Another key component of the program will be reaching out to patients and local communities to make them aware of new treatment options available to them. As they see the need in our area, Im hopeful these students will remain long term and help heal our diverse, underserved Inland Empire communities, Liu said.

(Cover image: stem cells: luismmolina/iStock/Getty)

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Cell Biology

New finding in roundworms upends classical thinking about animal cell differentiation – News-Medical.Net

April 8, 2023 medical

Researchers have spotted how specific proteins within the chromosomes of roundworms enable their offspring to produce specialized cells generations later, a startling finding that upends classical thinking that hereditary information for cell differentiation is mostly ingrained within DNA and other genetic factors.

The Johns Hopkins University team reports for the first time the mechanisms by which a protein known as histone H3 controls when and how worm embryos produce both highly specific cells and pluripotent cells, cells that can turn certain genes on and off to produce varying kinds of body tissue. The details are published today in Science Advances.

The new research could shed light on how mutations associated with these proteins influence various diseases. In children and young adults, for example, histone H3 is closely associated with various cancers.

These mutations are highly prevalent in different cancers, so understanding their normal role in regulating cell fate and potentially differentiation of tissues may help us understand why some of them are more prevalent in certain diseases. The histones that we're looking at are some of the most mutated proteins in cancer and other diseases."

Ryan J. Gleason, lead author, postdoctoral fellow in biology at Johns Hopkins

Histones are the building blocks of chromatin, the structural support of chromosomes within a cell's nucleus. While histone H3 is particularly abundant in multicellular organisms such as plants and animals, unicellular organisms teem with a nearly identical variant of H3. That's why scientists think the difference in rations of H3 and its variant hold crucial clues in the mystery of why pluripotent cells are so versatile during early development.

The researchers revealed that as C. elegans roundworm embryos grew, increasing H3 levels in their systems restricted the potential or "plasticity" of their pluripotent cells. When the team changed the worm's genome to lower the amount of H3, they successfully prolonged the window of time for pluripotency that is normally lost in older embryos.

"As cells differentiate, you start to get a hundredfold histone H3 being expressed at that time period, which coincides with that lineage-specific regulation," Gleason said. "When you lower the amount of H3 during embryogenesis, we were able to change the normal path of development to adopt alternative paths of cell fate."

In pluripotent cells, histones help switch certain genes on and off to commit to specific cell types, be they neurons, muscles, or other tissue. Highly regulated by histones, genes act as a voice that tell cells how to develop. How quiet or loud a gene is determines a cell's fate.

The new findings come from the gene-editing technique CRISPR, which helped the team track the role the two histones played as the worm's offspring developed. CRISPR has made it much easier for scientists in the last decade to study the nuts and bolts of changing genetic material and spot what that does to animal, plant, and microbe traits, Gleason said.

Even though the C. elegans roundworm gives finer insights into how these pluripotent cells evolve, further research is needed to zero in on how histones might also underpin embryogenesis in humans and animals composed of hundreds of types of cells, said Xin Chen, a Johns Hopkins biology professor and co-investigator.

"Even though we are using this small worm to make these discoveries, really this finding should not be specific to one animal," Chen said. "It's hard to imagine the findings are only going to be applicable to one histone or one animal but, of course, more research needs to be done."

The team includes Yanrui Guo of Johns Hopkins, Christopher S. Semancik of Tufts University, Cindy Ow of University of California, San Francisco, and Gitanjali Lakshminarayanan of Dana-Farber Cancer Institute.

Source:

Journal reference:

Gleason, R. J., et al. (2023) Developmentally programmed histone H3 expression regulates cellular plasticity at the parental-to-early embryo transition. Science Advances. doi.org/10.1126/sciadv.adh0411.

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New finding in roundworms upends classical thinking about animal cell differentiation - News-Medical.Net

Cell Biology

Biology’s unsolved chicken-or-egg problem: Where did life come from? – Big Think

April 8, 2023 medical

Biology has a chicken-or-egg problem. Two types of molecules are essential for life. Cells contain protein molecules, which perform most of the biochemical and physical functions. Cells also contain DNA and RNA molecules, which carry the blueprint information for making more cells. When life first arose on Earth 3.5 billion years ago, which came first: function or information? Its a major unsolved problem of how biology arose from prebiotic chemistry.

Some people think that life first got started call it Day One from RNA, because some RNA molecules can do double-duty and act like proteins. But, we believe proteins came first. The proteins-first perspective helps to solve another major mystery: Where did Darwinian evolution come from? We want to know not only what form of matter arose on Day One, but also why that matter would persist and adapt and go forward into Day Two, Day Three, and beyond.

Darwinian evolution is biologys planet-wide unrelenting drive to adapt, innovate, and change. Through survival of the fittest, organisms compete to win resources, beget other organisms, and adapt to their environments. Ever since Charles Darwin 160 years ago, we know much about how evolution works, but we have no idea how it got started. Evolution must have had a beginning. It is not a universal law, like the principles of physics or chemistry, which have operated since the beginning of the Universe. As far as we know, evolution has only been running since biology first arose about 3.5 billion years ago, a billion years after earth was formed.

Why would proteins come first? Proteins are most of a cells mass, so the differential growth rates that are the grist for the mill of cell evolution are largely a matter of differential protein production. And, proteins are the maker molecules that catalyze those growth reactions. Importantly, proteins are unique in having sequence > structure > function relationships. Most other polymers, including most RNAs, do not.

Proteins form specific folded structures, which are the bases for the molecular functions that create the actions and behaviors of the cell. Think of a proteins 20 amino acids as falling into roughly two classes: oil-like hydrophobic monomers and water-like polar monomers. Proteins fold up; that is, protein strings ball up in water into specific compact shapes because of the basic physics that oil avoids water that is, oily amino acids fold to be inside the ball, away from the surrounding water outside the protein. This makes proteins great catalysts. Folded proteins are miniature solids. Being a solid is exactly whats needed to catalyze chemical reactions, because catalyst atoms need to hold their places long enough to assist the reaction. Further, a 20-amino-acid alphabet spans a range of chemistries, so they catalyze a range of reactions.

But how did protein-making get started? First, we know from experiments that the amino acid building blocks of proteins plausibly could have existed on the early Earth. We also know there were simple catalysts that could initially link together amino acids into peptides minerals and clays or air-water surfaces will do. Short proteins, called peptides, are even found on some meteorites.

So, lets call the first catalyst the Founding Rock rock simply implying a site fixed in space, and founding implying that it was the first catalyst, before proteins themselves were catalysts, free-floating and capturable inside cells. However, proteins made on the Founding Rock would have been too short and possessed neither functions nor propagation principles nor specific informational sequences. How might these bio-like properties emerge from simple peptides? Emergence is when a small change in some parameter turns a simple behavior into a more complex one.

Our computer modeling tells a plausible story: A few of those little random peptides ball up in water from oil-water forces, creating stable folded surfaces, becoming primitive catalysts, and helping to elongate other chains. Foldcats are what we call such chains. Those sequences will be rare, extremely so. But, as is true in many such matters of statistical physics, the question is not how improbable the states are, but rather how cooperative they are. How might one molecular action enhance the next one, like a snowball growing as it rolls down a hill? It doesnt matter which was the first snowflake. It matters only what is the process of becoming a snowball. The foldcat hypothesis explains snowballing cooperativity and the tipping point going from chemistry to biology, and from molecules falling apart to their persistent growth.

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How might this all work? The few long chains that are made on the Founding Rock catalyze the making of even longer chains, producing additional stable and diverse catalysts. Thats because long chains fold more tightly, protecting their cores from chemical degradation. Short chains degrade faster. Longer chains win recycled amino acid monomers, slurping up more resources. Winner peptide molecules take all, as a beginning to Darwinian evolution.

A skeptic might claim that this violates the Second Law of Thermodynamics, but this is not correct. Long story short: While the Second Law says that dead matter tends toward equilibrium and degradation, the Second Law doesnt apply to things that are plugged in things like TV sets, that are driven away from equilibrium. In the foldcat hypothesis, whats plugged in is the peptide synthesis on the Founding Rock in the presence of plentiful amino acids. Thats the driver. It would generate huge amounts of junk peptides, and a very small number of foldable longer chains. But, thats all that is needed to get the snowball rolling.

In short, we believe that function (proteins) came before information (RNA). We know of no alternative, that is, no driving force for an information-first process. Rather than genes using proteins to make new genes, we believe that proteins use genes to make new proteins. And, the foldcat mechanism simply shows how the middleman the genes were simply not needed at first. Peptides made proteins as the first step toward the origin of life.

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Cell Biology

Azacitidine in Combination With Trametinib May Be Effective for … – The ASCO Post

April 8, 2023 medical

By The ASCO Post StaffPosted: 4/7/2023 11:01:00 AM Last Updated: 4/7/2023 10:47:27 AM

Researchers have found that the hypomethylating agent azacitidine plus the MEK inhibitor trametinib may be a promising new combination to treat patients with juvenile myelomonocytic leukemia (JMML), according to a preclinical study published by Pasupuleti et al in Molecular Therapy.

Background

JMML is caused by a specific genetic mutation that results in the overactivity of the RAS/MAPK cellular pathway. There are currently limited therapies available to treat patients with JMML, and other drug treatments have been ineffective.

The most common treatments for [patients with] JMML today are bone marrow transplants, but unfortunately, nearly 50% of those transplant recipients relapse, explained senior study author Reuben Kapur, PhD, the Frieda and Albrecht Kipp Professor of Pediatrics and Director of the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, as well as CoLeader of the Hematopoiesis and Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Chemotherapy and other medications have also been used, but their responses have not been great. We hypothesized that a combination of targeted medications could be a better option than whats available, and were thrilled our preclinical studies have shown that to be the case, he added.

Study Methods and Results

In the novel study, the researchers evaluated the efficacy of the combination of azacitidine and trametinib in a JMML model and found that it may have been capable of reducing some of the cancerous features of the disease. The researchers noted that the novel drug combination worked by decreasing the number of cancerous blood stem cells in the model and reducing the activity of the RAS/MAPK pathway.

Our research findings demonstrated the combination of two drug therapies reduced the number of cancerous stem cells and enlargement of the spleen, and improved blood cell abnormalities often seen in [patients with] JMML, explained lead study author Santhosh Kumar Pasupuleti, PhD, MSc, Assistant Research Professor of Pediatrics in the Program in Hematologic Malignancies and Stem Cell Biology at the Herman B. Wells Center for Pediatric Research at the Indiana University School of Medicine, and an associate member of Hematopoiesis & Hematologic Malignancies program at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. These results provide hope for improved therapeutic options for [patients with] JMML and highlight the potential of combination treatments in combating rare [pediatric] diseases.

Conclusions

A clinical trial funded by the National Institutes of Health (NIH) has been recently approved to further study azacitidine and trametinib combination treatment in patients with JMML whose previous lines of therapy have failed. The clinical trial will be led by Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. Dr. Stieglitz recently conducted a separate clinical trial that found trametinib to be effective but not curative on its own in patients with JMML who did not respond to regular chemotherapy.

Based on the information we learned, we will now test the combination of trametinib and azacitidine in patients with newly diagnosed JMML in the hope that the combination will be more effective than either drug alone, said costudy author Elliot Stieglitz, MD, Associate Professor of Pediatrics at the University of California, San Francisco School of Medicine. Importantly, certain lower-risk [patients with] JMML in the upcoming trial will receive this combination of targeted treatments in place of more intense treatment [with] stem cell transplantation. We anticipate this [National Institutes of Health]sponsored trial of targeted agents will decrease side effects and increase the number of patients who achieve remission compared [with] conventional treatments.

Disclosure: For full disclosures of the study authors, visit cell.com.

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Azacitidine in Combination With Trametinib May Be Effective for ... - The ASCO Post

Cell Biology

Researchers clear the way for well-rounded view of cellular defects – Phys.org

April 8, 2023 medical

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Amrinder Nain is an associate professor in the Virginia Tech Department of Mechanical Engineering, but he doesn't build cars or robots. The mechanics he champions are the tiny building blocks of life and how they behave and move.

Cellular dynamics research studies living cells and their life, death, division, and multiplication. Over the past several years, Nain has taken many journeys down the microscopic roads where cells live. His past work has analyzed how cells move and even included projects with colleagues to measure cell forces and nucleus shapes and to electrify cells and observe how they heal.

His latest collaboration investigates how cells divide, particularly in the fibrous environment of living tissue. Cells are typically studied in a flat environment, and the difference between flat and fibrous landscapes opens new windows into the behavior of cells and the diseases that impact them. The findings were published in the Proceedings of the National Academy of Sciences on Feb. 27.

Cell division, called mitosis, is essential for developmental, repair, and disease biology. A cell, at its most fundamental level, duplicates its chromosomes, which are then separated and distributed equally between two daughter cells, each with its own complete set of genetic information. As new cells perform the same function over and over, they form organs, heal wounds, and replace dead cells, sustaining the cycle of healthy tissues and organs.

But cell division doesn't always happen this smoothly. Sometimes, cells divide unevenly, or chromosomes can become unevenly split. When those misfires occur, the resulting cell will continue to duplicate copies of its faulty self, creating genetic defects that could cause widespread problems in a living body. These abnormalities account for many prenatal birth defects and can contribute to the origins of cancer.

Better understanding cellular mitosis increases our chances of diagnosing, treating, and preventing those mitotic defects. Nain's discovery puts valuable information in the hands of researchers by painting a complete picture of what's going on at the cellular level within the body's fibrous environment.

At the microscopic level, cells move by way of an extracellular matrix (ECM), a three-dimensional lattice of organic material that provides the framework for cells to form organs by underlaying a strong foundation that holds them together.

Nain's foundational research focuses on re-creating and studying that lattice, and his team's past studies on cellular motion have shown how cells travel along it. For a single fiber, a cell pulls itself along at each end, walking the fiber like a tightrope. Two fibers running parallel allow the cell to double those connections.

A dividing cell also makes use of the fibers around it. For a single fiber, each end of the cell adheres and pulls to create the division. If a cell is in an environment with multiple fibers, it will likely attach to those as well. The ECM may cross above and below the cell, providing a three-dimensional web onto which cells connect.

The number of fibers available for cells to attach to affects the timing of cell division and the types of defects a cell may produce. Cells take longer to divide on single fibers, and mitotic errors change with more attachments, creating a complex picture of the myriad ways in which a cell might fail.

This discovery affects future research because the complex view of cell division errors has not been previously investigated in fibrous environments. Schematic of a rounded cell body attached to a single fiber and held by actin retraction fiber cables (red) connecting adhesion clusters (green) with the cell cortex (blue). Credit: Amrinder Nain

"Cellular biology has predominantly been studied on a Petri dish, which is a flat, two-dimensional surface," said Nain. "Flat 2D is limited in physiological output because there are very few places in the body where the environment can be considered two-dimensional."

The team found that observing cells in the 3D environment of an ECM yielded new results beyond the capability of 2D Petri dishes. In this work, the team asked a central question: How does the shape of a cell affect its dividing behavior?

Cell shape depends on how a cell adheres to underlying substrates. For example, on a flat, two-dimensional Petri dish, a cell resembles a pancake. In a fibrous environment such as an ECM, shapes range from elongated aerofoils to kites, depending on the number of fibers and their architecture. While a cell might adhere above and below the fiber plane on suspended fibers, a flat surface causes the cell to flatten out and form connections outward. That flattening causes the cell to behave differently when it balls up and undergoes division.

As a rounded cell body divides, it's held in place by organic cables that attach the cell body, or cortex, to the fibers. On single fibers, near-perfect spherical cell bodies are held in place by two sets of cables, giving maximum freedom for the rounded cell body to move in 3D. As the number of fibers in the lattice increases, so does the number of places to which a cell can adhere. This results in multiple cable complexes that limit 3D movement of the rounded cell body.

This simple mechanical effect highlights the significant difference between the Petri dish and the ECM. On a Petri dish, monopolar spindle defects, which represent incomplete spindle pole (or centrosome) separation, do not often occur. However, when a cell is in a single-fiber environment with two cable attachment sites, monopolar spindle defects increase.

These results turn cell study quite literally on its head: In the environment of a Petri dish, some defects that occur during cellular mitosis cannot happen in the same way as they do in a living body.

"While bipolar division, the most common and error-free division mode, dominates division outcomes in fibrous environments, our work shows a switch in monopolar and multipolar defects by changing the number of fibers cells attach to," said Nain. "It offers a glimpse into how cell division might occur in actual living tissues."

Nain hopes that the fresh perspective provided by this foundational experimental-computational work will yield insights on how to treat disease and genetic disorders.

"With fiber networks, we provide more detail on a comprehensive in vivo picture, filling in some missing information and using our multi-disciplinary approach, we would like to ask some precise questions in mitotic biology as we move forward," he said.

More information: Aniket Jana et al, Mitotic outcomes and errors in fibrous environments, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2120536120

Journal information: Proceedings of the National Academy of Sciences

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Researchers clear the way for well-rounded view of cellular defects - Phys.org

Cell Biology

We were dancing around the lab cellular identity discovery has potential to impact cancer treatments – Newswise

April 8, 2023 medical

Newswise A team of scientists led by those in Trinity College Dublin has discovered new mechanisms involved in establishing cellular identity, a process that ensures the billions of different cells in our bodies do the correct job. This new discovery in stem cells a result so surprising that the team initially believed it to be an error in the lab has potential translational impacts in cancer biology and associated targeted treatments.

The research focuses on the workings of Polycomb protein complexes, PRC1 and PRC2, which are studied by Professor Adrian Bracken and his team, based in Trinitys School of Genetics and Microbiology. PhD student,Ellen Tuck, describes these proteins as strict librarians inside cells. PRC1 and PRC2 block access to certain areas of the genetic library, such that a neuron cell wont have access to muscle genes, and it doesnt get confused in its cellular identity.

A puzzle regarding PRC2 has intrigued the Bracken lab and other scientists in the field for years: two forms (PRC2.1 and PRC2.2) exist in the cell but the Bracken labpreviously showedthat the two forms of PRC2 target the same regions of DNA and do the same job. So why do we need two versions?

The new discovery from the lab takes an exciting step towards answering this conundrum, as the team found that PRC2.1 and PRC2.2 recruit different forms of the PRC1 complex to DNA, thereby finally explaining why two versions are needed.

This took us by complete surprise. We initially thought there must have been a technical issue with the experiment, but multiple replications confirmed that we had in fact stumbled upon a fascinating new process that reshapes our understanding of the hierarchical workflow of Polycomb complexes.We were dancing around the lab,saidDr Eleanor Glancy, recalling the evening the team finally realised what the data were telling them.

Successful PhD graduate of the Bracken lab, Dr Eleanor Glancy, together with Postdoctoral researcher, Dr Cheng Wang, spearheaded the work, with important collaborative support from scientists in Italy and the Netherlands. The team has published the work today in leading journal,Molecular Cell.

This research by Trinity scientists represents a massive contribution to the field of chromatin and epigenetics research and has further impact in cancer biology research as the genes encoding Polycomb proteins are frequently mutated in cancers.

Professor Brackensaid:My team currently studies the effects of these mutations in childhood brain cancers and adult lymphomas, seeking to understand what biological mechanisms go awry and how we can target these complexes with more effective treatments. A firm and comprehensive understanding of the workings of these complexes is critical to figuring out new ways to target them in cancer settings. Therefore, this work led by Dr Glancy and Dr Wang in my lab will be built upon here and by other researchers worldwide to advance our approach to many cancers.

The team worked through the COVID-19 pandemic shutdown, social distancing measures, failed hypotheses, failed experiments and tight deadlines, maintaining belief and determination, to ultimately make a significant advance in our biological knowledge.

More information about the Bracken lab and their research can be found on theirwebsite.

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We were dancing around the lab cellular identity discovery has potential to impact cancer treatments - Newswise

Cell Biology

Environmental stressors’ effect on gene expression explored in lecture – Environmental Factor Newsletter

April 8, 2023 medical

Anita Hopper, Ph.D., shared insights into how transfer ribonucleic acid (tRNA) responds to environmental stressors during the NIEHS Distinguished Lecture held March 14. The Ohio State University professor described how different tRNAs, which play a key role in protein synthesis, move around within cells and alter gene expression.

Robin Stanley, Ph.D., who leads the Nucleolar Integrity Group and holds a secondary appointment in the NIEHS Genome Integrity and Structural Biology Laboratory, hosted the lecture.

Over the years, work from the Hopper lab has beautifully established that tRNA trafficking inside the cell is bi-directional, Stanley said. Using yeast as a model system, her lab has identified the major cellular players involved and established that tRNA trafficking dynamically responds to environmental stress, leading to the regulation of gene expression.

According to Hopper, who is a member of the National Academy of Sciences, the American Association for the Advancement of Science, and member and past president of the RNA Society, researchers are still working to untangle the production, alternative functions and cell biology of tRNAs.

I am enthralled with the complexity and regulation of this molecule, Hopper said. It serves as a conduit from genome to the proteome. Any misstep in the production of tRNAs can cause a variety of diseases, both mitochondrial and neurological.

During the lecture, Hopper discussed the movement of tRNAs from a cells nucleus to cytoplasm, which is an essential step in every living organism, including humans. Although scientists knew of one cellular pathway that delivered tRNAs after transcription in the nucleus to the cytoplasm, it was not essential in all living organisms. The Hopper lab recently discovered two parallel pathways involving Mex67-Mtr2 and Crm1, respectively, through which tRNA is shuffled from nucleus to cytoplasm.

A subset of tRNAs contain introns segments of nucleic acid that interrupt the mature gene sequence. These introns need to be removed before a tRNA can function in protein synthesis. Failure to remove introns is one way that tRNA can become nonfunctional.

Cells make an enormous number of intron-containing tRNAs, Hopper explained. About 600,000 molecules of free introns are generated every cell cycle and you almost never see them. They are very efficiently turned over.

Still-attached introns are just one way that tRNA can become problematic. To synthesize proteins accurately, tRNAs must themselves form completely correctly within the cell. If not functioning properly, they misfold, decrease stability, and cause errors in decoding the genome.

Malformed tRNA occasionally move from the nucleus to cytoplasm prematurely. One of Hoppers mentees, Emily Kramer, found that retrograde movement back to the nucleus serves an important role in tRNA quality control.

One of my favorite ideas is that when they return to the nucleus, maybe they are given a second chance, Hopper said. They get their end processed and end up whole.

In addition to her research contributions, Hopper is known for her commitment to mentoring future scientists.

Throughout her career, Dr. Hopper has been an outstanding mentor and role model to budding RNA scientists both in her own lab and the larger RNA community, Stanley said. She has been an incredibly active member of the RNA Society, who honored her with the Societys Lifetime Service Award in 2009 and the Lifetime Achievement Award in 2015.

Citation: Kramer EB, Hopper AK. 2013. Retrograde transfer RNA nuclear import provides a new level of tRNA quality control in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 110(52):21042-7.

(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison.)