Seasoned industry veteran adds significant global biotech and biopharma experience to Skye’s Board of Directors Seasoned industry veteran adds significant global biotech and biopharma experience to Skye’s Board of Directors
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Skye Bioscience Appoints Dr. Karen Smith to Board of Directors
WESTLAKE VILLAGE, Calif., July 03, 2024 (GLOBE NEWSWIRE) -- Arcutis Biotherapeutics, Inc. (Nasdaq: ARQT), a commercial-stage biopharmaceutical company focused on developing meaningful innovations in immuno-dermatology, today reported the grant of an aggregate of 325,000 restricted stock units of Arcutis’ common stock as well as options to purchase an aggregate of 55,000 shares of Arcutis’ common stock to 43 newly hired employees. These awards were approved by the Compensation Committee of Arcutis’ Board of Directors and granted under the Arcutis Biotherapeutics, Inc. 2022 Inducement Plan, with a grant date of July 1, 2024, as an inducement material to the new employees entering into employment with Arcutis, in accordance with Nasdaq Listing Rule 5635(c)(4).
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Arcutis Biotherapeutics Reports Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)
Mehdi Nikkhah, an associate professor of biomedical engineering in the Ira A. Fulton Schools of Engineering at Arizona State University, and his collaborators at Mayo Clinic in Arizona have been awarded a $2.7 million grant by the National Institutes of Health to research how stem cell engineering and tissue regeneration can aid in heart attack recovery.
The research will be conducted in collaboration with Wuqiang Zhu, a cardiovascular researcher and professor of biomedical engineering at Mayo Clinic.
Nikkhah and Zhu are exploring stem cell transplantation to repair and possibly regenerate damaged myocardium, or heart tissue. Their work is focused on the development of a new class of engineered heart tissues with the use of human induced pluripotent stem cells, or hiPSCs, and has resulted in two published papers in ACS Biomaterials.
A heart attack, medically termed as a myocardial infarction, occurs when a coronary artery that sends blood and oxygen to the heart becomes obstructed. This blockage is often the result of an accumulation of fatty cholesterol-containing deposits, known as plaques, within the hearts arteries.
When these plaques rupture, a cascade of events is initiated, leading to the formation of a blood clot. These blood clots can obstruct the artery, impeding blood flow to the heart muscle, thus triggering a heart attack.
When someone has a heart attack, a portion of muscle tissue on the left ventricle, which pumps the blood throughout the whole body, is damaged, Nikkhah says. Over time, the other parts of the heart have to take on more workload, consequently leading to catastrophic heart failure.
A team of biomedical engineers in the School of Biological and Health Systems Engineering, part of the Fulton Schools, and medical researchers at Mayo Clinic in Arizona are taking a novel step forward in using stem cell technology and regenerative medicine to aid in heart attack recovery.
Nikkhah is developing engineered heart tissues, or EHTs, with electrical properties to simulate the contraction function typically found within the native hearts tissue.
He is integrating the EHTs with gold nanorods to enhance electrical conductivity among stem cells. Gold is a suitable material because it is conductive and non-toxic to human cells, making the nanorods safe for medical research and translational studies.
In the lab, Nikkhahs team mixes the gold nanorods with a biocompatible hydrogel to form a tissue construct a patch of stem cells to rejuvenate damaged cardiac muscle tissue, offering a promising outcome for heart regeneration.
After we generate the patch, we get the engineered hiPSCs from Dr. Zhus lab at Mayo Clinic, Nikkhah says. They seed the cells on the patch and look at their biological characterization, including cell proliferation, cell viability and gene expression analysis, to see how the cells respond to the conductive hydrogel.
We have successfully used hiPSC-derived cardiomyocytes and cardiac fibroblasts to create beating heart tissues, Nikkhah says. After the tissue maturation, we transfer the patch to Dr. Zhus lab to be implanted into an animal model.
The successful integration and proliferation of these cells can lead to the formation of new, healthy heart tissue, potentially reversing the damage caused by the heart attack and enhancing the recovery process.
Reprogrammed human stem cells have nearly limitless potential because they can be differentiated into various cell types. That means hiPSCs can also be used to construct capillaries and blood vessels, which are essential for restoring adequate blood flow and oxygen supply to the damaged areas of the heart.
This process involves the differentiation of hiPSCs into endothelial cells, which form the lining of blood vessels, thereby facilitating the reconstruction of the hearts vascular network.
Michelle Jang, a graduate student in Nikkhahs lab, is currently studying EHTs to improve cell maturation and observe its electrical properties.
My engagement in this project showed a deep interest in how biomedical engineering technology and biology intersect to create new therapeutic possibilities in the field of regenerative medicine, Jang says. Im excited to see how my current research will further evolve and potentially contribute valuable insights to biomedical research.
Using these techniques, Nikkhah and Zhu can observe the capacity of programmed cells to regenerate damaged heart tissue. With continued advancement in regenerative medicine, there is potential for significant positive impact on outcomes for patients suffering from heart attacks.
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Harnessing benefits of stem cells for heart regeneration - Full Circle
In remarkable parallel, the more overgrowth a BCO demonstrated, the more overgrowth was found in social regions of the profound autism childs brain and the lower the childs attention to social stimuli. These differences were clear when compared against norms of hundreds and thousands of toddlers studied by the UC San Diego Autism Center of Excellence. Whats more, BCOs from toddlers with profound autism grew too fast as well as too big.
The bigger the brain, the better isnt necessarily true, agreed Alysson Muotri, Ph.D., director of the Sanford Stem Cell Institutes Integrated Space Stem Cell Orbital Research Center at the university. Muotri and Courchesne collaborated on the study, with Muotri contributing his proprietary BCO-development protocol that he recently shared via publication in Nature Protocols, as well as his expertise in BCO measurement.
Because the most important symptoms of profound autism and mild autism are experienced in the social affective and communication domains, but to different degrees of severity, the differences in the embryonic origins of these two subtypes of autism urgently need to be understood, Courchesne said. That understanding can only come from studies like ours, which reveals the underlying neurobiological causes of their social challenges and when they begin.
One potential cause of BCO overgrowth was identified by study collaborator Mirian A.F. Hayashi, Ph.D., professor of pharmacology at the Federal University of So Paulo in Brazil, and her Ph.D. student Joo Nani. They discovered that the protein/enzyme NDEL1, which regulates growth of the embryonic brain, was reduced in BCOs of those with autism. The lower the expression, the more enlarged the BCOs grew.
Determining that NDEL1 was not functioning properly was a key discovery, Muotri said.
Courchesne, Muotri and Hayashi now hope to pinpoint additional molecular causes of brain overgrowth in autism discoveries that could lead to the development of therapies that ease social and intellectual functioning for those with the condition.
Co-authors of the study include Vani Taluja, Sanaz Nazari, Caitlin M. Aamodt, Karen Pierce, Kuaikuai Duan, Sunny Stophaeros, Linda Lopez, Cynthia Carter Barnes, Jaden Troxel, Kathleen Campbell, Tianyun Wang, Kendra Hoekzema, Evan E. Eichler, Wirla Pontes, Sandra Sanchez Sanchez, Michael V. Lombardo and Janaina S. de Souza.
Funding: This work was supported by grants from the National Institute of Deafness and Communication Disorders, the National Institutes of Health, the California Institute for Regenerative Medicine and the Hartwell Foundation. We thank the parents of the toddlers in San Diego whose stem cells were reprogrammed to BCOs.
Disclosures: Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis and human brain organogenesis, focusing on therapeutic applications customized for autism spectrum disorders and other neurological disorders origin genetics. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. Eichler is a scientific advisory board member of Variant Bio, Inc. The other authors have no conflicts of interest to declare.
The UCSD Autism Center of Excellence is a world leader in autism research. It has made pioneering discoveries that enable early detection and treatment of autism in infants and toddlers through innovative behavior and eye tracking tests. The Centers groundbreaking discoveries on the developmental neurobiology of autism have led to fundamental knowledge of the molecular, cellular, and brain growth and function causes of autism.
The Sanford Stem Cell Institute (SSCI) is a global leader in regenerative medicine and a hub for stem cell science and innovation in space. SSCI aims to catalyze critical basic research discoveries, translational advances and clinical progress terrestrially and in space to develop and deliver novel therapeutics to patients. The SSCI is directed by Catriona Jamieson, M.D., Ph.D., a leading physician-scientist in cancer stem cell biology whose research explores the fundamental question of how space alters cancer progression.
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Embryonic Brain Overgrowth Dictates Autism Severity, New Research Suggests - University of California San Diego
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A safer regenerative medicine process that removes the risk of tumor formation.
Credit: Atsushi Intoh
Ikoma, Japan Pluripotent stem cells (PSCs) are a type of stem cells capable of developing into various cell types. Over the past few decades, scientists have been working towards the development of therapies using PSCs. Thanks to their unique ability to self-renew and differentiate (mature) into virtually any given type of tissue, PSCs could be used to repair organs that have been irreversibly damaged by age, trauma, or disease.
However, despite extensive efforts, regenerative therapies involving PSCs still have many hurdles to overcome. One being the formation of tumors (via the process of tumorigenesis) after the transplantation of PSCs. Once the PSCs differentiate into a specific type for stem cell therapy, there is a high probability of tumor formation after differentiated stem cells are introduced to the target organ. For the success of PSC-based therapies, the need of the hour is to minimize the risk of tumorigenesis by identifying potentially problematic cells in cultures, prior to transplantation.
Against this backdrop, a research team led by Atsushi Intoh and Akira Kurisaki from Nara Institute of Science and Technology, Japan, has recently achieved a breakthrough discovery regarding stem cell therapy and tumorigenesis. Our findings present advancements that could bridge the gap between stem cell research and clinical application, says Intoh, talking about the potential of their findings. Their study was published in Stem Cells Translational Medicine and focuses on a membrane protein called EPHA2, which was previously found to be elevated in PSCs prior to differentiation by the team.
Through several experiments involving both mouse and human stem cell cultures, the researchers gained insights into the role of EPHA2 in preserving the potency of PSCs to develop into several cell types. They found that EPHA2 in stem cells is co-expressed with OCT4a transcription factor protein which controls the expression of genes which are critically involved in the differentiation of embryonic stem cells. Interestingly, when the EPHA2 gene was knocked down from the cells, cultured stem cells spontaneously differentiated. These results suggest that EPHA2 plays a central role in keeping stem cells in an undifferentiated state.
The researchers thus theorized that EPHA2-expressing stem cells, which would fail to differentiate, might be responsible for tumorigenesis upon transplantation into the target organ.
To test this hypothesis, the researchers prepared PSC cultures and artificially induced their differentiation into liver cells. Using a magnetic antibody targeting EPHA2, they extracted EPHA2-positive cells from a group of cultures prior to transplantation into mice. Interestingly, the formation of tumors in mice receiving transplants from cultures from which EPHA2 had been removed was vastly suppressed.
Taken together, these results point to the importance of EPHA2 in emerging stem cell-based therapies. EPHA2 conclusively emerges as a potential marker for selecting undifferentiated stem cells, providing a valuable method to decrease tumorigenesis risks after stem cell transplantation in regenerative treatments, remarks Kurisaki.
Further in-depth studies on this protein may lead to the development of protocols that make PSCs safer to use. Luckily, however, these findings pave the way towards a future where we will be able to finally restore damaged organs and even overcome degenerative conditions.
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Resource
Title: EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells.
Authors: Atsushi Intoh, Kanako Watanabe-Susaki, Taku Kato, Hibiki Kiritani, Akira Kurisaki
Journal: Stem Cells Translational Medicine
DOI: 10.1093/stcltm/szae036
Information about Laboratory for Stem Cell Technologies can be found at the following website: https://bsw3.naist.jp/eng/courses/courses215.html
About Nara Institute of Science and Technology (NAIST)
Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow's leaders in science and technology.
Stem Cells Translational Medicine
Experimental study
Animals
EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
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Tackling the hurdle of tumor formation in stem cell therapies - EurekAlert
A stem cell-based therapy for Parkinson's disease entered higher dose clinical testing after a positive initial safety evaluation.
STEM-PD uses human pluripotent stem cells that have been programmed to develop into dopamine nerve cells, which produce a chemical called dopamine that helps to control body movement. The stem cells are then transplanted into the brains of Parkinson's disease patients to replace cells that are lost during the course of the disease and to repair the damage caused. Current drugs, such as levodopa, only temporarily replace dopamine, but do not target the underlying disease.
'The vision is that it could be given as a one-time treatment and the hope is that the patients can reduce their medication, avoid side effects of the drug treatment and get a long-term good motor effect from the cells for life," Dr Gesine Paul-Visse, principal investigator from Lund University and Skne University Hospital, both in Sweden, said.
The method of growing transplantable dopamine cells from stem cells was initially developed by scientists at Lund University. The trial is now a collaboration between Lund University, Skne University Hospital, the University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, and Imperial College London.
The human pluripotent stem cells used for generating the STEM-PD product are obtained from human embryonic stem cells, grown in the laboratory from a surplus embryo from IVF. The cells are then transplanted into a specific area of the patient's brain that is involved in motor control. After a few months, they start sending out nerve fibres and producing dopamine.
STEM-PD has already been shown to be safe and effective at reverting motor deficits in animal models of Parkinson's disease, and entered a first-in-human clinical trial in February 2023 at Skne University Hospital (see BioNews 1164).
An initial four patients were injected with a lower dose of seven million cells, with the team reporting no concerning side effects from the therapy. Furthermore, imaging of the patient brains 6-12 months' post transplantation showed signs of dopamine cell survival. Yet, the team cautions that it is still too early to evaluate the clinical effects of the transplanted stem cells.
The first patient to receive the stem cell therapy a year ago, Thomas Matsson, was diagnosed with Parkinson's disease when he was 42. He can now move freely again and has regained his sense of smell: 'I've reduced my medication for Parkinson's. Before, everything was slow and everything was difficult I do long-distance skating, slalom, cross-country skiing, padel tennis, and, above all, golf,' he said.
Now, a further patient has been injected with a higher dose of 14 million cells, with a further three patients to be treated in 2024. The primary objective of this trial is to assess the safety and tolerability of the therapy after one year, however, the patients will be monitored for three years with a secondary objective to evaluate the clinical efficacy of the therapy.
'There is absolutely hope. Absolutely there is!', added Dr Paul-Visse.
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Stem cell therapy success in early trial to treat Parkinson's disease | PET - BioNews
In the early stages of human embryonic development, a zygote divides into two identical totipotent cells that eventually become eight cells.1 Cell fate decisions begin to differentiate this totipotent population into specific lineages, giving rise to the blastocyst.2 At least, this has been the working model. Now, a new study published in Cell suggests this may not be the full story.3
They are not identical, said Magdalena Zernicka-Goetz, a developmental and stem cell biologist at the California Institute of Technology and the University of Cambridge and study coauthor. Only one of the two cells is truly totipotent, meaning it can give rise to body and placenta, and the second cell gives rise mainly to placenta. The findings help elucidate what happens during the earliest periods in development.
I was always interested in how cells decide their fate, Zernicka-Goetz said. In the mouse developing embryo, she previously demonstrated a bias at the two-cell stage: one cell contributed more to fetal tissue and the other to the placenta.4
We know so little about the very early stages of human development, said Nicolas Plachta, a developmental biologist at the University of Pennsylvania who was not involved with the study.
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To understand this process better, Zernicka-Goetz set out to investigate if human embryonic development resembled that of mice. She and her team first tracked cell lineage from the two-cell stage; they injected mRNA for green fluorescent protein (GFP) fused to a membrane trafficking sequence into one of the two cells of the zygote. Thus, they could determine the contribution of each cell to the development of two early structures: the trophectoderm (TE) that becomes the placenta and the inner cell mass (ICM) that eventually produces the epiblast, or fetal tissue, and the hypoblast, or the yolk sac.
When they tracked GFP expression, the team found that one population of cells dominated in either the ICM or the TE, but that this imbalance was greatest in the ICM. Within the ICM, progeny from one clone at the two-cell stage dominated the population of the epiblast, while the composition of the hypoblast was split between cells of the two originating clones. This means that at the two-cell stage we have a cell fate bias of these two cells, but it's not a deterministic process, said Zernicka-Goetz.
To further investigate the cell contribution to the ICM, the researchers labeled DNA and actin and, starting at the eight-cell stage, tracked cellular positions after division using live cell imaging. Asymmetric cell divisions (ACD) involve cells that intrude into the growing cell mass rather than remain on the surface, and these interior cells contribute to the ICM. The team observed that while ACD were less common overall, their composition resembled that of the ICM.
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In mice, the two-cell stage clone that contributed more to the ICM divided faster than the second cell, so the team studied whether or not this pattern applied to human embryonic development.5 The team studied movies of actively dividing embryos and determined that in most of the embryos, one cell at the two-cell stage divided faster, and its progeny also inherited this feature. The team also noticed that the first cell to undergo ACD was one of these fast-dividing cells.
This is the first study to do some nice cell tracking in a human embryo at those early stages, said Platcha. However, he noted that the inherent variability in human embryos compared to established mouse models makes it difficult to draw conclusions in this research area. This is further complicated by the limited number of zygotes available for research because clinics typically preserve embryos at later developmental stages.
Next, Zernicka-Goetz aims to investigate the features and origins of the differences between clones at the two-cell stage.
Zernicka-Goetzs workwas nominated throughThe ScientistsPeer Profile Program submissions.
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The First Two Cells in a Human Embryo Contribute Disproportionately to Fetal Development - The Scientist
Though over 8 million babies have been born through in vitro fertilization (IVF), 70 percent of IVF implantations fail. As IVF is becoming a more common route to pregnancy in cases of infertility, there is a need for better understanding of embryonic development at this early stage.
Researchers in the laboratory of Caltech's Magdalena Zernicka-Goetz, Bren Professor of Biology and Biological Engineering, study the biological processes underlying the earliest days of human development. Now, a new study from the Zernicka-Goetz lab demonstrates that when human embryos are composed of two cells, at just 1 day old, only one of these cells will create most of the fetal body cells in addition to placental cells, while the other will only create placental cells. The research changes the long-standing paradigm that the two cells at this stage both contribute equally to all parts of the developing embryo, suggesting that "specification"the phenomenon of cells having specific individual roleshappens much earlier in development than previously believed.
The findings have implications for how embryos intended for IVF implantation are assessed for abnormalities.
"Often, in an IVF clinic, a few placental cells from the outside of the 6-day-old embryo will be selected for a genetic diagnosis to determine if they have chromosomal abnormalities," says Zernicka-Goetz. "Our results show that, by extrapolation, those outside cells chosen are unlikely to be contributing to the fetal body. The genetic information from those cells may not be as informative as sampling the fetal cells themselves."
A paper describing the research appears on May 13 in the journal Cell.
The 1-day-old human embryo is composed of just two cells, each called a blastomere. Using embryos donated for research by IVF clinics, the team labeled blastomeres with a colored dye, then used time-lapse imaging to watch as the cells divided over the course of six days. New cells carried the same color dye as their parent cell. Through this process, the team determined that fetal body cells exclusively originated from a single blastomere, while placental cells came from both.
"In addition to being valuable information for improving IVF, our study is part of a large body of research into evolutionary processes within the body," says postdoctoral scholar Sergi Junyent, a co-first author on the new paper. "Studying how different cell lineages populate from original cells has implications for understanding what happens after mutations, how they lead to cancer, and so on."
The paper is titled "The first two blastomeres contribute unequally to the human embryo." Caltech's Junyent and Maciej Meglicki of the University of Cambridge are co-first authors. Additional Caltech co-authors are undergraduate Ekta M. Patel, scientific assistant Clare Reynell, and postdoctoral scholar Dong-Yuan Chen. Other co-authors are Catherine King and Lisa Iwamoto-Stohl of the University of Cambridge; Roman Vetter and Dagmar Iber of ETH Zurich and the Swiss Institute of Bioinformatics; Rachel Mandelbaum, Patrizia Rubino, and Richard J. Paulson of USC; and Nabil Arrach of Progenesis Inc. Funding was provided by the Human Frontier Science Program, NOMIS Foundation, Wellcome Trust, Open Philanthropy Project, and Curci and Weston Heavens Foundations. Magdalena Zernicka-Goetz is an affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.
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Fetal Cells Can Be Traced Back to the First Day of Embryonic Development - Caltech
Fifty-four years ago, I did something extraordinary. I built myself. I was a single, round cell with not the slightest hint of my final form. Yet the shape of my body now the same body is dazzlingly complex. I am comprised of trillions of cells. And hundreds of different kinds of cells; I have brain cells, muscle cells, kidney cells. I have hair follicles, though tragically few still decorate my head.
But there was a time when I was just one cell. And so were you. And so were my cats, Samson and Big Mitch. That salmon I had for dinner last night and the last mosquito that bit you also started as a single cell. So did Tyrannosaurus rex and so do California redwoods. No matter how simple or complex, every organism starts as a single cell. And from that humble origin emerges what Charles Darwin called endless forms most beautiful.
Once youve come to terms with that mind-boggling fact, consider this: all organisms, including humans, build themselves. Our construction proceeds with no architects, no contractors, no builders; it is our own cells that build our bodies. Watching an embryo, then, is rather like watching a pile of bricks somehow make themselves into a house, to paraphrase the biologist Jamie Davies in Life Unfolding (2014).
This process of body sculpting is called embryonic development, and it is a symphony of cells and tissues conducted by genetics, biochemistry and mechanics. People who study this, like me, are called developmental biologists. And while you may not know it, our field is in a period of tremendous excitement, but also upheaval.
In the summer of 2022, I sat in the back of a lecture hall in Santa Cruz, California listening to a lecture from Magdalena ernicka-Goetz, professor of mammalian development and stem cell biology at the University of Cambridge, UK. She is a controversial figure and one of many scientists trying to push the limits of understanding human embryos. I heard, too, from Ruth Lehmann, director of MITs prestigious Whitehead Institute for Biomedical Research. Shed been in the news for firing a famous scientist for sexual harassment, but whats made her an international leader in biology for decades is her brilliant and creative study of developmental biology, in fruit flies.
This juxtaposition of fly and human embryos wasnt surprising; developmental biology is propelled by a whole zoo of embryos fruit flies, yes, but also sea urchins, worms, frogs, mice. Indeed, our great triumph in the 20th century was revealing the astonishing molecular similarity of all embryos; and, for precisely that reason, studies of animal embryos have garnered seven Nobel Prizes in the past 30 years alone. What surprised me in Santa Cruz was just how fast our collective understanding of animal embryos is making possible truly explosive advances in human embryology. So, while Lehmanns fascinating new work on cell migration in fly embryos kept the audience rapt, it was ernicka-Goetz who caught the medias attention.
Developmental biology is something society needs to understand. And dont we want to?
Together with Jacob Hannas lab in Israel, ernicka-Goetz was building what scientists call embryo models. These biological entities look a lot like embryos; they start as relatively few cells and few cell types, and they grow and elaborate over time. But theyre not made in the usual way. Eschewing both egg and sperm, embryo models are created by manipulating embryonic stem cells. Perhaps best known to the public for their promised miracle cures or as proxies for abortion debates, these cells display a remarkable power. They can be made to differentiate into essentially any cell type in the body. Now, it seems, we might even use them to make embryos.
When Hanna and ernicka-Goetz each published their findings after the meeting in Santa Cruz, The Washington Post wrote that the advances put the possibility of a complete human synthetic embryo on the horizon. That nomenclature was unfortunate, as these arent synthetic at all, but rather entirely biological. (Thats why scientists prefer the term embryo models.) But they were spot on about the implications. And about the timing: reports of embryo models made from human stem cells hit newspapers exactly a year later, in the summer of 2023.
This is no incremental change and, despite the flawed press narrative, ernicka-Goetz and Hanna arent the only or even the most important players in the game. Other influential biologists are making huge strides too, though their names arent often in the press. Some have even argued that the new advances challenge the current legal definitions of the embryo, which prompts the question: how should we define an embryo? And what do we do when, as they certainly will, scientists definitions differ from the general publics? As embryo models become more sophisticated, how will we know when that clump of tissue in the dish becomes an embryo?
Ive studied embryos for more than 30 years, and while it doesnt often catch the publics attention, developmental biology is something society needs to understand. And dont we want to? Isnt it just another way of framing that ancient and universal question: How did I get here?
Human contemplation of embryonic development is nearly as old as writing. In the Old Testament story, Job asks of God: Didst thou not pour me out like milk and curdle me like cheese? Half a world away, the Buddha uses the same dairy-based metaphor in the Garbhavakrantisutra, a 1st-century scripture. Some of the earliest cultures in Southern Mexico left no writing, but they made statues of human fetuses. Anywhere you go in the ancient world, you find embryos.
In ancient Greece, as light began to show in the cracks that separate religion, philosophy and science, a remarkable treatise appeared. To modern eyes, On the Nature of the Child attributed to Hippocrates is bent on explaining human development, though it does so largely by describing the development of a hens egg. Actually, not an egg but 20 eggs, each of which the author exhorts us to open on successive days, so we can observe development over time: You will find everything as I say in so far as a bird can resemble a man.
Aristotle rejected preformation, and argued instead for a progressive development
That ancient appreciation of time is critical, for it frames the first key question in the history of developmental biology: does an embryo acquire its complexity piece by piece, somehow progressively assembling itself? Or is that new organism already present in the egg or sperm, preformed, as it were, and needing only to be spurred somehow to grow? Some readers will be familiar with the iconic image of preformation a tiny human curled up inside a sperm. Its late-17th-century printing underscores just how long we struggled to resolve these two poles of thought, progressive versus preformed.
Aristotle himself was the first to weigh in. Consulting farmers and fishermen with the same enthusiasm with which he debated scholars, the philosopher described everything from the live births of dolphins to the size of elephant embryos. He compared the embryos of chickens, fish, insects and, yes, humans. He rejected preformation: our senses tell us plainly that this does not happen. He argued instead for a progressive development, and while it took 2,000 years to resolve, he was exactly right.
Just how this progression happens remains the core question of developmental biology. And as we begin to explore the truly uncharted morality of embryo models and their progressive development, what strikes me most about the concept is how neatly it parallels ancient thoughts about inchoate humanity.
In the modern debate over abortion, the doctrine that life begins at conception is now so constantly repeated that its often assumed to have an ancient, perhaps even scriptural origin. It does not.
In fact, in Catholic canon law, the doctrine dates precisely to 12 October 1869, when Pope Pius IX declared excommunication as the penalty for anyone involved in obtaining any abortion. For the nearly 2,000 years that had gone before, however, many Christian thinkers held the embryo to acquire its humanity only gradually. This concept, linked to the animation or ensoulment of the embryo, arose in laws first set down more than 3,000 years ago that imposed increasingly harsher penalties for causing the loss of a pregnancy as it progressed.
The idea was widely, if not uniformly, adopted by early Christian jurists. St Augustine held this view; St Basil was opposed. None wielded greater influence than St Thomas Aquinas, whose 13th-century rendering of Aristotles progressive acquisition of humanity in utero became a prominent, perhaps dominant concept in Western Christianity. It surfaced everywhere from Dantes poetry to Celtic law for 500 years.
The embryos of scientists are not the embryos of the public, or the Church
Of course, saints werent the only ones thinking about embryos. Leonardo da Vinci drew several in the 16th century, one now famous for its inaccuracy. When the modern university was being developed in a 16th-century Italy roiled by Protestant Reformation and Catholic Counter-Reformation, scholars on both sides cracked open chicken eggs to study embryos. A century later, a less divided group (all Royalists in the English civil wars) still hotly debated the chick embryo. And when modern science began to emerge in the 17th century, its founding figures had more than a passing interest in the embryo.
By the 19th century, the new scientists had reached consensus. The concept of progressive embryonic development of animal embryos was established once and for all. But then as now, the embryos of scientists are not the embryos of the public, or the Church. In an odd synchronicity, science and Church staked out opposite views at essentially the same time.
A mere 23 days separated Pope Piuss decision and an important lecture by the embryologist Wilhelm His. Propounding a new vision for understanding progressive development of the embryo, His would go on to publish The Form of Our Body and the Physiological Problem of Its Development (1874). It was despite the possessive in the title a thoroughgoing discussion of chicken embryos. But His said exactly what he meant. Soon after, he would combine lessons learned from chickens with a network of physicians, and become the first to comprehensively define, cogently describe, and accurately display the progressive development of human embryos.
Selections from the normal table of human development: the embryologist Wilhelm His et al produced the scientific conception of the human embryo in the 1870s using careful staging and illustration. From Anatomie menschlicher Embryonen (1880-85). Courtesy the Wellcome Library
As the Cambridge historian Nick Hopwood put it, His and others produced the very concept of the embryo as we know it. And, while embryos certainly exist as tangible, biological entities, this concept is so central to the work of developmental biologists that we rarely notice it. Were also slow to consider how others in society relate to it. And thats important, because, in the 20th century, the concept of the embryo changed radically yet again.
By the time the famous double helix structure of DNA was discovered in the early 1950s, fruit flies like Lehmanns had taught us that genes direct the inheritance of traits from one generation to the next; sea urchins showed us that genes reside on chromosomes in the cell nucleus; and bacteria and viruses revealed that genes were made of DNA. But the relationship between our genes and our development was still mostly a black box. When we first peeked in, it wasnt through the ascendant disciplines of genetics and biochemistry, but a more hands-on approach: transplantation. Not of organs, but of cellular bits.
In Nobel Prize-winning work, the British developmental biologist John Gurdon showed that if he destroyed the gene-containing nucleus of a one-cell frog embryo, normal development could be restored by transplanting the nucleus of some other cell. Fascinatingly, any cell nucleus might do the job, suggesting the tools needed to guide development of an entire organism are present in each and every one of its cells.
But there was a catch. Donor nuclei from early embryonic cells were far better at restoring development than those taken from later embryos. Such decreasing potency over time was a crucial revelation for understanding progressive development. The concept has its apotheosis in the British developmental biologist Conrad Waddingtons landscape, an iconic image depicting an early embryonic cell as a marble set to roll down a branching network of increasingly deep valleys. At the top, the marble might still roll into any number of valleys, but its inventory of potential shrinks with its descent. It cant roll back uphill.
Waddingtons landscape: in the iconic metaphor for progressive development, the marble represents a cell in an embryo; as the embryo develops, the cell rolls downhill. At the first decision point, the cell might choose one of two valleys, thus becoming one of two very general cell types, for example mesoderm or ectoderm. At the next branch, the cell will become one of two very specific cell types, and so on. From The Strategy of the Genes by C H Waddington (1957) George Allen & Unwin (London)
If the marble rolls down the valley biologists call mesoderm, it might roll further into clefts such as muscle or blood. But its cut off from the valleys of skin and brain, what we call ectoderm. Becoming an embryo, then, is the collective navigation of an ever-branching decision-tree by a constantly multiplying population of cells. So its tempting to think that some notion of sufficient complexity, a far-enough journey down the valleys, might help us divine precisely when its an embryo, and when its a human.
Edwards had studied the possibility of IVF in mice, then sheep, cows, pigs, monkeys
But, again, theres a catch. While most cells in the early embryo rush down the valleys, a privileged few will linger at the top of the landscape. Described first in rabbits by Waddingtons own pupil at the University of Edinburgh, Robert Edwards, we now call these embryonic stem cells, and by the turn of the 21st century they were as much a part of politics as of biology. But when first described in the early 1960s, neither Edwards nor anyone else capitalised on their potential. And, anyway, Edwards was busy with another project. The era of test-tube babies was upon us.
Late in 1977, Edwards wrote a note to one of his patients, Lesley Brown: [Y]ou might be in early pregnancy. So please take things quietly no skiing. Some weeks earlier, shed had one of her eggs laparoscopically inserted into her uterus; it had been fertilised in vitro with her husband Johns sperm. In 1978, Louise Brown, the first child conceived by IVF, was born.
The feat capped more than a decade of hard work. Edwards had studied the possibility of IVF in mice, then sheep, cows, pigs, monkeys. Eventually, human oocytes removed in a hospital in Oldham made the four-hour journey to Edwards lab in Cambridge. And, there, he was the first to glimpse the moment when the Church says life begins. Coming precisely a century after Pius IXs decision, his co-authored 1969 paper describing human fertilisation for the first time had been a watershed moment in the 3,000-year history of embryology. But it was also, well, just developmental biology: Penetration of spermatozoa into the perivitelline space was first seen in eggs examined 7-7.25 h after insemination.
The human embryo had become one of the scientists embryos and, in another remarkable synchronicity, the very same embryo had also exploded into the public consciousness. Not in a scientific journal, but in a glossy magazine.
The cover of Life magazine from 30 April 1965 is a startling artefact, filled by a colour photo of an 18-week human fetus. The essay inside produced the concept of human embryos for the public just as His did for scientists during the previous century. Read by millions, it forever changed our idea of what a living, developing, growing human embryo looks like. But it was just that, an idea. In reality, the fetus on the cover of Life magazine was dead.
Drama of life before birth: cover of Life magazine, 30 April 1965. Courtesy Photo12/Getty
The essay was filled with similarly lifelike photos, all but one of which actually show dead or dying embryos and fetuses, the results of either miscarriage or termination. This fact was ignored by anti-abortion activists who made these images ubiquitous; it suited their needs. Depicting these surgically removed embryos as somehow both alive and autonomous made it easy to ignore the mother, whose adult body is so essential for the embryos growth and development, and who is so at risk. Volumes have now been written about these images and their role in the US abortion debate.
Just 77 seconds of airtime for the entire essence of development as science knows it
But what strikes the developmental biologist in me is just how accurately the essay conveyed progressive human development. We see the fertilised egg, and we follow the changes of the largely unformed embryo at three, four, and six weeks. Only at eight weeks do we finally see its gradual transition to the more obviously human fetus.
Sadly, this narrative was lost when the images were packaged into a documentary film in 1982. Influenced perhaps by Louise Browns birth and that of the modern fertility industry The Miracle of Life runs for an hour, yet the first 41 minutes show only egg or sperm. Mostly sperm. By 48 minutes, weve seen fertilisation, but the embryo is still just a round clump, perhaps eight cells. Its only at 48:33 that we catch our first glimpse of the real action of development, the progressive emergence of form. And by 49:50, its all over. Suddenly, there are tiny fingers, eyes looking right at us. Just 77 seconds of airtime for the entire essence of development as science knows it. Shown on the BBC, PBS and outlets around the world, the award-winning documentary easily eclipsed the Life essay. The public human embryo had truly arrived and, besides a few seconds of embryonic development shown on fast-forward, it was a fully developed fetus.
Not long after, the joyful presentations of sonograms, with their beating heart or their shadow of a face, became a core ritual of pregnancy. But these very public fetuses are wildly at odds with the biological reality of embryos, the majority of which abort spontaneously at an early stage; this led an academic theologian to muse that, if life began at fertilisation, then it would appear that heaven is mostly populated by them [embryos] rather than by people who had actually been born.
Over a scant two decades, what we now call the human embryo went from a largely intangible entity to something scientists could routinely manipulate and the public thought they understood. As the 1980s dawned, august bodies of scientists, religious leaders, lawyers and philosophers unanimously settled on a progressive view of development.
They concluded that human embryos should be kept alive in vitro only for the most important, highly regulated reproductive or research purposes. Moreover, they must be kept alive only for 14 days. This time point, chosen on the advice of a developmental biologist, was at once appropriate and arbitrary. On the one hand, it marks the onset of a process called gastrulation, by which the embryo leaves behind its early ball-like form and begins to build an elongate body. Its also the last point at which twinning can occur, and so makes the embryo truly singular and unique. But gastrulation takes some time and embryos are variable. Only a true expert could glean the distinction between embryos at 13, 14 and 15 days. Yet, as any lawyer will tell you, laws (and even guidelines) must be specific to be meaningful, and The 14-Day Rule was both.
Their genesis in unused embryos of IVF patients and therapeutic terminations sparked a culture war
Those were exciting times for animal embryology too, given the Nobel Prize-winning work of Christiane Nsslein-Volhard, Eric Wieschaus and Edward Lewis. They showed that the entire zoo of animals wed studied for decades, centuries, even millennia all use a shockingly similar genetic toolkit to guide development. When chick embryos were first compared with humans in ancient Greece, it was exactly right.
A single genetic toolkit for development: flies with mutations in what scientists call homeobox genes display duplicated wings (above photo courtesy Nicolas Gompel). Mice with mutations in these genes display duplicated ribs (below, Daniel C McIntyre et al, Development [2007])
Around the same time, the biologist Gail Martin at the University of California, San Francisco made good on Edwardss abandoned project. Coining the term embryonic stem cells, she and her colleagues learned how to get these cells from mice, keep them alive in culture dishes, and make them differentiate into cartilage or even neuron-like cells. When the same was done with human embryonic stem cells in 1998, their genesis in unused embryos of IVF patients and therapeutic terminations sparked a culture war. But neither politics nor the resulting welter of regulations dented enthusiasm for their tremendous promise both real and as imagined by charlatans.
By tinkering with the genetic toolkit that developmental biologists discovered in animal embryos, the new stem cell scientists coaxed their wards down Waddington valleys of their choosing. Their arcane recipes recall ancient alchemy, but the ecosystems they conjured in little plastic dishes were entirely real. First, they made single human cell types, neurons, muscle, blood. Not long after, they devised functional, three-dimensional tissues, first eyes in a dish, then miniguts and minibrains, an array we collectively call organoids.
It was only a matter of time before the idea arose that we might construct whole embryos out of stem cells. Guided by a desire to understand human development (and in some cases, surely, by at least a little hubris), progress came with unnerving speed.
At the 2022 meeting on developmental biology in Santa Cruz, I was giddy, mesmerised by the confluence of developmental and stem cell biology. Lehmanns lecture on flies and my own about frogs joined others about fish and worms. There was even a lecture about jerboas, a strange hopping rodent from Mongolia. One talk really blew my mind: unable to study rhinoceros embryos, for obvious reasons, one group has convinced their stem cells to make rhino embryo models of a sort.
My joy, however, soon bled into dismay when The Washington Post, describing the mouse embryo models developed by Hanna and by ernicka-Goetz, noted rightly that human models were all but inevitable. Given that years of debate went into the 14-Day Rule in the 1980s, we might have expected that move to be cautious and deliberate. It wasnt. At a conference in Boston in June 2023, ernicka-Goetz claimed that we can create human embryo-like models by the reprogramming of [embryonic stem] cells, a statement The Guardian blasted out to the public the following day without any back-up from the peer review. Once the peer-reviewed paper appeared, it became clear that ernicka-Goetzs initial claim had been overstated. Hannas group reported more impressive human embryo models soon after, but these couldnt justify the media commentary either.
The work, while vetted and approved by the appropriate ethics committees, is a far cry from helping us frame the ethical considerations these embryo models will raise. Indeed, while the current embryo models cannot develop into a viable fetus, it sure looks like we will get to that point. And it doesnt help that the International Society for Stem Cell Research in 2021 relaxed the 14-Day Rule for research with human embryos made the old-fashioned way. Unlike the careful deliberation with stakeholders in the 1980s, the new decision was reached without public engagement. I think the entire field is obligated to bring more people into the conversation and to better articulate why the work is necessary why, in fact, we must make human embryos from scratch.
This science has always been a proxy, however imperfect, for understanding how our own bodies come to be
Its troubling, too, that the scientists getting the most attention dont always use their cachet to communicate the nuance, both ethical and biological. Instead, its left to others. Alfonso Martinez Arias, Nicolas Rivron and Kathy Niakan, for example, are among those who have provided thoughtful commentary on the complexities in scientific journals. And, while ernicka-Goetz in June 2023 told The New York Times that we do it to save lives, not create it, the medical applications are not at all clear to me. Exactly how will these models save lives? And exactly how do they compare with alternative solutions to the problem? Without such details, how can we weigh whats to be gained against our ethical and moral obligations?
By contrast, the decades of research with old-fashioned human embryos, all conducted within the confines of the 14-Day Rule, brought us a remarkably safe and effective fertility industry, as well as important advances in genetic diagnosis and prevention of diseases and birth defects. These advances continue, with benefits that are clear.
Weve pondered embryos for thousands of years, in part because they spark our inherent wonder; theirs is the ultimate emergent property. Across that long arc, its usually been animal embryos under our microscopes, organisms that assemble themselves just like we do but whose development we have fewer qualms about interrupting for the sake of knowledge. Like any basic science, animal embryos provide a glimpse of what is possible in this world, Lehmann writes. But this science has always been a proxy, however imperfect, for understanding how our own bodies come to be. And, quite suddenly now, we seem to have the tools and the appetite to get far more than just a glimpse at the human embryo.
Martinez Arias recently told me that when you put the word human there, you are talking to the whole of society. Its worth recalling, then, that this conversation is also thousands of years old. And history tells us that our collective decisions on issues of the human embryo will ultimately be influenced by both science and faith.
Science can tell us how the human embryo develops, and it is an undisputed certainty that embryos develop progressively, building complexity and identity only over time. But there is no scientific consensus on when during that progression life begins. Likewise, there is no consensus among faiths on when life begins. Certain Christian faiths now hold that life begins at conception, and these have an outsized influence. Yet, even within Christianity, that view is a recent stance, and one that reversed centuries of thought. Other Western religious traditions dont share Christianitys ambiguity. Cleaving to the ancient gradualist view of development, Islamic tradition generally holds the embryo to become human 120 days after fertilisation, though some use the 40-day mark; in most Jewish traditions, it happens only at birth.
We are 3,000 years deep in the adventure called developmental biology, yet the embryo remains in many ways just as mysterious as ever. As we enter a new era of explicitly human developmental biology, we should approach it with all the grace and humility we possibly can.
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After 3,000 years of science, the embryo is very different - Aeon
Embryonic stem cells that play a critical role in determining our facial features during development can be hindered from growing when placed under increased pressure.
An international team of researchers took a look at the growth of mouse and frog embryos, as well as human embryoids (clusters of embryonic cells developed in the lab) to better understand how some cells tell others how to grow and differentiate.
They noticed that when an increase in hydrostatic pressure was applied externally to the embryo or embryoid, important cell signaling pathways in neural crest cells were disrupted.
The findings imply tissue development could be affected at crucial moments in an animal's development, placing them at risk of craniofacial malformations. These abnormalities are thought to be caused by a mix of genetic and environmental factors, including nutrient supply.
"Our findings suggest that facial malformations could be influenced not only by genetics but by physical cues in the womb such as pressure," says neurobiologist Roberto Mayor from University College London (UCL).
In what's known as embryonic induction, cells are sent along different biological paths during development by chemical signals from other nearby tissues. Scientists know about some, but not all, of the triggers that determine how stem cells interpret these cues.
In particular, the analysis looked at a fluid-filled cavity called the blastocoel, close to where the neural crest develops. Pressure on the blastocoel was shown to decrease the activity of a protein called Yap, which in turn impairs a group of signaling molecules known as Wnt, which are responsible for telling the neural crest how to develop.
While the study didn't investigate the causes of increased pressures inside the human uterus, the findings provide insight into mechanical influences on the embryo where most studies tend to focus on the influence of biochemical factors instead.
"When an organism is experiencing a change in pressure, all the cells including the embryo inside the mother are able to sense it," says Mayor.
The research gives scientists an important step forward in their understanding of how humans (and other vertebrates) form, right down to the individual molecules and signals involved in the earliest stages of development.
While it's clear pressure can cause neural crest signaling to become less efficient, it remains to be seen how particular changes in the uterine environment might give rise to specific outcomes in a developing human child.
"Our work shows that embryos are sensitive to pressure, but we do not know how sensitive they are," says Mayor. "For instance, will a change in the pressure inside the uterus be able to affect the embryo?"
"This will require further research to understand how changes inside the body as well as in environmental pressure might influence human embryo development."
The research has been published in Nature Cell Biology.
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Your Face May Have Been Shaped by Pressure in The Womb, Study Finds - ScienceAlert