NODAL

Formation of the body axes is a critical part of embryonic development. They guarantee that all body parts end up where they belong and that no ears grow on our backs. The head-tail axis, for example, determines the orientation of the two ends of the body. It was previously assumed that this axis is largely determined by the interplay between the Nodal and BMP signals. However, there appears to be another player in this system, as researchers have now discovered by using an embryo-like model system they developed. In the absence of BMP, the signalling molecule beta-catenin takes on the role of the Nodal antagonist. This new mechanism could be a flexible solution for axis formation in embryos with different shapes. Formation of the body axes is a critical part of embryonic development. They guarantee that all body parts end up where they belong and that no ears grow on our backs. The head-tail axis, for example, determines the orientation of the two ends of the body. It was previously assumed that this axis is largely determined by the interplay between the Nodal and BMP signals. However, there appears to be another player in this system, as the research groups led by Christian Schröter at the Max Planck Institute of Molecular Physiology in Dortmund and Ivan Bedzhov at the Max Planck Institute of Molecular Biomedicine in Münster have now discovered by using an embryo-like model system they developed. In the absence of BMP, the signalling molecule beta-catenin takes on the role of the Nodal antagonist. This new mechanism could be a flexible solution for axis formation in embryos with different shapes. Our basic body plan is determined early during embryonic development by the formation of three body axes. Put simply, they determine where up and down, front and back and right and left are. The head-tail axis determines the position of the two body openings, the mouth and anus. The activation of various regulatory genes along the head-tail axis and two further body axes leads to the development of certain cell types and tissues. In this way, the axes determine the blueprint for the later body shape. However, despite this important role, many questions about axis formation remain unanswered. Mice look like cups ... In evolutionary terms, the head-tail axis is the oldest body axis and is determined early on in embryonic development. In mice, it develops just a few days after fertilisation. At this stage, the embryo looks like a cup consisting of two layers of cells and a thick lid. At the bottom of the cup, a new cell population develops in the outer cell layer, the visceral endoderm. The cells of this so-called anterior visceral endoderm (AVE) then move towards the edge of the cup and stop approximately halfway. At this point, the head develops from the inner cell layer of the cup, the epiblast, and the tail develops on the opposite side. It was previously assumed that this process is triggered and controlled by the antagonism of two molecular signals. The epiblast emits Nodal, while the lid, the extraembryonic endoderm, releases the counterpart BMP. The bottom of the cup, which is furthest away from the lid, receives the least amount of the BMP signal. As a result, the Nodal signal predominates there and the AVE population differentiates. ... Humans like discs In their current study, the Max Planck researchers were able to identify another key player in axis formation. To this end, they developed a novel embryo-like model system consisting of a layer of epiblast and a layer of VE cells -- a cup without a lid. They achieved this with the targeted and controlled treatment of embryonic mouse stem cells with growth factors. And despite the lack of BMP signalling from the extra-embryonic tissue, an AVE cell population was able to form from the VE cells -- the starting point for the development of the first body axis. The researchers were able to show that beta-catenin, a signalling molecule that was previously only known as a regulator of another body axis in embryonic development, is required for this. "It is quite possible that beta-catenin also plays an important role in the development of the head-tail axis in human embryos. The human embryo is more reminiscent of a disc than a cup. It is therefore quite likely that the distribution of BMP is quite different from that in the mouse embryo and that other mechanisms play a role in the formation of the first body axis," says Christian Schröter. Stem cells on the same wavelength "Our two-layer embryo-like aggregates were the key to our success. Other studies usually use a mixture of different stem cell lines. However, the cell populations we used come from just one stem cell line. This means that they not only have an identical genetic background, but also utilise the same communication systems. You could also say that they are on the same wavelength," says Schröter. "Aggregates of human embryonic stem cells modelled on our system could be a promising experimental tool for investigating events during embryonic development in the future."

Bricklayer, banker, teacher -- choosing a career is one of the most exciting and important decisions in our lives. At the beginning of embryonic development, our cells are also faced with this decision. Some of them become blood cells, others muscle cells and still others become nerve cells. A team has now unveiled how the antagonism between the two signaling molecules FGF and BMP influences the stem cells' career choice. Particularly interesting is the fact that stem cells can also direct their own fate. These findings help to better understand cell differentiation and could thus be a basis for future developments in the field of targeted culturing of tissue in cell replacement therapies. Bricklayer, banker, teacher -- choosing a career is one of the most exciting and important decisions in our lives. At the beginning of embryonic development, our cells are also faced with this decision. Some of them become blood cells, others muscle cells and still others become nerve cells. A team led by Christian Schröter at the Max Planck Institute of Molecular Physiology in Dortmund has now unveiled how the antagonism between the two signaling molecules FGF and BMP influences the stem cells' career choice. Particularly interesting is the fact that stem cells can also direct their own fate. These findings help to better understand cell differentiation and could thus be a basis for future developments in the field of targeted culturing of tissue in cell replacement therapies. People usually make their career choice in their teens. In the growing embryo, however, stem cells make this decision just a few days after the fusion of egg and sperm. At this point gastrulation begins and the so-called germ layers form. After gastrulation, the embryo can be thought of as an onion with three layers: the ectoderm, the mesoderm and the endoderm. These will later become the internal organs. Cocktail of signal molecules A cocktail of different signaling molecules such as BMP, FGF, Wnt and Nodal plays a decisive role in determining what a stem cell in the early embryo will eventually become. This cocktail is mixed by the surrounding extraembryonic tissue and -- depending on its mixture -- e.g. heart or nerve cells are formed. The composition of the various signal cocktails is well understood. However, the role of one ingredient, fibroblast growth factor (FGF), which plays an important role in stem cell migration and growth, still remains unclear to a large extent. For the first time scientists led by Christian Schröter could show that FGF acts as an antagonist of the signal molecule BMP. If there is little FGF, BMP has a strong effect and heart cells and extraembryonic mesoderm are more likely to develop. However, if there is much FGF, the effect of BMP is suppressed and cells of the posterior body axis are more likely to grow. Instructive or intuitive? In the past, parents played a decisive role in determining their children's career choices. In the development of stem cells, a similarly instructive process -- based on the secretion of signaling molecules -- was assumed by developmental biologists. However, the researchers' results indicate that stem cells are not exclusively guided by external signals, but can indeed take their fate into their own hands. Even if, for example, stem cells in the culture dish were instructed by continuous FGF addition to form heart cells, groups of completely different cell types developed nevertheless. The scientists suspect that this supposedly intuitive process is a based on a community effect: Cells that are close together manage to communicate with each other. They send out signals themselves so that the neighboring cells develop in the same direction: They once become the same cell type and take up the same profession. "Our research contributes to a better understanding of the process itself and the key players involved in cell differentiation," explains Christian Schröter. "In the future, these and other findings could help to generate specific cell types from stem cells in a targeted manner, for example to replace dead tissue after a heart attack. So far, selective culturing of specific cell types is not yet possible."

AbCellera Chief Executive Officer Carl Hansen pictured above. (AbCellera) Vancouver-based AbCellera is in a deal-making mood. The company, focused on antibody discovery, struck two separate collaborations over the past two days in order to advance the development of new, innovative medications. This morning, the company announced a deal with Cambridge, Mass.-based EQRX that will leverage its AI-powered technology platform to identify novel antibody drug candidates for multiple disease targets across several therapeutic areas. AbCellera will use its technology platform to investigate natural immune responses in order to identify those antibody drug candidates. The initial programs will focus on targets in oncology and immunology. The collaboration aims to expand EQRx’s early-stage pipeline of novel medicines. EQRx, which launched last year, intends to then deliver these medications (upon approval) at “radically lower prices.” Carlos Garcia-Echeverria, chief of Rx creation at EQRx, said AbCellera’s operating system for antibody discovery and development provides the tools necessary to improve the development of new and affordable medications. He said EQRx looks forward to working with AbCellera to “advance unique clinical candidates against key disease targets.” Financial terms of the collaboration were not disclosed. AbCellera Chief Executive Officer Carl Hansen, Ph.D., said the company exists to create value through the connection of technology and innovation. He expressed pride in the collaboration with EQRx as it will accelerate that company’s goal of providing affordable medications for people across the United States. “This partnership is yet another example of how we can apply our business model, creating greater value and alignment through deals that include the option to invest in programs,” Hansen said in a statement. One day ago, AbCellera struck a deal with Texas-based Tachyon Therapeutics, Inc. to assist in the discovery of a new antibody that targets LEFTY1, which the companies said is a member of the transforming growth factor β (TGF-β) superfamily. LEFTY1 is a validated extracellular drug target that is expressed in advanced cancers. Tachyon’s scientific founder Michael F. Clarke, Ph.D., noted that LEFTY1 is an important, but difficult drug target in solid tumors. The TGF-β superfamily, including LEFTY1, control numerous cellular functions, including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition, adhesion, and migration, Tachyon said. LEFTY1 suppresses NODAL/SMAD2 and BMP7/SMAD5 pathways. In its announcement, Tachyon said as a secreted extracellular protein, “LEFTY1 represents an important target to control SMAD-dependent signals that promote the long-term growth and self-renewal of cancer stem cells.” Hansen said the collaboration with Tachyon provides an opportunity to advance the LEFTY1 research into a first-in-class antibody therapeutic for cancer patients with advanced disease and limited treatment options. “This collaboration exemplifies innovative deal structures that align our interest with our partners’ and provides AbCellera with optionality to deepen our participation in the success of the antibodies we discover. We are excited to partner with Tachyon to pursue a previously unexplored mechanism and develop therapies that we anticipate will impact cancer treatment,” Hansen said. Under the terms of the agreement, AbCellera is eligible to receive milestone payments and royalties on products derived from its antibody discovery platform. Additionally, AbCellera has the option to invest in preclinical and clinical development in exchange for an increased share of product sales.