One of the challenges in creating these so-called synthetic embryos is to generate all the cell types normally found in a young embryo before it implants into the wall of the uterus. Some of these cells eventually give rise to the placenta. Others become the amniotic sac in which the fetus grows. Both the placenta and the amniotic sac are crucial for the survival of the fetus, and defects in these embryo components are major causes of early pregnancy loss.

A group of scientists from Gladstone Institutes, the Center for iPS Cell Research and Application (CiRA) from Kyoto University, and the RIKEN Center for Biosystems Dynamics Research in Kobe, Japan, has now demonstrated the presence of precursors of the placenta and the amniotic sac in synthetic embryos they created from mouse stem cells.

“Our findings provide strong evidence that our system is a good model for studying the early, pre-implantation stages of embryo development,” says Kiichiro Tomoda, PhD, research investigator at the recently opened iPS Cell Research Center at Gladstone and first author of the study published in the journal Stem Cell Reports. “Using this model, we will be able to dissect the molecular events that take place during these early stages, and the signals that the different embryonic cells send to each other.”

Ultimately, this knowledge might help scientists develop strategies to decrease infertility due to early embryonic development gone awry.

The new findings could also shed light on a defining property of the earliest embryo cells that has been difficult to capture in the lab: their ability to produce all the cell types found in the embryo and, ultimately, the whole body. Scientists refer to this property as “totipotency.”

“Totipotency is a very unique and short-lived property of early embryonic cells,” says Cody Kime, PhD, an investigator at the RIKEN Center for Biosystems Dynamics Research and the study’s senior author.

“It has been much harder to harness in the lab than pluripotency,” he adds, referring to the ability of some cells to give rise to several — but not all — cell types. “A very exciting prospect of our work is the ability to understand how we can reprogram cells in the lab to achieve totipotency.”

Growing the Fundamental Components of Early Embryos in the Lab

To generate synthetic embryos, the scientists started from mouse pluripotent stem cells that normally give rise to the fetus only — not the placenta or amniotic sac. They can grow these cells, called epiblast stem cells, and multiply them indefinitely in the lab.

In previous work, the team had discovered a combination of nutrients and chemicals that could make epiblast stem cells assemble into small cell structures that closely resemble pre-implantation embryos. In fact, the structures could even reach the implantation stage when transferred into female mice, though they degenerated shortly thereafter.

“This meant that we might successfully reprogram the epiblast cells to revert to an earlier stage, when embryonic cells are totipotent, and provided a clue to how we might generate both the fetus and the tissues that support its implantation,” explains Tomoda, who is also a program-specific research center associate professor at CiRA.

To build on that work and better understand the reprogramming process, the scientists needed molecular resolution. In their new study, they turned to single-cell RNA sequencing, a technique that allows scientists to study individual cells based on the genes they turn on or off.

After analyzing thousands of individual cells reprogrammed from epiblast stem cells, and sifting the data through computer-powered analyses, they confirmed that, after 5 days of reprogramming, some cells closely resembled all three precursors of the fetus, the placenta, and the amniotic sac.

Moreover, as they were grown in the lab for a few more days, the three cell types displayed more distinct molecular profiles with striking similarity to real embryonic model cells. This is the same as would be expected during the growth of a normal embryo, when the three tissues acquire distinct physical properties and biological functions.

“Our single-cell RNA-sequencing analysis confirms the emergence in our synthetic embryo system of the cell types that lead to the three fundamental components of an early mammalian embryo,” says Kime. “In addition, it unveils in amazing detail the genes and biological pathways involved in the development of these precursors and their maturation into specific tissues.”

This knowledge provides a comprehensive backdrop against which to understand the mechanisms of early embryo development and the possible causes of its failure.

For now, the scientists plan to work on ways to increase the efficiency of their reprogramming process, so as to reliably produce large amounts of pre-implantation-like synthetic embryos for further studies. This would allow them to carry out experiments that were up to now unthinkable, such as large-scale screens for gene mutations that disrupt early embryos. And it may shed light on the causes of pregnancy loss due to early embryo failure.

They also want to better understand the molecular steps involved in reprogramming. In particular, they plan to look earlier than 5 days into the reprogramming process, with the hope of pinpointing truly totipotent cells at the origin of their synthetic embryos.

“The discovery that we could reprogram cells to adopt earlier, more pluripotent states revolutionized developmental biology 15 years ago,” says Tomoda, referring to the discovery of induced pluripotent stem cells by his and Kime’s mentor, Nobel Laureate Shinya Yamanaka.

“In the last few years, the field of synthetic embryology utilizing stem cells has seen a true explosion,” he says. “Our method of generating synthetic embryos is simpler than others, and quite efficient. We think it will be a great resource for many labs.”

BBS is a rare genetic disorder that causes intellectual disability, vision loss and obesity, and sometimes kidney problems and extra fingers and toes. It is one of several ciliopathies, which are diseases that stem from defective cilia — tiny, finger-like projections on the surface of cells that play important roles in moving fluids, sensing the environment and signaling between cells. Pak, Carter, Sheffield and colleagues wanted to learn more about how ciliopathies cause intellectual disability, so they studied a type of mouse with the same symptoms as people with BBS.

In the new study, the researchers showed that normal mice could quickly be trained to associate a specific environment to a fearful event, but the BBS mice had a harder time with fear memory. Further investigation showed that these learning problems come from an inability to make new neurons in the hippocampus. Treating the mice with lithium, however, increased cell production and improved their learning and memory.

Intellectual disability is the most common type of neurodevelopmental disorder, but few drugs are available to treat it. The new study suggests that lithium may be an effective treatment for the learning and memory defects caused by BBS, and the researchers suggest that further studies should be performed to test the use of this FDA-approved drug. The new findings also demonstrate a novel role for cilia in learning and memory in the brain, potentially improving our understanding of the mechanisms that cause intellectual disability.

Pak adds, “A mouse model of a cilia disease, Bardet-Biedl Syndrome, has impaired fear memory and hippocampal neurogenesis. In this mouse model, lithium treatment improves fear memory and hippocampal neurogenesis.”

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In a new paper published in JGR: Planets, researchers on the NASA-JPL Mars Science Laboratory mission used the Curiosity rover to add another piece to the puzzle of Mars’ ancient past by investigating a unit of rocks within Gale crater.

They found evidence of an ancient dune field preserved as a layer of rocks in Gale crater, which overlies rock layers that were deposited in a large lake. The rock remnants of the dune field are known today as the Stimson formation.

The findings help scientists understand surface and atmospheric processes — such as the direction the wind blew sand to form dunes — and potentially how Mars’ climate evolved from an environment that potentially harboured microbial life, to an uninhabitable one.

By looking at the preserved rock layers through images collected by the Curiosity rover, the researchers reconstructed the shape, migration direction and size of the large dunes, also known as draas, that occupied that part of the crater.

The models of ancient dunes, created by Imperial researchers, show that dunes were nestled next to the central peak of Gale crater — known as Mount Sharp — on a wind-eroded surface at a five-degree angle. The research also found that the dunes were compound dunes — large dunes which hosted their own set of smaller dunes which travelled in a different directions to the main dune.

Lead author Dr Steven Banham of Imperial’s Department of Earth Science and Engineering said: “As the wind blows, it transports sand grains of a certain size, and organises them into piles of sand we recognise as sand dunes. These landforms are common on Earth in sandy deserts, such as the Sahara, the Namibian dune field, and the Arabian deserts. The strength of the wind and its uniformity of direction control the shape and size of the dune, and evidence of this can be preserved in the rock record.

“If there is an excess of sediment transported into a region, dunes can climb as they migrate and partially bury adjacent dunes. These buried layers contain a feature called ‘cross-bedding’, which can give an indication of the size of the dunes, and the direction which they were migrating. By investigating these cross beds, we were able to determine these strata were deposited by specific dunes that form when competing winds transport sediment in two different directions.

“It’s amazing that from looking at Martian rocks we can determine that two competing winds drove these large dunes across the plains of Gale crater three and a half billion years ago. This is some of the first evidence we have of variable wind directions — be they seasonal or otherwise.”

The lower part of Mount Sharp is composed of ancient lakebed sediments. These sediments accumulated on the lakebed when the crater flooded, shortly after its formation 3.8 billion years ago. Curiosity has spent much of the last nine years investigating these rocks for signs of habitability.

Dr Banham added: “More than 3.5 billion years ago this lake dried out, and the lake bottom sediments were exhumed and eroded to form the mountain at the centre of the crater — the present-day Mount Sharp. The flanks of the mountain are where we have found evidence that an ancient dune field formed after the lake, indicating an extremely arid climate.”

However, the new findings suggest that the ancient dune field might have been less nurturing of life than previously thought. Dr Banham said: “The vast expanse of the dune field wouldn’t have been a particularly hospitable place for microbes to live, and the record left behind would rarely preserve evidence of life, if there was any.

“This desert sand represents a snapshot of time within Gale crater, and we know that the dune field was preceded by lakes — yet we don’t know what overlies the desert sandstones further up Mount Sharp. It could be more layers deposited in arid conditions, or it could be deposits associated with more humid climates. We will have to wait and see.”

Rovers on Mars are allowing researchers to explore the planet in detail like never before. Dr Banham added: “Although geologists have been reading rocks on Earth for 200 years, it’s only in the last decade or so that we’ve been able to read Martian rocks with the same level of detail as we do on Earth.”

The researchers continue to examine rocks found by Curiosity and are now focusing on the wind patterns recorded by dunes further up Mount Sharp. Dr Banham said: “We’re interested to see how the dunes reflect the wider climate of Mars, its changing seasons, and longer-term changes in wind direction. Ultimately, this all relates to the major driving question: to discover whether life ever arose on Mars.”

The research was funded by the UK Space Agency and forms part of the preparation for the forthcoming ESA ExoMars mission to explore Mars for signs of ancient life.

Less than two years ago, Helms announced the invention of a new plastic that could tackle the waste crisis head on. Called poly(diketoenamine), or PDK, the material has all the convenient properties of traditional plastics while avoiding the environmental pitfalls, because unlike traditional plastics, PDKs can be recycled indefinitely with no loss in quality.

Now, the team has released a study that shows what can be accomplished if manufacturers began using PDKs on a large scale. The bottom line? PDK-based plastic could quickly become commercially competitive with conventional plastics, and the products will get less expensive and more sustainable as time goes on.

“Plastics were never designed to be recycled. The need to do so was recognized long afterward,” explained Nemi Vora, first author on the report and a former postdoctoral fellow who worked with senior author Corinne Scown. “But driving sustainability is the heart of this project. PDKs were designed to be recycled from the get-go, and since the beginning, the team has been working to refine the production and recycling processes for PDK so that the material could be inexpensive and easy enough to be deployed at commercial scales in anything from packaging to cars.”

The study presents a simulation for a 20,000-metric-ton-per-year facility that puts out new PDKs and takes in used PDK waste for recycling. The authors calculated the chemical inputs and technology needed, as well as the costs and greenhouse gas emissions, then compared their findings to the equivalent figures for production of conventional plastics.

“These days, there is a huge push for adopting circular economy practices in the industry. Everyone is trying to recycle whatever they’re putting out in the market,” said Vora. “We started talking to industry about deploying 100% percent infinitely recycled plastics and have received a lot of interest.”

“The questions are how much it will cost, what the impact on energy use and emissions will be, and how to get there from where we are today,” added Helms, a staff scientist at Berkeley Lab’s Molecular Foundry. “The next phase of our collaboration is to answer these questions.”

Checking the boxes of cheap and easy

To date, more than 8.3 billion metric tons of plastic material have been produced, and the vast majority of this has ended up in landfills or waste incineration plants. A small proportion of plastics are sent to be recycled “mechanically,” meaning they are melted down and then re-shaped into new products. However, this technique has limited benefit. Plastic resin itself is made of many identical molecules (called monomers) bound together into long chains (called polymers). Yet to give plastic its many textures, colors, and capabilities, additives like pigments, heat stabilizers, and flame retardants are added to the resin. When many plastics are melted down together, the polymers become mixed with a slew of potentially incompatible additives, resulting in a new material with much lower quality than newly produced virgin resin from raw materials. As such, less than 10% of plastic is mechanically recycled more than once, and recycled plastic usually also contains virgin resin to make up for the dip in quality.

PDK plastics sidestep this problem entirely — the resin polymers are engineered to easily break down into individual monomers when mixed with an acid. The monomers can then be separated from any additives and gathered to make new plastics without any loss of quality. The team’s earlier research shows that this “chemical recycling” process is light on energy and carbon dioxide emissions, and it can be repeated indefinitely, creating a completely circular material lifecycle where there is currently a one-way ticket to waste.

Yet despite these incredible properties, to truly beat plastics at their own game, PDKs also need to be convenient. Recycling traditional petroleum-based plastic might be hard, but making new plastic is very easy.

“We’re talking about materials that are basically not recycled,” said Scown. “So, in terms of appealing to manufacturers, PDKs aren’t competing with recycled plastic — they have to compete with virgin resin. And we were really pleased to see how cheap and how efficient it will be to recycle the material.”

Scown, who is a staff scientist in Berkeley Lab’s Energy Technologies and Biosciences Areas, specializes in modeling future environmental and financial impacts of emerging technologies. Scown and her team have been working on the PDK project since the outset, helping Helms’ group of chemists and fabrication scientists to choose the raw materials, solvents, equipment, and techniques that will lead to the most affordable and eco-friendly product.

“We’re taking early stage technology and designing what it would look like at commercial-scale operations” using different inputs and technology, she said. This unique, collaborative modeling process allows Berkeley Lab scientists to identify potential scale-up challenges and make process improvements without costly cycles of trial and error.

The team’s report, published in Science Advances, models a commercial-scale PDK production and recycling pipeline based on the plastic’s current state of development. “And the main takeaways were that, once you’ve produced the PDK initially and you’ve got it in the system, the cost and the greenhouse gas emissions associated with continuing to recycle it back to monomers and make new products could be lower than, or at least on par with, many conventional polymers,” said Scown.

Planning to launch

Thanks to optimization from process modeling, recycled PDKs are already drawing interest from companies needing to source plastic. Always looking to the future, Helms and his colleagues have been conducting market research and meeting with people from industry since the project’s early days. Their legwork shows that the best initial application for PDKs are markets where the manufacturer will receive their product back at the end of its lifespan, such as the automobile industry (through trade-ins and take-backs) and consumer electronics (through e-waste programs). These companies will then be able to reap the benefits of 100% recyclable PDKs in their product: sustainable branding and long-term savings.

“With PDKs, now people in industry have a choice,” said Helms. “We’re bringing in partners who are building circularity into their product lines and manufacturing capabilities, and giving them an option that is in line with future best practices.”

Added Scown: “We know there’s interest at that level. Some countries have plans to charge hefty fees on plastic products that rely on non-recycled material. That shift will provide a strong financial incentive to move away from utilizing virgin resins and should drive a lot of demand for recycled plastics.”

After infiltrating the market for durable products like cars and electronics, the team hopes to expand PDKs into shorter-lived, single-use goods such as packaging.

A full circle future

As they forge plans for a commercial launch, the scientists are also continuing their techno-economic collaboration on the PDK production process. Although the cost of recycled PDK is already projected to be competitively low, the scientists are working on additional refinements to lower the cost of virgin PDK, so that companies are not deterred by the initial investment price.

And true to form, the scientists are working two steps ahead at the same time. Scown, who is also vice president for Life-cycle, Economics & Agronomy at the Joint BioEnergy Institute (JBEI), and Helms are collaborating with Jay Keasling, a leading synthetic biologist at Berkeley Lab and UC Berkeley and CEO of JBEI, to design a process for producing PDK polymers using microbe-made precursor ingredients. The process currently uses industrial chemicals, but was initially designed with Keasling’s microbes in mind, thanks to a serendipitous cross-disciplinary seminar.

“Shortly before we started the PDK project, I was in a seminar where Jay was describing all the molecules that they could make at JBEI with their engineered microbes,” said Helms. “And I got very excited because I saw that some of those molecules were things that we put in PDKs. Jay and I had a few chats and, we realized that nearly the entire polymer could be made using plant material fermented by engineered microbes.”

“In the future, we’re going to bring in that biological component, meaning that we can begin to understand the impacts of transitioning from conventional feedstocks to unique and possibly advantaged bio-based feedstocks that might be more sustainable long term on the basis of energy, carbon, or water intensity of production and recycling,” Helms continued. “So, where we are now, this is the first step of many, and I think we have a really long runway in front of us, which is exciting.”

The Molecular Foundry is a Department of Energy (DOE) Office of Science user facility that specializes in nanoscale science. JBEI is a Bioenergy Research Center funded by DOE’s Office of Science.

This work was supported by the DOE’s Bioenergy Technologies Office and Berkeley Lab’s Laboratory Directed Research and Development (LDRD) program.

PDK technology is available for licensing and collaboration.

“Many of the galaxies that existed in the early Universe were so small that their brightness is well below the limit of the current largest telescopes on Earth and in Space, making difficult to study their properties and internal structure,” says Nicolas Laporte, a Kavli Senior Fellow at the University of Cambridge. “However, the light coming from the galaxy named RXCJ0600-z6, was highly magnified by gravitational lensing, making it an ideal target for studying the properties and structure of a typical baby galaxies.”

Gravitational lensing is a natural phenomenon in which light emitted from a distant object is bent by the gravity of a massive body such as a galaxy or a galaxy cluster located in the foreground. The name “gravitational lensing” is derived from the fact that the gravity of the massive object acts like a lens. When we look through a gravitational lens, the light of distant objects is intensified and their shapes are stretched. In other words, it is a “natural telescope” floating in space.

The ALMA Lensing Cluster Survey (ALCS) team used ALMA to search for a large number of galaxies in the early Universe that are enlarged by gravitational lensing. Combining the power of ALMA, with the help of the natural telescopes, the researchers are able to uncover and study fainter galaxies.

Why is it crucial to explore the faintest galaxies in the early Universe? Theory and simulations predict that the majority of galaxies formed few hundred millions years after the Big-Bang are small, and thus faint. Although several galaxies in the early Universe have been previously observed, those studied were limited to the most massive objects, and therefore the less representative galaxies, in the early Universe, because of telescopes capabilities. The only way to understand the standard formation of the first galaxies, and obtain a complete picture of galaxy formation, is to focus on the fainter and more numerous galaxies.

The ALCS team performed a large-scale observation program that took 95 hours, which is a very long time for ALMA observations, to observe the central regions of 33 galaxy clusters that could cause gravitational lensing. One of these clusters, called RXCJ0600-2007, is located in the direction of the constellation of Lepus, and has a mass 1000 trillion times that of the Sun. The team discovered a single distant galaxy that is being affected by the gravitational lens created by this natural telescope. ALMA detected the light from carbon ions and stardust in the galaxy and, together with data taken with the Gemini telescope, determined that the galaxy is seen as it was about 900 million years after the Big Bang (12.9 billion years ago). Further analysis of these data suggested that a part of this source is seen 160 times brighter than it is intrinsically.

By precisely measuring the mass distribution of the cluster of galaxies, it is possible to “undo” the gravitational lensing effect and restore the original appearance of the magnified object. By combining data from Hubble Space Telescope and the European Southern Observatory’s Very Large Telescope with a theoretical model, the team succeeded in reconstructing the actual shape of the distant galaxy RXCJ0600-z6. The total mass of this galaxy is about 2 to 3 billion times that of the Sun, which is about 1/100th of the size of our own Milky Way Galaxy.

What astonished the team is that RXCJ0600-z6 is rotating. Traditionally, gas in the young galaxies was thought to have random, chaotic motion. Only recently has ALMA discovered several rotating young galaxies that have challenged the traditional theoretical framework, but these were several orders of magnitude brighter (larger) than RXCJ0600-z6.

“Our study demonstrates, for the first time, that we can directly measure the internal motion of such faint (less massive) galaxies in the early Universe and compare it with the theoretical predictions,” says Kotaro Kohno, a professor at the University of Tokyo and the leader of the ALCS team.

“The fact that RXCJ0600-z6 has a very high magnification factor also raises expectations for future research,” explains Seiji Fujimoto, a DAWN fellow at the Niels Bohr Institute. “This galaxy has been selected, among hundreds, to be observed by the James Webb Space Telescope (JWST), the next generation space telescope to be launched this autumn. Through joint observations using ALMA and JWST, we will unveil the properties of gas and stars in a baby galaxy and its internal motions. When the Thirty Meter Telescope and the Extremely Large Telescope are completed, they may be able to detect clusters of stars in the galaxy, and possibly even resolve individual stars. There is an example of gravitational lensing that has been used to observe a single star 9.5 billion light-years away, and this research has the potential to extend this to less than a billion years after the birth of the Universe.”