Amazing Science

This is the story of the revolutionary development of mini-organs (organoids) and their countless applications on how they help us to develop and implement tailored therapy for each patient. A tale for the future of medicine from a group of scientists in Utrecht that started it all - out of wonder.

In 2009, Hans Clevers, a stem cell biologist at Utrecht University, made a discovery that would forever transform healthcare. His lab at the Hubrecht Institute had grown what, under the microscope, looked like a real gut outside the body (made from mouse intestinal cells). It was the first in a series of organs-in-a-dish that would revolutionize personalized medicine in every corner of the world. Today, the possibilities of these mini-organs are enormous: from finding the right treatment to otherwise lethal genetic diseases, numerous cancers and infectious diseases, to understanding furtive neurological disorders such as schizophrenia, bipolar disorder or autism without having to poke one’s brain. We also know deaths from organ donor shortages could soon be a thing of the past. Welcome the organoids: mini-organs that could save your or your family’s life one day…

But how do organoids work exactly? What can you do with organoids now, and which doors will they open for patients and healthcare in the future? They may sound like science fiction to you, but organoids are already transforming patients’ reality.

A team of scientists designed a unique nanocapsule for efficient single CRISPR-Cas9 encapsulation, noninvasive brain delivery and tumor cell targeting, and was able to demonstrate an effective and safe strategy for glioblastoma gene therapy. Their newly developed CRISPR-Cas9 nanocapsules can easily be produced by encapsulating the single Cas9/sgRNA complex within a glutathione-sensitive polymer shell incorporating a dual-action ligand that facilitates BBB penetration, tumor cell targeting, and Cas9/sgRNA selective release. These nanocapsules provide promising glioblastoma tissue targeting that led to high PLK1 gene editing efficiency in a brain tumor (up to 38.1%) with negligible (less than 0.5%) off-target gene editing in high-risk tissues.

Treatment with nanocapsules extended the median survival time (68 days versus 24 days) in mice. Thus, this new CRISPR-Cas9 delivery system addresses various delivery challenges to demonstrate safe and tumor-specific delivery of gene editing Cas9 ribonucleoprotein for improved glioblastoma treatment that may potentially be therapeutically useful for several other brain diseases.

Researchers at Ulsan National Institute of Science and Technology in South Korea have developed a CRISPR-Cas9-based method to eliminate tumor cells. In this first proof-of-concept study, they confirm the feasibility of using CRISPR-Cas9 to selectively kill cancer cells in various disease models by targeting cancer-specific InDels.

Despite recent advances in cancer treatment using drugs that induce DNA damage or boost anti-tumor immune responses, eliminating tumor cells whilst leaving normal cells intact remains a major challenge.bIn a recent proof-of-concept study, researchers from the Institute of Basic Science and Ulsan National Institute of Science and Technology (UNIST), Republic of Korea, developed CINDELA, a new CRISPR-Cas9-based method for selectively inducing DNA damage and cell death in cancer cells.

»We developed an innovative CRISPR-Cas9-based approach to target multiple cancer-specific mutations that are accumulated in cancer cells during tumor development,« said Taejoon Kwon, PhD, Associate Professor at UNIST and first author of the study. »Using this method, we can introduce multiple DNA double-strand breaks (DSBs) and induce cell death selectively in cancer cells,« he added. The team’s findings were published in PNAS late last month.

Dr Kwon also noted that they validated the ability of CINDELA to selectively eliminate tumor cells in cancer cell lines, patient-derived cancer cells, mouse models, and patient-derived xenografts. This extensive validation makes him confident that the novel approach may open new avenues for personalized cancer treatment.

Dr Sandra Rodriguez-Perales, an expert in the use of CRISPR-Cas9 to engineer tumor cells, agrees that there is a clear need for new therapeutic alternatives that can selectively target cancer cells without affecting healthy cells. She is the head of the Molecular Cytogenetics Unit, Spanish National Cancer Centre (CNIO) and did not participate in the study. »This study has advanced a little further along the long road that could lead to the future treatment of different types of tumors,« she said.

A new machine learning system can predict the structure formed when two proteins dock, in a process that’s between 50 to 800 times faster than some software-based methods. This could help scientists better understand biological processes or speed the development of new therapies.

A technology at the leading edge of genetic medicine—known as prime editing—is getting ever closer to the clinic after researchers reported major improvements that could let them repair disorders unreachable by other genetic therapies.

Prime editing derives from the Nobel Prize-winning technique called Crispr-Cas9, which lets scientists reach into defective genes and snip the flawed DNA underlying a genetic disorder such as sickle cell disease. Crispr therapies are already being tested by Crispr Therapeutics (ticker: CRSP), Intellia Therapeutics (NTLA), Editas Medicine (EDIT), and Caribou Biosciences (CRBU).

Building on Crispr-Cas9's ability to zero-in on a specific stretch in our DNA’s 3-billion long string of “base” letters, Harvard University professor David Liu and his colleagues at the Broad Institute of MIT and Harvard introduced “base editing” in 2016. It can correct single-letter typos in DNA, with less disruption to the cell than Crispr-Cas9. The company Beam Therapeutics (BEAM) is bringing base edits into clinical trials.

Base editing can fix four of the 12 possible typos that can cause disease when there’s a single wrong letter in our DNA. In 2019, Liu and his team unveiled “prime editing”, which can correct all 12 typos—they account for 90% of genetic disorders. Prime editing can also insert, delete, or replace a string of several dozen DNA base letters—all without disruptively breaking both of the twisted strands that compose our DNA. This insertion capability might allow prime-editing to fix the flaws responsible for some kinds of cystic fibrosis.

Beam Therapeutics is applying prime-editing technology to repair sickle cell, while other applications of the new gene-editing technique are being pursued by the still-private Prime Medicine.

For all its promise, prime editing suffered shortcomings that left it less efficient than base editing, and kept it from working well in certain kinds of cells. A recent paper4 published in Cell shows that those problems are being overcome, though. Liu and collaborators from Princeton and the University of California, San Francisco, engineered new prime editors that work much more efficiently than earlier tools, with fewer unwanted byproducts.

In clearing away obstacles to prime editing, the technology gets closer to human trials, where it could address genetic flaws that can’t be treated by other kinds of gene editing—including cystic fibrosis and many neurological disorders. “These advancements,” said Prime Medicine CEO Keith Gottesdiener in a press release., “will broaden the areas where prime editing might work, potentially extending our reach to additional diseases that no gene editing approach has yet been able to address.”

Original Article

Researchers from the Université de Montpellier, France, and the University of Pittsburgh, have published a study (“Mycobacteriophage-antibiotic therapy promotes enhanced clearance of drug-resistant Mycobacterium abscessus”) in Disease Models & Mechanisms that describes the antibacterial effects of treating infections caused by the antibiotic-resistant bacteria M. abscessus with a bacteriophage and an antibiotic.

“Infection by multidrug-resistant Mycobacterium abscessus is increasingly prevalent in cystic fibrosis (CF) patients, leaving clinicians with few therapeutic options. A compassionate study showed the clinical improvement of a CF patient with a disseminated M. abscessus (GD01) infection, following injection of a phage cocktail, including phage Muddy. Broadening the use of phage therapy in patients as a potential antibacterial alternative necessitates the development of biological models to improve the reliability and successful prediction of phage therapy in the clinic,” write the investigators.

“Herein, we demonstrate that Muddy very efficiently lyses GD01 in vitro, an effect substantially increased with standard drugs. Remarkably, this cooperative activity was retained in an M. abscessus model of infection in CFTR-depleted zebrafish, associated with a striking increase in larval survival and reduction in pathological signs. The activity of Muddy was lost in macrophage-ablated larvae, suggesting that successful phage therapy relies on functional innate immunity.

“CFTR-depleted zebrafish represent a practical model to rapidly assess phage treatment efficacy against M. abscessus isolates, allowing the identification of drug combinations accompanying phage therapy and treatment prediction in patients.”

Previously, the Pittsburgh team had identified one bacteriophage out of 10,000, known as “Muddy,” that efficiently kills bacteria in a petri dish and could be a candidate for treating these infections in humans. However, the team wanted to find an alternative to testing their new therapy in patients.

Knowing that human cystic fibrosis patients are particularly vulnerable to M. abscessus infections, Laurent Kremer, PhD, at the Université de Montpellier, and colleagues decided to test their new combination therapy on zebrafish carrying the key genetic mutation that causes cystic fibrosis in humans and mimics how our immune system responds to bacterial infections. Then the team obtained samples of an antibiotic-resistant form of M. abscessus from a cystic fibrosis patient to infect the cystic fibrosis zebrafish and test their new treatment.

First, they needed to find out how these cystic fibrosis zebrafish reacted to the M. abscessus infection. Monitoring the animals for 12 days, they found that the fish developed serious infections with abscesses and suffered a high death rate; only 20% survived.

Next the team tested how well the infected fish recovered when injected with Muddy, the antibacterial bacteriophage, over a period of 5 days. This time, the fish had much less severe infections, increased chances of survival (40%) and had fewer of the abscesses suffered by the fish during a severe infection.

Then the authors searched for an antibiotic to pair up with Muddy and found that rifabutin could treat the M. abscessus infection as effectively as the bacteriophage alone. After identifying rifabutin, Kremer and colleagues treated the infected fish for 5 days with the antibiotic and bacteriophage. With this combination treatment, the fishes’ infections were much less severe; the fishes’ survival rate reached 70% and they suffered far fewer abscesses. This is a significant improvement compared to fish treated with only the antibiotic, which had a 40% survival rate.

Cells contain machinery that duplicates DNA into a new set that goes into a newly formed cell. That same class of machines, called polymerases, also build RNA messages, which are like notes copied from the central DNA repository of recipes, so they can be read more efficiently into proteins. But polymerases were thought to only work in one direction DNA into DNA or RNA. This prevents RNA messages from being rewritten back into the master recipe book of genomic DNA.

Now, Thomas Jefferson University researchers provide the first evidence that RNA segments can be written back into DNA, which potentially challenges the central dogma in biology and could have wide implications affecting many fields of biology. "This work opens the door to many other studies that will help us understand the significance of having a mechanism for converting RNA messages into DNA in our own cells," says Richard Pomerantz, PhD, associate professor of biochemistry and molecular biology at Thomas Jefferson University.

"The reality that a human polymerase can do this with high efficiency, raises many questions." For example, this finding suggests that RNA messages can be used as templates for repairing or re-writing genomic DNA.

The work was published June 11th in the journal Science Advances. Together with first author Gurushankar Chandramouly and other collaborators, Dr. Pomerantz's team started by investigating one very unusual polymerase, called polymerase theta. Of the 14 DNA polymerases in mammalian cells, only three do the bulk of the work of duplicating the entire genome to prepare for cell division. The remaining 11 are mostly involved in detecting and making repairs when there's a break or error in the DNA strands. Polymerase theta repairs DNA, but is very error-prone and makes many errors or mutations. The researchers therefore noticed that some of polymerase theta's "bad" qualities were ones it shared with another cellular machine, albeit one more common in viruses -- the reverse transcriptase. Like Pol theta, HIV reverse transcriptase acts as a DNA polymerase, but can also bind RNA and read RNA back into a DNA strand.

In a series of elegant experiments, the researchers tested polymerase theta against the reverse transcriptase from HIV, which is one of the best studied of its kind. They showed that polymerase theta was capable of converting RNA messages into DNA, which it did as well as HIV reverse transcriptase, and that it actually did a better job than when duplicating DNA to DNA.

Polymerase theta was more efficient and introduced fewer errors when using an RNA template to write new DNA messages, than when duplicating DNA into DNA, suggesting that this function could be its primary purpose in the cell. The group collaborated with Dr. Xiaojiang S. Chen's lab at USC and used x-ray crystallography to define the structure and found that this molecule was able to change shape in order to accommodate the more bulky RNA molecule -- a feat unique among polymerases.

Programmed ribosomal frameshifting is a key event during translation of the SARS-CoV-2 RNA genome allowing synthesis of the viral RNA-dependent RNA polymerase and downstream proteins. A team of scientists now presents the cryo-electron microscopy structure of a translating mammalian ribosome primed for frameshifting on the viral RNA. The viral RNA adopts a pseudoknot structure that lodges at the entry to the ribosomal mRNA channel to generate tension in the mRNA and promote frameshifting, whereas the nascent viral polyprotein forms distinct interactions with the ribosomal tunnel. Biochemical experiments validate the structural observations and reveal mechanistic and regulatory features that influence frameshifting efficiency. Finally, the researchers compare compounds previously shown to reduce frameshifting with respect to their ability to inhibit SARS-CoV-2 replication, establishing coronavirus frameshifting as a target for antiviral intervention.

Rudimentary cross-catalytic replication can be established by double-hairpins of tRNA-like sequences, implying that replication and translation could have emerged along a common evolutionary trajectory.

Can replication and translation emerge in a single mechanism via self-assembly? The key molecule, transfer RNA (tRNA), is one of the most ancient molecules and contains the genetic code. Our experiments show how a pool of oligonucleotides, adapted with minor mutations from tRNA, spontaneously formed molecular assemblies and replicated information autonomously using only reversible hybridization under thermal oscillations. The pool of cross-complementary hairpins self-selected by agglomeration and sedimentation. The metastable DNA hairpins bound to a template and then interconnected by hybridization.

Thermal oscillations separated replicates from their templates and drove an exponential, cross-catalytic replication. The molecular assembly could encode and replicate binary sequences with a replication fidelity corresponding to 85–90 % per nucleotide. The replication by a self-assembly of tRNA-like sequences suggests that early forms of tRNA could have been involved in molecular replication. This would link the evolution of translation to a mechanism of molecular replication.

Blocking cell receptors for glucagon, the counter-hormone to insulin, cured mouse models of diabetes by converting glucagon-producing cells into insulin producers instead, a team reports in a new study. The findings could offer a new way to treat both Type 1 and Type 2 diabetes in people.

Both type 1 and type 2 diabetes are associated with reduced β-cell mass or function, resulting from decreased proliferation and increased apoptosis. Understanding the signals governing β-cell survival and regeneration is critical for developing strategies to maintain healthy populations of these cells in individuals. Both forms of diabetes are associated with hyperglucagonemia and an increased plasma glucagon:insulin ratio. Glucagon excess contributes to metabolic dysregulation of the diabetic state and glucagon receptor antagonism is a potential target area for the treatment and prevention of diabetes. The new study suggests that blockade of glucagon signaling lowers glycemia in mouse models of type 1 diabetes while enhancing formation of functional β-cell mass and production of insulin-positive cells from α-cell precursors.

Tiny fragments of DNA combined with fluorescent probes can be used to take temperature at the nanoscale.

Scientists from the University of Montreal, Canada have developed the world’s smallest programmable thermometer, known as Nano-thermometer from DNA. This could recast nanotechnology. Scientists made this Nano-thermometer from actual DNA. This new device is nearly about 20,000 thousand times tinier as compared to human hair.

This new device is made from getting inspiration of “heated DNA always unfolds at a specific temperature”. It can be used in different sectors like Physics, Chemistry and atomic & molecular levels and engineering. This technology has become as a solution to the problem of checking temperature changes in nano-technology. Currently, these devices are so big for doing such things.

A scientist has cultivated DNA structure which can fold and unfold at a certain temperature. They got this idea from natural minute thermometers. Alexis Valle Belisle, Professor at University of Montreal said, “In recent years, biochemists also discovered that biomolecules such as proteins and RNA (Ribonucleic Acid, an important molecule with long chains of nucleotides, like DNA) are employed as Nano-thermometers in living organism and report temperature variation by folding or unfolding.”

Researchers are making some slight adjustment to the product so that it can be combined with new electronic devices. In the field of Science and Technology, this device allows the researcher to answer other problematical questions which have been gone unanswered for years. Were the questions like, can human body runs hotter than 37 degrees Celsius on the natural scale? Or what if naturally occurring Nanomachines overheat when operating at a high rate?

Arnaud Desrosiers, one of the researchers from the team, said, “By adding optical reporters to these DNA structures, we can, therefore, create 5nm wide thermometer that produces an easily detectable signal as a function of temperature.”

Some key feature of this Nano-thermometer:

• It is 5 nanometres wide in the size which is 20,000 times smaller than a human hair.
• It is reversible, robust and efficient.
• It has different applications in different sectors like, in various nanotechnology fields: cell imaging, nano-fluidics, Nano-medicine, Nano-electronics, nano-material, and artificial biology.
• It is used to create super strong structures, repairing cells and help Nano-computing to become more efficient.

Three teams working independently have found evidence that suggests the Z-genome in bacteria-invading viruses is much more widespread than thought. All three of the groups have used a variety of genomic techniques to identify parts of the pathways that lead development of the Z-genome in bacteria-invading viruses known as bacteriophages. The first team was made up of researchers from several institutions in China and one in Singapore, the second with members from several institutions in France; the third was an international effort. All three teams have published their results in the journal Science. Michael Grome and Farren Isaacs with Yale University have also published a Perspectives piece in the same journal issue outlining the work of all three teams.

In general, cells have two purine pathways that synthesize adenine and guanine ribonucleotides from phosphoribose via inosylate. A chemical hybrid between adenine and guanine, 2-aminoadenine (Z), replaces adenine in the DNA of the cyanobacterial virus S-2L. A group of scientists was able to show now that S-2L and Vibrio phage PhiVC8 encode a third purine pathway catalyzed by PurZ, a distant paralog of succinoadenylate synthase (PurA), the enzyme condensing aspartate and inosylate in the adenine pathway. PurZ condenses aspartate with deoxyguanylate into dSMP (N6-succino-2-amino-2′-deoxyadenylate), which undergoes defumarylation and phosphorylation to give dZTP (2-amino-2′-deoxyadenosine-5′-triphosphate), a substrate for the phage DNA polymerase. Crystallography and phylogenetics analyses indicate a close relationship between phage PurZ and archaeal PurA enzymes. This important work elucidates the biocatalytic innovation that remodeled a DNA building block beyond canonical molecular biology.

Leading a double life in water and on land, frogs have many breathing techniques – through the gills, lungs, and skin – over the course of their lifetime. Now German scientists have developed another method that allows tadpoles to “breathe” by introducing algae into their bloodstream to supply oxygen. The method developed, presented October 13 in the journal iScience, provided enough oxygen to effectively rescue neurons in the brains of oxygen-deprived tadpoles.

“The algae actually produced so much oxygen that they could bring the nerve cells back to life, if you will,” says senior author Hans Straka of Ludwig-Maximilians-University Munich. “For many people, it sounds like science fiction, but after all, it’s just the right combination of biological schemes and biological principles.”

Straka was studying oxygen consumption in tadpole brains of African clawed frogs (Xenopus laevis) when a lunch conversation with a botanist sparked an idea to combine plant physiology with neuroscience: harnessing the power of photosynthesis to supply nerve cells with oxygen. The idea didn’t seem far-fetched. In nature, algae live harmoniously in sponges, corals, and anemones, providing them with oxygen and even nutrients. Why not in vertebrates like frogs? To explore the possibility, the team injected green algae (Chlamydomonas renhardtii) or cyanobacteria (Synechocystis) into tadpoles’ hearts. With each heartbeat, the algae inched through blood vessels and eventually reached the brain, turning the translucent tadpole bright green. Shining light on these tadpoles prompted both algae species to pump out oxygen to nearby cells.

After distributing algae to the brain, the researchers isolated the tadpole’s head and placed it in an oxygen bubble bath with essential nutrients that would preserve the functioning of the cells, allowing the team to monitor neural activity and oxygen levels. As the researchers depleted oxygen from the bath, the nerves ceased firing and fell silent. However, illuminating the tadpole head restarted the neural activity within 15 to 20 minutes, which is about two times faster than replenishing the bath with oxygen without the algae. The revived nerves also performed as well or even better than before oxygen depletion, showing that the researchers’ method was quick and efficient.

“We succeeded in showing the proof of principle experiment with this method. It was amazingly reliable and robust, and in my eyes, a beautiful approach,” says Straka. “Working in principle doesn’t really mean that you could apply it at the end, but it’s the first step in order to initiate other studies.”

Genetically encoded reporter proteins have been a mainstay of biotechnology research, allowing scientists to track gene expression, understand intracellular processes and debug engineered genetic circuits. But conventional reporting schemes that rely on fluorescence and other optical approaches come with practical limitations that could cast a shadow over the field's future progress. Now, researchers at the University of Washington and Microsoft have created a "nanopore-tal" into what is happening inside these complex biological systems, allowing scientists to see reporter proteins in a whole new light.

The team introduced a new class of reporter proteins that can be directly read by a commercially available nanopore sensing device. The new system ? dubbed "Nanopore-addressable protein Tags Engineered as Reporters" or "NanoporeTERs" can detect multiple protein expression levels from bacterial and human cell cultures far beyond the capacity of existing techniques.

The study was published Aug. 12, 2021 in Nature Biotechnology. "NanoporeTERs offer a new and richer lexicon for engineered cells to express themselves and shed new light on the factors they are designed to track. They can tell us a lot more about what is happening in their environment all at once," said co-lead author Nicolas Cardozo, a doctoral student with the UW Molecular Engineering and Sciences Institute.

"We're essentially making it possible for these cells to 'talk' to computers about what's happening in their surroundings at a new level of detail, scale and efficiency that will enable deeper analysis than what we could do before." For conventional labeling methods, researchers can track only a few optical reporter proteins, such as green fluorescent protein, simultaneously because of their overlapping spectral properties. For example, it's difficult to distinguish between more than three different colors of fluorescent proteins at once. In contrast, NanoporeTERs were designed to carry distinct protein "barcodes" composed of strings of amino acids that, when used in combination, allow at least ten times more multiplexing possibilities.

These synthetic proteins are secreted outside of a cell into the surrounding environment, where researchers can collect and analyze them using a commercially available nanopore array. Here, the team used the Oxford Nanopore Technologies MinION device.

Researchers have created a new gene editing tool called Retron Library Recombineering (RLR) that can generate up to millions of mutations simultaneously, and 'barcodes' mutant bacterial cells so that the entire pool can be screened at once. It can be used in contexts where CRISPR is toxic or not feasible, and results in better editing rates.

While the CRISPR-Cas9 gene editing system has become the poster child for innovation in synthetic biology, it has some major limitations. CRISPR-Cas9 can be programmed to find and cut specific pieces of DNA, but editing the DNA to create desired mutations requires tricking the cell into using a new piece of DNA to repair the break. This bait-and-switch can be complicated to orchestrate, and can even be toxic to cells because Cas9 often cuts unintended, off-target sites as well.

Alternative gene editing techniques called recombineering instead perform this bait-and-switch by introducing an alternate piece of DNA while a cell is replicating its genome, efficiently creating genetic mutations without breaking DNA. These methods are simple enough that they can be used in many cells at once to create complex pools of mutations for researchers to study. Figuring out what the effects of those mutations are, however, requires that each mutant be isolated, sequenced, and characterized: a time-consuming and impractical task.

Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard Medical School (HMS) have created a new gene editing tool called Retron Library Recombineering (RLR) that makes this task easier. RLR generates up to millions of mutations simultaneously, and "barcodes" mutant cells so that the entire pool can be screened at once, enabling massive amounts of data to be easily generated and analyzed. The achievement, which has been accomplished in bacterial cells, is described in a recent paper in PNAS.

"RLR enabled us to do something that's impossible to do with CRISPR: we randomly chopped up a bacterial genome, turned those genetic fragments into single-stranded DNA in situ, and used them to screen millions of sequences simultaneously," said co-first author Max Schubert, Ph.D., a postdoc in the lab of Wyss Core Faculty member George Church, Ph.D. "RLR is a simpler, more flexible gene editing tool that can be used for highly multiplexed experiments, which eliminates the toxicity often observed with CRISPR and improves researchers' ability to explore mutations at the genome level."

Investigators in China and the United States have injected human stem cells into primate embryos and were able to grow chimeric embryos for a significant period of time -- up to 20 days. The research, despite its ethical concerns, has the potential to provide new insights into developmental biology and evolution. It also has implications for developing new models of human biology and disease. The work appears April 15, 2021 in the journal Cell.

"As we are unable to conduct certain types of experiments in humans, it is essential that we have better models to more accurately study and understand human biology and disease," says senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences. "An important goal of experimental biology is the development of model systems that allow for the study of human diseases under in vivo conditions."

Interspecies chimeras in mammals have been made since the 1970s, when they were generated in rodents and used to study early developmental processes. The advance that made the current study possible came last year when this study's collaborating team -- led by Weizhi Ji of Kunming University of Science and Technology in Yunnan, China -- generated technology that allowed monkey embryos to stay alive and grow outside the body for an extended period of time.

In the current study, six days after the monkey embryos had been created, each one was injected with 25 human cells. The cells were from an induced pluripotent cell line known as extended pluripotent stem cells, which have the potential to contribute to both embryonic and extra-embryonic tissues. After one day, human cells were detected in 132 embryos. After 10 days, 103 of the chimeric embryos were still developing. Survival soon began declining, and by day 19, only three chimeras were still alive.

Importantly, though, the percentage of human cells in the embryos remained high throughout the time they continued to grow.

Someday, scientists believe, tiny DNA-based robots and other nanodevices will deliver medicine inside our bodies, detect the presence of deadly pathogens, and help manufacture increasingly smaller electronics. Researchers took a big step toward that future by developing a new tool that can design much more complex DNA robots and nanodevices than were ever possible before in a fraction of the time.

In a paper published on April 19, 2021 in the journal Nature Materials, researchers from The Ohio State University -- led by former engineering doctoral student Chao-Min Huang -- unveiled new software they call MagicDNA. The software helps researchers design ways to take tiny strands of DNA and combine them into complex structures with parts like rotors and hinges that can move and complete a variety of tasks, including drug delivery.

Researchers have been doing this for a number of years with slower tools with tedious manual steps, said Carlos Castro, co-author of the study and associate professor of mechanical and aerospace engineering at Ohio State. "But now, nanodevices that may have taken us several days to design before now take us just a few minutes," Castro said. And now researchers can make much more complex -- and useful -- nanodevices.

"Previously, we could build devices with up to about six individual components and connect them with joints and hinges and try to make them execute complex motions," said study co-author Hai-Jun Su, professor of mechanical and aerospace engineering at Ohio State. "With this software, it is not hard to make robots or other devices with upwards of 20 components that are much easier to control. It is a huge step in our ability to design nanodevices that can perform the complex actions that we want them to do."

The software has a variety of advantages that will help scientists design better, more helpful nanodevices and -- researchers hope -- shorten the time before they are in everyday use. One advantage is that it allows researchers to carry out the entire design truly in 3D. Earlier design tools only allowed creation in 2D, forcing researchers to map their creations into 3D. That meant designers couldn't make their devices too complex.

The software also allows designers to build DNA structures "bottom up" or "top down." In "bottom up" design, researchers take individual strands of DNA and decide how to organize them into the structure they want, which allows fine control over local device structure and properties. But they can also take a "top down" approach where they decide how their overall device needs to be shaped geometrically and then automate how the DNA strands are put together. Combining the two allows for increasing complexity of the overall geometry while maintaining precise control over individual component properties, Castro said.

Another key element of the software is that it allows simulations of how designed DNA devices would move and operate in the real world. "As you make these structures more complex, it is difficult to predict exactly what they are going to look like and how they are going to behave," Castro said. "It is critical to be able to simulate how our devices will actually operate. Otherwise, we waste a lot of time."

As a demonstration of the software's ability, co-author Anjelica Kucinic, a doctoral student in chemical and biomolecular engineering at Ohio State, led the researchers in making and characterizing many nanostructures designed by the software. Some of the devices they created included robot arms with claws that can pick up smaller items, and a hundred nanometer-sized structure that looks like an airplane. The "airplane", however, is about 1,000 times smaller than the width of a human hair!

The ability to make more complex nanodevices means that they can do more useful things and even carry out multiple tasks with one device, Castro said.

Proteins are large, highly complex and naturally occurring molecules can be found in all living organisms. These unique substances, which consist of amino acids joined together by peptide bonds to form long chains, can have a variety of functions and properties.

The specific order in which different amino acids are arranged to form a given protein ultimately determines the protein's 3D structure, physicochemical properties and molecular function. While scientists have been studying proteins for decades, designing proteins that elicit specific chemical reactions has so far proved to be highly challenging.

Researchers at Biomatter Designs, Vilnius University in Lithuania, and Chalmers University of Technology in Sweden have recently developed ProteinGAN, a generative adversarial network (GAN) that can process and 'learn' different natural protein sequences. This unique network, presented in a paper published in Nature Machine Intelligence, subsequently uses the information it acquired to generate new functional protein sequences.

"Proteins are long sequences of amino acids that make processes occur in all living systems, inducing humans," Aleksej Zelezniak, Associate professor at Chalmers University of Technology who led the study, told Phys.org. " Proteins are commonly used in our daily lives and are included in countless products, from washing powders to therapies against cancer and coronavirus. They are made of 20 amino acids that are arranged in different sequences and their order determines a protein's function."

Creating functional protein sequences is a very challenging task, as even a slight alteration in a given sequence can make a protein non-functional. Non-functional proteins can have harmful and undesirable effects, for instance causing humans or animals to develop cancer or other diseases.