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Wrong number of fingers leads down wrong track

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Researchers from the Universities of Bonn and Opole examined a fossil that raises questions

Have you ever wondered why our hands have five fingers? And what about amphibians? They usually only have four. Until now it was assumed that this was already the case with the early ancestors of today’s frogs and salamanders, the Temnospondyli. However, a new find of the crocodile-like Temnospondyl Metoposaurus krasiejowensis from the late Triassic (about 225 million years old) in Poland shows five metacarpal bones and thus five fingers. As the researchers from the Universities of Bonn and Opole (Poland) note, this finding is very important, because until now, fossil animal tracks may have been wrongly assigned. The results have now been published in the Journal of Anatomy.

Modern amphibians usually have four fingers on the forelimb (and never more), which is called a “four-rayed hand”, as opposed to our five-rayed hand. Of all groups of terrestrial vertebrates, amphibians show the greatest variation in the number of frontfingers Reptiles are the most conservative and usually have five. In birds, the finger bones in the wing have been lost completely. In mammals, the number of toes in the forelimb also varies greatly: Primates and raccoons have five, in horses only the third has survived, while in cattle and other even-toed ungulates fingers three and four remain. What they all have in common, however, is that this loss of toes or fingers originates from a five-ray pattern, which is why amphibians cannot be the ancestors of all these terrestrial vertebrate groups.

Exact number of toes is controversial

It has been known for some time that the earliest quadrupeds had significantly more fingers than five, such as Acanthostega, which had eight in the forelimb, or Ichthyostega with seven in the hind foot. As early as 300 million years ago, all but the five-fingered forms became extinct. The five-ray pattern was then retained in the real land animals, but was reduced again and again (see horses). The ancestors of today’s amphibians, the Temnospondyli, presented contradictory evidence of skeletons with four fingers, but also tracks that had five.

Temnospondyli is an important group of the early, very diverse quadrupeds. Some temnospondyls became as big as crocodiles, others were rather small. However, like all amphibians, they were dependent on water during their larval stage. Their most famous representatives include Eryops or Mastodonsaurus. “It’s also important to understand the evolution of modern amphibians, as this group probably evolved from the Temnospondyli,” says Dr. Dorota Konietzko-Meier from the Institute for Geosciences at the University of Bonn, who discovered and prepared the left forelimb of a Metoposaurus krasiejowensis in Krasiejów (southwest Poland).

However, despite the long history of research, the exact number of fingers in Metoposaurus and other temnospondyls is still controversial. “It’s remarkable that even in the case of the very well-researched Eryops, the skeletal reconstruction exhibited at the Muséum National d’Histoire Naturelle in Paris has five fingers, while only four fingers can be seen at the National Museum of Natural History in Washington,” says Ella Teschner, a doctoral student from Bonn and Opole. Lately, science has assumed that, similar to most modern amphibians, all Temnospondyli have only four toes in their forelimbs. This resulted in the five-toed footprints common in the Permian and Triassic periods being almost automatically assumed to not belong to Temnospondyli.

“The find from the famous Upper Triassic site Krasiejów in Poland therefore offers a new opportunity to study the architecture and development of the hand of the early quadrupeds,” says paleontologist Prof. Dr. Martin Sander from the University of Bonn. A considerably broader view of the entire group of Temnospondyli did not show a clear trend with regard to the five-ray pattern and suggested that the number of digits was not as limited in the phylogenetic context as was assumed. “Evidently, the temnospondyls were already experimenting with the four-ray pattern, and the five-ray pattern died out before the emergence of modern amphibians,” adds Sander.

Five fingers on each hand?

“Even if the ossification of five metacarpal bones described here was only a pathology, it still shows that a five-ray pattern was possible in Temnospondyli,” says Konietzko-Meier. However, it could not be assumed with certainty that the reduction in the number of fingers/digits from five to four always affected the fifth place on the hand in these fossil taxa. The possibility that some of the four-fingered taxa were caused by the loss of the first ray cannot be excluded. Sander: “The new finding of a five-fingered hand is particularly important for the interpretation of tracks, as it shows that a five-fingered forefoot print could also belong to the Temnospondyli and thus indicate a considerably wider distribution area of these animals.”

These results are also of general importance, since limb development plays an important role in evolutionary biology and medicine, and fossils may therefore provide important information for the evaluation of theories of hand development.

###

Publication: Dorota Konietzko-Meier, Elzbieta M. Teschner, Adam Bodzioch, P. Martin Sander: Pentadactyl manus of the Metoposaurus krasiejowensis from the Late Triassic of Poland, the first record of pentadactyly among Temnospondyli, Journal of Anatomy, DOI:10.1111/joa.13276

Media contact:

Dr. Dorota Konietzko-Meier

Institut für Geowissenschaften

Universität Bonn

Tel. 0228/73-60043

E-mail: [email protected]

Prof. Dr. Martin Sander

Institut für Geowissenschaften

Universität Bonn

Tel. 0228/733105

E-mail: [email protected]

Source: https://bioengineer.org/wrong-number-of-fingers-leads-down-wrong-track/

Biotechnology

Chemical engineering meets cancer immunotherapy

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Sachin Bhagchandani, a graduate student in the Department of Chemical Engineering currently working at the Koch Institute for Integrative Cancer Research, has won the National Cancer Institute Predoctoral to Postdoctoral Fellow Transition (F99/K00) Award. Bhagchandani is the first student at MIT to receive the award.

The fellowship is given to outstanding graduate students with high potential and interest in becoming independent cancer researchers. Bhagchandani is one of 24 candidates selected for the fellowship this year. Nominations were limited to one student per institution. The award provides six years of funding, which will support Bhagchandani as he completes his PhD in chemical engineering and help him transition into a mentored, cancer-focused postdoctoral research position — one draws on his wide-ranging interests and newfound experiences in synthetic chemistry and immunology.

Making change

Bhagchandani’s research has evolved since his undergraduate days studying chemical engineering at the Indian Institute of Technology, Roorkee. He describes the experience as rigorous, but constraining. While at MIT, he has found more opportunities to explore, leading to highly interdisciplinary projects that allow him to put his training in chemical engineering in service of human health.

Before Bhagchandani arrived at his doctoral project, many pieces had to fall into place. While completing his Master’s thesis, Bhagchandani discovered his interest in the biomedical space while working on a project advised by MIT Institute Professor Robert Langer and Harvard Medical School Professor Jeffrey Karp developing different biomaterials for the sustained delivery of drugs for treating arthritis. As a PhD candidate, he joined the laboratory of chemistry Professor Jeremiah Johnson to learn macromolecular synthesis with a focus on nanomaterials designed for drug delivery. The final piece would fall into place with Bhagchandani’s early forays into immunology — with Darrell Irvine, the Underwood-Prescott Professor of Biological Engineering and Materials Science and Engineering at MIT and Stefani Spranger, the Howard S. (1953) and Linda B. Stern Career Development Professor and assistant professor of biology at MIT.

“When I was exposed to immunology, I learned how relevant the immune system is to our daily life. I found that the biomedical challenges I was working on could be encapsulated by immunology,” Bhagchandani explains. “Drug delivery was my way in, but immunology is my path forward, where I think I will be able to make a contribution to improving human health.”

As a result, his interests have shifted toward cancer immunotherapy — aiming to make these treatments more viable for more patients by making them less toxic. Supported, in part, by the Koch Institute Frontier Research Program, which provides seed funding for high-risk, high-reward/innovative early-stage research, Bhagchandani is focusing on imidazoquinolines, a promising class of drugs that activates the immune system to fight cancer, but can also trigger significant side effects when administered intravenously. In the clinic, topical administration has been shown to minimize these side effects in certain localized cancers, but additional challenges remain for metastatic cancers that have spread throughout the body.

In order to administer imidazoquinolines systemically with minimal toxicity to treat both primary and metastatic tumors, Bhagchandani is adapting a bottlebrush-shaped molecule developed in the Johnson lab to inactivate imidazoquinolines and carry them safely to tumors. Bhagchandani is fine-tuning linking molecules that release as little of the drug as possible while circulating in the blood, and then slowly release the drug once inside the tumor. He is also optimizing the size and architecture of the bottlebrush molecule so that it accumulates in the desired immune cells present in the tumor tissue.

“A lot of students work on interdisciplinary projects as part of a larger team, but Sachin is a one-man crew, able to synthesize new polymers using cutting edge chemistry, characterize these materials, and then test them in animal models of cancer and evaluate their effects on the immune system,” said Irvine. “His knowledge spans polymer chemistry to cancer modeling to immunology.”

Significant figures

Prior to enrolling at MIT, Bhagchandani already had a personal connection to cancer, both through his grandfather, who passed away from prostate cancer, and through working at a children’s hospital in his hometown of Mumbai, spending time with children with cancer. Once on campus, he discovered that working in the biomedical space would allow him to put his skills as a chemical engineer in service of addressing unmet medical needs. In addition, he found that the interdisciplinary nature of the work offered a variety of perspectives on which to build his career.

His doctoral project sits at the nexus of polymer chemistry, drug delivery, and immunology, and requires the collaboration of several laboratories, all members of the Koch Institute for Integrative Cancer Research at MIT. In addition to the Johnson lab, Bhagchandani is working with the Irvine lab for its expertise in immune engineering and the Langer lab for its expertise in drug delivery, and collaborating with the Spranger lab for its expertise in cancer immunology.

“For me, working at the Koch Institute has been one of the most formative experiences of my life, because I’ve gone from traditional chemical engineering training to being exposed to experts in all these different fields with many different perspectives,” said Bhagchandani. When working from the perspective of chemical engineering alone, Bhagchandani said he could not always find solutions to problems that arose.

“I was making the materials and testing them in mouse models, however I couldn’t understand why my experiments weren’t working,” he says. “But by having scientists and engineers who understand immunology, immune engineering, and drug delivery together in the same room, looking at the problem from different angles, that’s when you get that ‘a-ha’ moment, when a project actually works.”

“It is wonderful having brilliant, interdisciplinary scientists like Sachin in my group,” said Johnson. “He was the first student from the Chemical Engineering department to join my group in the Department of Chemistry for their PhD studies, and his ability to bring new perspectives to our work has been highly impactful. Now, led by Sachin, and through our collaborations with Darrell Irvine, Bob Langer, Stefani Spranger, and many others in the Koch Institute, we are able to translate our chemistry in ways we couldn’t have imagined before.”

In his postdoctoral training, Bhagchandani plans to dive deeper into the regulation of the immune system, particularly how different dosing regimens change the body’s response to immunotherapies. Ultimately, he hopes to continue his work as a faculty member leading his own immunology lab — one that focuses on understanding and harnessing early immune responses in cancer therapies.

“I would love to get to a point where I can recreate a lab environment for chemists, engineers, and immunologists to come together and interact and work on interdisciplinary problems. For cancer especially, you need to attack the problem on all different fronts.”

As well as advancing his work in the biomedical space, Bhagchandani hopes to serve as a mentor for future students figuring out their own paths.

“I feel like a lot of people at MIT, myself included, face challenges throughout their PhD where they start to lose belief: ‘Am I the right person, am I good enough for this?’ Having overcome a lot of challenging times when the project wasn’t working as we hoped it would, I think it is important to share these experiences with young trainees to empower them to pursue careers in research. Winning this award helps me look back at those challenges, and persevere, and know, yes, I’m still on the right path. Because I genuinely felt that this is what I want to do with my life and I’ve always felt really passionate coming in to work, that this is where I belong.”

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Source: https://news.mit.edu/2021/chemical-engineering-meets-cancer-immunotherapy-sachin-bhagchandani-0916

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Biotechnology

Chemical engineering meets cancer immunotherapy

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Sachin Bhagchandani, a graduate student in the Department of Chemical Engineering currently working at the Koch Institute for Integrative Cancer Research, has won the National Cancer Institute Predoctoral to Postdoctoral Fellow Transition (F99/K00) Award. Bhagchandani is the first student at MIT to receive the award.

The fellowship is given to outstanding graduate students with high potential and interest in becoming independent cancer researchers. Bhagchandani is one of 24 candidates selected for the fellowship this year. Nominations were limited to one student per institution. The award provides six years of funding, which will support Bhagchandani as he completes his PhD in chemical engineering and help him transition into a mentored, cancer-focused postdoctoral research position — one draws on his wide-ranging interests and newfound experiences in synthetic chemistry and immunology.

Making change

Bhagchandani’s research has evolved since his undergraduate days studying chemical engineering at the Indian Institute of Technology, Roorkee. He describes the experience as rigorous, but constraining. While at MIT, he has found more opportunities to explore, leading to highly interdisciplinary projects that allow him to put his training in chemical engineering in service of human health.

Before Bhagchandani arrived at his doctoral project, many pieces had to fall into place. While completing his Master’s thesis, Bhagchandani discovered his interest in the biomedical space while working on a project advised by MIT Institute Professor Robert Langer and Harvard Medical School Professor Jeffrey Karp developing different biomaterials for the sustained delivery of drugs for treating arthritis. As a PhD candidate, he joined the laboratory of chemistry Professor Jeremiah Johnson to learn macromolecular synthesis with a focus on nanomaterials designed for drug delivery. The final piece would fall into place with Bhagchandani’s early forays into immunology — with Darrell Irvine, the Underwood-Prescott Professor of Biological Engineering and Materials Science and Engineering at MIT and Stefani Spranger, the Howard S. (1953) and Linda B. Stern Career Development Professor and assistant professor of biology at MIT.

“When I was exposed to immunology, I learned how relevant the immune system is to our daily life. I found that the biomedical challenges I was working on could be encapsulated by immunology,” Bhagchandani explains. “Drug delivery was my way in, but immunology is my path forward, where I think I will be able to make a contribution to improving human health.”

As a result, his interests have shifted toward cancer immunotherapy — aiming to make these treatments more viable for more patients by making them less toxic. Supported, in part, by the Koch Institute Frontier Research Program, which provides seed funding for high-risk, high-reward/innovative early-stage research, Bhagchandani is focusing on imidazoquinolines, a promising class of drugs that activates the immune system to fight cancer, but can also trigger significant side effects when administered intravenously. In the clinic, topical administration has been shown to minimize these side effects in certain localized cancers, but additional challenges remain for metastatic cancers that have spread throughout the body.

In order to administer imidazoquinolines systemically with minimal toxicity to treat both primary and metastatic tumors, Bhagchandani is adapting a bottlebrush-shaped molecule developed in the Johnson lab to inactivate imidazoquinolines and carry them safely to tumors. Bhagchandani is fine-tuning linking molecules that release as little of the drug as possible while circulating in the blood, and then slowly release the drug once inside the tumor. He is also optimizing the size and architecture of the bottlebrush molecule so that it accumulates in the desired immune cells present in the tumor tissue.

“A lot of students work on interdisciplinary projects as part of a larger team, but Sachin is a one-man crew, able to synthesize new polymers using cutting edge chemistry, characterize these materials, and then test them in animal models of cancer and evaluate their effects on the immune system,” said Irvine. “His knowledge spans polymer chemistry to cancer modeling to immunology.”

Significant figures

Prior to enrolling at MIT, Bhagchandani already had a personal connection to cancer, both through his grandfather, who passed away from prostate cancer, and through working at a children’s hospital in his hometown of Mumbai, spending time with children with cancer. Once on campus, he discovered that working in the biomedical space would allow him to put his skills as a chemical engineer in service of addressing unmet medical needs. In addition, he found that the interdisciplinary nature of the work offered a variety of perspectives on which to build his career.

His doctoral project sits at the nexus of polymer chemistry, drug delivery, and immunology, and requires the collaboration of several laboratories, all members of the Koch Institute for Integrative Cancer Research at MIT. In addition to the Johnson lab, Bhagchandani is working with the Irvine lab for its expertise in immune engineering and the Langer lab for its expertise in drug delivery, and collaborating with the Spranger lab for its expertise in cancer immunology.

“For me, working at the Koch Institute has been one of the most formative experiences of my life, because I’ve gone from traditional chemical engineering training to being exposed to experts in all these different fields with many different perspectives,” said Bhagchandani. When working from the perspective of chemical engineering alone, Bhagchandani said he could not always find solutions to problems that arose.

“I was making the materials and testing them in mouse models, however I couldn’t understand why my experiments weren’t working,” he says. “But by having scientists and engineers who understand immunology, immune engineering, and drug delivery together in the same room, looking at the problem from different angles, that’s when you get that ‘a-ha’ moment, when a project actually works.”

“It is wonderful having brilliant, interdisciplinary scientists like Sachin in my group,” said Johnson. “He was the first student from the Chemical Engineering department to join my group in the Department of Chemistry for their PhD studies, and his ability to bring new perspectives to our work has been highly impactful. Now, led by Sachin, and through our collaborations with Darrell Irvine, Bob Langer, Stefani Spranger, and many others in the Koch Institute, we are able to translate our chemistry in ways we couldn’t have imagined before.”

In his postdoctoral training, Bhagchandani plans to dive deeper into the regulation of the immune system, particularly how different dosing regimens change the body’s response to immunotherapies. Ultimately, he hopes to continue his work as a faculty member leading his own immunology lab — one that focuses on understanding and harnessing early immune responses in cancer therapies.

“I would love to get to a point where I can recreate a lab environment for chemists, engineers, and immunologists to come together and interact and work on interdisciplinary problems. For cancer especially, you need to attack the problem on all different fronts.”

As well as advancing his work in the biomedical space, Bhagchandani hopes to serve as a mentor for future students figuring out their own paths.

“I feel like a lot of people at MIT, myself included, face challenges throughout their PhD where they start to lose belief: ‘Am I the right person, am I good enough for this?’ Having overcome a lot of challenging times when the project wasn’t working as we hoped it would, I think it is important to share these experiences with young trainees to empower them to pursue careers in research. Winning this award helps me look back at those challenges, and persevere, and know, yes, I’m still on the right path. Because I genuinely felt that this is what I want to do with my life and I’ve always felt really passionate coming in to work, that this is where I belong.”

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Source: https://news.mit.edu/2021/chemical-engineering-meets-cancer-immunotherapy-sachin-bhagchandani-0916

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Biotechnology

Biologists identify new targets for cancer vaccines

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Over the past decade, scientists have been exploring vaccination as a way to help fight cancer. These experimental cancer vaccines are designed to stimulate the body’s own immune system to destroy a tumor, by injecting fragments of cancer proteins found on the tumor.

So far, none of these vaccines have been approved by the FDA, but some have shown promise in clinical trials to treat melanoma and some types of lung cancer. In a new finding that may help researchers decide what proteins to include in cancer vaccines, MIT researchers have found that vaccinating against certain cancer proteins can boost the overall T cell response and help to shrink tumors in mice.

The research team found that vaccinating against the types of proteins they identified can help to reawaken dormant T cell populations that target those proteins, strengthening the overall immune response.

“This study highlights the importance of exploring the details of immune responses against cancer deeply. We can now see that not all anticancer immune responses are created equal, and that vaccination can unleash a potent response against a target that was otherwise effectively ignored,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

MIT postdoc Megan Burger is the lead author of the new study, which appears today in Cell.

T cell competition

When cells begin to turn cancerous, they start producing mutated proteins not seen in healthy cells. These cancerous proteins, also called neoantigens, can alert the body’s immune system that something has gone wrong, and T cells that recognize those neoantigens start destroying the cancerous cells.

Eventually, these T cells experience a phenomenon known as “T cell exhaustion,” which occurs when the tumor creates an immunosuppressive environment that disables the T cells, allowing the tumor to grow unchecked.

Scientists hope that cancer vaccines could help to rejuvenate those T cells and help them to attack tumors. In recent years, they have worked to develop methods for identifying neoantigens in patient tumors to incorporate into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer.

“These therapies work amazingly in a subset of patients, but the vast majority still don’t respond very well,” Burger says. “A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding.”

Previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small number generate a T cell response.

The new MIT study helps to shed light on why that is. In studies of mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets of T cells that target different cancerous proteins compete with each other, eventually leading to the emergence of one dominant population of T cells. After these T cells become exhausted, they still remain in the environment and suppress any competing T cell populations that target different proteins found on the tumor.

However, Burger found that if she vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate those T cell populations.

“If you vaccinate against antigens that have suppressed responses, you can unleash those T cell responses,” she says. “Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies.”

Shrinking tumors

In this study, the researchers found that they had the most success when vaccinating with neoantigens that bind weakly to immune cells that are responsible for presenting the antigen to T cells. When they used one of those neoantigens to vaccinate mice with lung tumors, they found the tumors shrank by an average of 27 percent.

“The T cells proliferate more, they target the tumors better, and we see an overall decrease in lung tumor burden in our mouse model as a result of the therapy,” Burger says.

After vaccination, the T cell population included a type of cells that have the potential to continuously refuel the response, which could allow for long-term control of a tumor.

In future work, the researchers hope to test therapeutic approaches that would combine this vaccination strategy with cancer drugs called checkpoint inhibitors, which can take the brakes off exhausted T cells, stimulating them to attack tumors. Supporting that approach, the results published today also indicate that vaccination boosts the number of a specific type of T cells that have been shown to respond well to checkpoint therapies.

The research was funded by the Howard Hughes Medical Institute, the Ludwig Center at Harvard University, the National Institutes of Health, the Koch Institute Support (core) Grant from the National Cancer Institute, the Bridge Project of the Koch Institute and Dana-Farber/Harvard Cancer Center, and fellowship awards from the Jane Coffin Childs Memorial Fund for Medical Research and the Ludwig Center for Molecular Oncology at MIT.

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Source: https://news.mit.edu/2021/tumor-vaccine-t-cells-0916

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Biotechnology

New programmable gene editing proteins found outside of CRISPR systems

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Within the last decade, scientists have adapted CRISPR systems from microbes into gene editing technology, a precise and programmable system for modifying DNA. Now, scientists at MIT’s McGovern Institute for Brain Research and the Broad Institute of MIT and Harvard have discovered a new class of programmable DNA modifying systems called OMEGAs (Obligate Mobile Element Guided Activity), which may naturally be involved in shuffling small bits of DNA throughout bacterial genomes.

These ancient DNA-cutting enzymes are guided to their targets by small pieces of RNA. While they originated in bacteria, they have now been engineered to work in human cells, suggesting they could be useful in the development of gene editing therapies, particularly as they are small (about 30 percent of the size of Cas9), making them easier to deliver to cells than bulkier enzymes. The discovery, reported Sept. 9 in the journal Science, provides evidence that natural RNA-guided enzymes are among the most abundant proteins on Earth, pointing toward a vast new area of biology that is poised to drive the next revolution in genome editing technology.

The research was led by McGovern Investigator Feng Zhang, who is the James and Patricia Poitras Professor of Neuroscience at MIT, a Howard Hughes Medical Institute investigator, and a Core Institute Member of the Broad Institute. Zhang’s team has been exploring natural diversity in search of new molecular systems that can be rationally programmed.

“We are super excited about the discovery of these widespread programmable enzymes, which have been hiding under our noses all along,” says Zhang. “These results suggest the tantalizing possibility that there are many more programmable systems that await discovery and development as useful technologies.”

Natural adaptation

Programmable enzymes, particularly those that use an RNA guide, can be rapidly adapted for different uses. For example, CRISPR enzymes naturally use an RNA guide to target viral invaders, but biologists can direct Cas9 to any target by generating their own RNA guide. “It’s so easy to just change a guide sequence and set a new target,” says Soumya Kannan, MIT graduate student in biological engineering and co-first author of the paper. “So one of the broad questions that we’re interested in is trying to see if other natural systems use that same kind of mechanism.”

The first hints that OMEGA proteins might be directed by RNA came from the genes for proteins called IscBs. The IscBs are not involved in CRISPR immunity and were not known to associate with RNA, but they looked like small, DNA-cutting enzymes. The team discovered that each IscB had a small RNA encoded nearby and it directed IscB enzymes to cut specific DNA sequences. They named these RNAs “ωRNAs.”

The team’s experiments showed that two other classes of small proteins known as IsrBs and TnpBs, one of the most abundant genes in bacteria, also use ωRNAs that act as guides to direct the cleavage of DNA.

IscB, IsrB, and TnpB are found in mobile genetic elements called transposons. Han Altae-Tran, MIT graduate student in biological engineering and co-first author on the paper, explains that each time these transposons move, they create a new guide RNA, allowing the enzyme they encode to cut somewhere else.

It’s not clear how bacteria benefit from this genomic shuffling — or whether they do at all. Transposons are often thought of as selfish bits of DNA, concerned only with their own mobility and preservation, Kannan says. But if hosts can “co-opt” these systems and repurpose them, hosts may gain new abilities, as with CRISPR systems that confer adaptive immunity.

IscBs and TnpBs appear to be predecessors of Cas9 and Cas12 CRISPR systems. The team suspects they, along with IsrB, likely gave rise to other RNA-guided enzymes, too — and they are eager to find them. They are curious about the range of functions that might be carried out in nature by RNA-guided enzymes, Kannan says, and suspect evolution likely already took advantage of OMEGA enzymes like IscBs and TnpBs to solve problems that biologists are keen to tackle.

“A lot of the things that we have been thinking about may already exist naturally in some capacity,” says Altae-Tran. “Natural versions of these types of systems might be a good starting point to adapt for that particular task.”

The team is also interested in tracing the evolution of RNA-guided systems further into the past. “Finding all these new systems sheds light on how RNA-guided systems have evolved, but we don’t know where RNA-guided activity itself comes from,” Altae-Tran says. Understanding those origins, he says, could pave the way to developing even more classes of programmable tools.

This work was made possible with support from the Simons Center for the Social Brain at MIT, the National Institutes of Health and its Intramural Research Program, Howard Hughes Medical Institute, Open Philanthropy, G. Harold and Leila Y. Mathers Charitable Foundation, Edward Mallinckrodt, Jr. Foundation, Poitras Center for Psychiatric Disorders Research at MIT, Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, Yang-Tan Center for Molecular Therapeutics at MIT, Lisa Yang, Phillips family, R. Metcalfe, and J. and P. Poitras.

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Source: https://news.mit.edu/2021/new-programmable-gene-editing-proteins-found-outside-crispr-systems-0915

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