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Humans have been tinkering with the genetics of food for millennia, but modern genetic engineering techniques have proven controversial

Author of the article:

Clustered regularly interspaced short palindromic repeats.

Otherwise known as CRISPR, it is a term many people know is associated with genetic engineering particularly of food. But, what exactly is genetic engineering?

The science of adjusting the genetic makeup of plants has been in process for thousands of years. From the time humans transitioned from hunter-gatherers to farmers, weve been tinkering with food. This plant has those characteristics and if we wed them to this one, will it grow better in this environment? Will it taste better? Will it be drought-resistant? Will it be disease tolerant? And so on.

By the middle of the last century, scientists were rapidly moving toward sequencing the genomes of everything, including people. Genetics now play a vitally important role in innovations in medicine, trees, food, etc.

Somewhere along the way, genetic engineering of food got a bad rap and, now, many people are openly campaigning against bioengineering of plants.

I wanted to ask someone who actually does this type of work, what they do, why they do it, and can we trust them and the foods they produce. Larry Gilbertson of Bayer Crop Sciences joined a Conversation That Matters about innovations in plant biotechnology.

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Conversations That Matter: Talk GMO with a GMO scientist - Vancouver Sun

More than 10% of the worlds crop land grow Genetically Modified crops or GM crops. Scientists around the world have been asserting that GM crops can solve the worlds hunger problem. Still concerns about health and environment prevail. What are GM crops and what are their merits and demerits? Lets find out...

As the name suggests, GM food involves the editing of genes of a crop in such a way that it incorporates beneficial traits from another crop or organism. This could mean changing the way the plant grows, or making it resistant to a particular disease. Food produced using the edited crop is called GM food. This is done using the tools of genetic engineering.

Let us assume that scientists want to produce wheat with high protein content and they decide to incorporate the high protein quality of beans into wheat. To make this possible, a specific sequence of DNA with protein-making trait is isolated from the bean (which is called the donor organism) and is inserted into the gene structure of wheat, in a laboratory process. The new gene or the transgene thus produced is transferred into the recipient cells (wheat cells). The cells are then grown in tissue culture where they develop into plants. The seeds produced by these plants will inherit the new DNA structure.

Traditional cultivation of these seeds will then be undertaken and we will have genetically modified wheat with high protein content. The trait can be anything. A DNA from a plant that has high resistance to pests can be introduced into another so that the second plant variety will have the pest-resistant trait. A DNA of blueberry could be inserted into that of a banana to get a blue banana. The exchange could be effected between two or more organisms. One can even introduce a gene of a fish into a plant. You dont believe it? Consider this fact. Genes from an Arctic fish were inserted into tomatoes to make it tolerant to frost. This tomato gained the moniker fish tomato. But it never reached the market.

GM crops are perceived to offer benefits to both producers and consumers. Some of them are listed below...

Genetic engineering can improve crop protection. Crops with better resistance to pest and diseases can be created. The use of herbicides and pesticides can be reduced or even eliminated.

Farmers can achieve high yield, and thereby get more income.

Nutritional content can be improved.

Shelf life of foods can be extended.

Food with better taste and texture can be achieved.

Crops can be engineered to withstand extreme weather

Genetically engineered foods often present unintended side effects. Genetic engineering is a new field, and long-term results are unclear. Very little testing has been done on GM food.

Some crops have been engineered to create their own toxins against pests. This may harm non-targets such as farm animals that ingest them. The toxins can also cause allergy and affect digestion in humans.

Further, GM crops are modified to include antibiotics to kill germs and pests. And when we eat them, these antibiotic markers will persist in our body and will render actual antibiotic medications less effective over a period of time, leading to superbug threats. This means illnesses will become more difficult to cure.

Besides health and environmental concerns, activists point to social and economic issues. They have voiced serious concern about multinational agribusiness companies taking over farming from the hands of small farmers. Dependence on GM seed companies could prove to be a financial burden for farmers.

Farmers are reluctant because they will have limited rights to retain and reuse seeds.

Their concern also includes finding a market that would accept GM food.

People in general are wary of GM crops as they are engineered in a lab and do not occur in Nature

Excerpt from:
The science behind GM crops - The Hindu

One of the most powerful tools available to biologists these days is CRISPR-Cas9, a combination of specialized RNA and protein that acts like a molecular scalpel, allowing researchers to precisely slice and dice pieces of an organism's genetic code.

But even though CRISPR-Cas9 technology has offered an unprecedented level of control for those studying genetics and genetic engineering, there has been room for improvement. Now, a new technique developed at Caltech by biology graduate student Shashank "Sha" Gandhi in the lab of Marianne Bronner, Distinguished Professor of Biology and director of the Beckman Institute, is taking CRISPR-Cas9 accessibility to the next level.

In a paper appearing in the journal Development, Gandhi and members of Bronner's lab describe the new technique, which has been designed specifically to disable or remove genes from a genome. This is known as "knocking out" a gene.

Gene knockout is an important method for studying what genes do because researchers can compare the behavior of a cell that has a working gene to the behavior of a cell in which that gene has been disabled. CRISPR-Cas9 has already been used for this, usually alongside genetic material that encodes a fluorescent protein, which makes it easy to identify cells from which a gene has been removed; cells with a knocked-out gene will glow.

One drawback of the technique, however, is that each part of the payload that makes it workthe Cas9 protein, the guide RNA, and the code for the fluorescent proteinhave to be delivered separately using a technique called electroporation, which opens the membranes of cells by zapping them with electricity. This can result in some cells receiving only some of the pieces. Thus, a cell could receive the code for making fluorescent protein, but not end up with a knocked-out gene. Or a cell could end up with its targeted gene knocked out, but not have the code to make fluorescent protein. Either case makes it more challenging for researchers to study how the cells are behaving.

"The advent of CRISPR has allowed people like me and Sha to work on just about any organism," Bronner says. "The caveat is that not every cell gets the same cocktail."

Another, bigger problem, has been that these CRISPR-Cas9 combinations often did not work across species lines because of a component known as a U6 promotera DNA sequence that tells a cell's machinery when and where to start making the guide RNA from a plasmid, a short loop of DNA that can be easily introduced into cells. A promoter that works in a fruit fly's genome will not necessarily work in that of a mouse, for example.

"The problem with the U6 promoter is that every species has its own version, so if you're working on a new system, you might not have a U6 to use," says Gandhi.

The new tool developed by Gandhi and other researchers in Bronner's lab eliminates both problems. Whereas the old CRISPR-Cas9 delivered each part of their payload separately, the new tool packages them together on a single plasmid. Because the plasmid contains all three required parts, the problem of a cell receiving only one or two of them is eliminated. The team's design also bypasses the need for using a U6 promoter, thereby enabling CRISPR-Cas9-based editing across multiple species.

"If you use plasmids for your CRISPR-Cas9 knockout experiments in an organism, this is the best way so far," Gandhi says.

Gandhi says that there is a growing interest in the tool among other research teams.

"We've actually been getting requests from around the world from people who are interested in using these tools in their research," he says. "I think that it will take a little bit of time for the tool to really pick up, but we've already received a lot of requests."

Bronner adds that her lab is working with Niles Pierce, professor of applied and computational mathematics and bioengineering, to develop more elaborate implementations of the tool.

"We're working on making this tool conditional, so you could say 'I want to lose gene X when gene Y turns on,' and the results are looking really promising," she says.

The paper describing their work, titled, "A single-plasmid approach for genome editing coupled with long-term lineage analysis in chick embryos," appears in the April 1 issue of the journal Development. Co-authors are biology graduate student Weiyi Tang; senior postdoctoral scholar in biology and biological engineering; Michael L. Piacentino, senior postdoctoral scholar research associate in biology and biological engineering; former postdoctoral scholars Yuwei Li and Felipe M. Vieceli; graduate student Hugo A. Urrutia; and Jens B. Christensen from the University of Copenhagen.

Funding for the research was provided by the National Institutes of Health and the American Heart Association.

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Researchers Improve Efficiency and Accessibility of CRISPR - Caltech

REDWOOD CITY, Calif., June 10, 2021 (GLOBE NEWSWIRE) -- Codexis, Inc., a leading enzyme engineering company enabling the promise of synthetic biology, today announced the expansion of its strategic collaboration and license agreement with Takeda Pharmaceutical Company Limited (Takeda) for the research and development of an additional gene therapy for a lysosomal storage disorder bringing the total number of programs under the agreement to four.

Under the terms of the original March 2020 agreement, Codexis leveraged its CodeEvolver protein engineering platform to generate novel gene sequences encoding enzyme variants that are tailored to enhance efficacy by increasing activity, stability, and cellular uptake. Takeda is combining these improved transgenes with its gene therapy capabilities to develop novel candidates for the treatment of rare genetic disorders.

We are thrilled to expand our collaboration with Takeda to advance novel gene therapies for the treatment of rare diseases. Over the past year, our CodeEvolver technology has generated novel genetic sequences that encode more efficacious enzymes for the potential treatment of Fabry and Pompe Diseases, as well as an undisclosed blood factor deficiency. Codexis and Takeda are excited about the prospect for each of these improved sequences to enable differentiated gene therapies for patients with rare genetic diseases, stated John Nicols, Codexis President and CEO.

Gjalt Huisman, Codexis Senior Vice-President, Biotherapeutics added, Within a year of embarking on our collaboration, the Codexis and Takeda research teams have made tremendous progress in generating and evaluating engineered gene sequences for the three separate therapeutic indications. We are proud that based on the results to date Takeda has exercised its option to initiate a fourth program.

Terms of AgreementUnder the terms of the original agreement, the parties began collaborative work on three initial programs. Takeda had the contractual option to expand the collaboration into a fourth program. Codexis is responsible for the creation of novel enzyme sequences for advancement as gene therapies into pre-clinical development. Takeda is responsible for the pre-clinical and clinical development and commercialization of gene therapy products resulting from the collaboration programs. Subject to the terms of the agreement, Codexis is eligible to receive an upfront payment, reimbursement for research and development fees, development and commercial milestone payments, and low- to mid-single digit percentage royalties on sales of any commercial product developed through programs initiated under the agreement.

About Codexis, Inc.Codexis is a leading enzyme engineering company leveraging its proprietary CodeEvolver platform to discover and develop novel, high performance enzymes and novel biotherapeutics. Codexis enzymes have applications in the sustainable manufacturing of pharmaceuticals, food, and industrial products; in the creation of the next generation of life science tools; and as gene therapy and biologic therapeutics. The Companys unique performance enzymes drive improvements such as: reduced energy usage, waste generation and capital requirements; higher yields; higher fidelity diagnostics; and more efficacious therapeutics. Codexis enzymes enable the promise of synthetic biology to improve the health of people and the planet. For more information, visit http://www.codexis.com.

Forward-Looking StatementsTo the extent that statements contained in this press release are not descriptions of historical facts regarding Codexis, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including Codexis expectations regarding the prospects for the development and future commercialization by Takeda of novel gene therapies for specified target indications. You should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors that are, in some cases, beyond Codexis control and that could materially affect actual results. Factors that could materially affect actual results include, among others: Codexis dependence on its licensees and collaborators; the regulatory approval processes of the FDA and comparable foreign authorities are lengthy, time consuming and inherently unpredictable; results of preclinical studies and early clinical trials of product candidates may not be predictive of results of later studies or trials; even if we or our collaborators obtain regulatory approval for any products that are developed during a collaboration, such products will remain subject to ongoing regulatory requirements, which may result in significant additional expense; and there may be potential adverse effects to Codexis business if our collaborators products are not received well in the markets. Additional information about factors that could materially affect actual results can be found in Codexis Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on March 1, 2021 and in Codexis Quarterly Report on Form 10-Q filed with the SEC on May 7, 2021, including under the caption Risk Factors and in Codexis other periodic reports filed with the SEC. Codexis expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law.

Investor Contact:Argot PartnersStephanie Marks/Carrie McKimCodexis@argotpartners.com(212) 600-1902

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Codexis and Takeda Expand Strategic Collaboration and License Agreement to Discover Additional Gene Therapy for a Fourth Rare Genetic Disorder -...

Opinion

Recently, I did something I had not done in a long time. I ate in a restaurant with my family. Actually, we ate on the outdoor patio, since my kids are too young to be vaccinated and we are somewhat more squeamish than average about COVID, but it was nevertheless a refreshing return to normality and a welcome rest from battling traffic on the way to the Delaware seashore.

I ordered a salad with blackened salmon. If we make the trip again, I will make a different choice.

Thats because last week, biotech company AquaBounty Technologies Inc. announced that it is harvesting several tons of genetically modified salmon, which will soon be sold at restaurants and other away-from-home dining retailers around the country. So far just one distributor Philadelphia-based Samuels and Son Seafoodhas reportedly said that it will be selling the novel salmon. But AquaBounty has announced plans to sell its salmon via food service channels across the Midwest and East Coast.

By selling to restaurants and cafeterias, rather than retailers, AquaBounty can avoid the federal GMO labeling law. And this sets a troubling precedent. Consumers who do not want to eat GMO fish will have to avoid salmon altogether when dining out.

There are many reasons why someone might not wish to consume meat from genetically engineered animals. They may not trust the U.S. Food and Drug Administrations (FDAs) safety assessment of the food. FDA conducted a lengthy review process of AquaBountys salmon, and concluded that it was no different in its nutrition profile and levels of hormones than conventional farm-raised salmon. But the salmon is a novel food, and some consumers may justifiably want to take a wait and see approach.

Other consumers may have concerns about the environmental risks associated with bioengineering animals, including the risk of transgenic contamination, whereby escaped GMO species crossbreed with native fish. Last year, a federal court ruled in favor of the advocacy group Center for Food Safety, ordering FDA to conduct an environmental assessment of its AquaBounty approval that takes the risk of fish escaping and reproducing in the environment into account. However, the judge allowed FDAs approval to stand pending completion of that assessment, because he deemed the near-term risk of such environmental harm to be low.

A consumer may worry that genetically engineering animals could harm animal welfare, just as conventional breeding has in some cases, or even that genetic engineering is fundamentally incompatible with the increasing recognition that livestock animals (and all sentient animals) deserve some moral standing, independent of their value as a commodity.

A consumer may see genetically engineered animals as synonymous with a corporate takeover of the food system, or as an affront to indigenous communities who have traditionally depended on wild salmon. This concern features prominently in Aramarks statement explaining its decision not to serve GMO salmon.

Aramark is not alone. Compass Group, Sodexo, Costco, Kroger, Walmart and Whole Foods have all pledged not to sell GMO salmon, at the behest of groups like the Center for Food Safety. But plenty of other outlets have made no such commitment, including (as far as I can tell) the restaurant where my family ate the other day.

AquaBounty and its supporters have a lot of good responses to concerns about GMO salmon, and ultimately, their arguments may win out in the court of public opinion. Personally, while I might aspire to one day eat an exclusively vegan, locavore diet that makes the world a better place with every bite, I might try the GMO salmon myself at some point.

But not like this. Consumers deserve to know whether the salmon on the menu comes from the first ever genetically engineered animal approved for human consumption. Food safety aside, consumers deserve the opportunity to consider the ethical and political issues enmeshed in genetically engineered animals before chowing down. At the very least, they should have the chance to notice whether this novel food tastes any different than its conventional counterpart. Pretending like this information is not important is an insult to the public, and creates the risk of a backlash that could erode confidence in both genetic engineering technology and the food system as a whole.

From what I know about FDAs food safety assessment, AquaBountys salmon seems safe to eat. But food safety concerns will nevertheless lead me to abstain from salmon of questionable origin for the foreseeable future. I want what I eat to contribute to a safer food system. And all else equal, a safer food system is a more transparent food system. How much transparency do we need? Reasonable people will disagree. But for me, secretly serving unsuspecting restaurant patrons genetically engineered salmonor pork or whatever else gets approved by FDAdeserves protest.

Thats a shame because a lot of difficult problemsfrom climate change to antibiotic resistance to invasive speciesmight conceivably get easier with the help of genetic engineering. But without public support, or trust, the technology is more likely to just serve the bottom line of a few unscrupulous companies.

(To sign up for a free subscription to Food Safety News, click here.)

Original post:
Not ready to eat GMO animals? Then you might not want to order the salmon - Food Safety News

Marianne Bronner and Shashank Gandhi (Credit: Caltech)

One of the most powerful tools available to biologists these days is CRISPR-Cas9, a combination of specialized RNA and protein that acts like a molecular scalpel, allowing researchers to precisely slice and dice pieces of an organisms genetic code.

But even though CRISPR-Cas9 technology has offered an unprecedented level of control for those studying genetics and genetic engineering, there has been room for improvement. Now, a new technique developed at Caltech by biology graduate student Shashank Sha Gandhi in the lab ofMarianne Bronner, Distinguished Professor of Biology and director of the Beckman Institute, is taking CRISPR-Cas9 accessibility to the next level.

In a paper appearing in the journalDevelopment, Gandhi and members of Bronners lab describe the new technique, which has been designed specifically to disable or remove genes from a genome. This is known as knocking out a gene.

Gene knockout is an important method for studying what genes do because researchers can compare the behavior of a cell that has a working gene to the behavior of a cell in which that gene has been disabled. CRISPR-Cas9 has already been used for this, usually alongside genetic material that encodes a fluorescent protein, which makes it easy to identify cells from which a gene has been removed; cells with a knocked-out gene will glow.

One drawback of the technique, however, is that each part of the payload that makes it workthe Cas9 protein, the guide RNA, and the code for the fluorescent proteinhave to be delivered separately using a technique called electroporation, which opens the membranes of cells by zapping them with electricity. This can result in some cells receiving only some of the pieces. Thus, a cell could receive the code for making fluorescent protein, but not end up with a knocked-out gene. Or a cell could end up with its targeted gene knocked out, but not have the code to make fluorescent protein. Either case makes it more challenging for researchers to study how the cells are behaving.

The advent of CRISPR has allowed people like me and Sha to work on just about any organism, Bronner says. The caveat is that not every cell gets the same cocktail.

Another, bigger problem, has been that these CRISPR-Cas9 combinations often did not work across species lines because of a component known as a U6 promotera DNA sequence that tells a cells machinery when and where to start making the guide RNA from a plasmid, a short loop of DNA that can be easily introduced into cells. A promoter that works in a fruit flys genome will not necessarily work in that of a mouse, for example.

The problem with the U6 promoter is that every species has its own version, so if youre working on a new system, you might not have a U6 to use, says Gandhi.

The new tool developed by Gandhi and other researchers in Bronners lab eliminates both problems. Whereas the old CRISPR-Cas9 delivered each part of their payload separately, the new tool packages them together on a single plasmid. Because the plasmid contains all three required parts, the problem of a cell receiving only one or two of them is eliminated. The teams design also bypasses the need for using a U6 promoter, thereby enabling CRISPR-Cas9-based editing across multiple species.

If you use plasmids for your CRISPR-Cas9 knockout experiments in an organism, this is the best way so far, Gandhi says.

Gandhi says that there is a growing interest in the tool among other research teams.

Weve actually been getting requests from around the world from people who are interested in using these tools in their research, he says. I think that it will take a little bit of time for the tool to really pick up, but weve already received a lot of requests.

Bronner adds that her lab is working with Niles Pierce, professor of applied and computational mathematics and bioengineering, to develop more elaborate implementations of the tool.

Were working on making this tool conditional, so you could say I want to lose gene X when gene Y turns on, and the results are looking really promising, she says.

The paper describing their work, titled, A single-plasmid approach for genome editing coupled with long-term lineage analysis in chick embryos, appears in the April 1 issue of the journalDevelopment. Co-authors are biology graduate student Weiyi Tang; senior postdoctoral scholar in biology and biological engineering; Michael L. Piacentino, senior postdoctoral scholar research associate in biology and biological engineering; former postdoctoral scholars Yuwei Li and Felipe M. Vieceli; graduate student Hugo A. Urrutia; and Jens B. Christensen from the University of Copenhagen.

Funding for the research was provided by the National Institutes of Health and the American Heart Association.

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Caltech Researchers Improve Usefulness of Powerful Tool Used to Edit Genes Pasadena Now - Pasadena Now

This image shows specialized lung cells (resembling a beaded necklace) that may mount a cytokine storm in response to some viral infections. Credit: UC San Diego Health Sciences

Gene expression patterns associated with pandemic viral infections provide a map to help define patients immune responses, measure disease severity, predict outcomes and test therapies for current and future pandemics.

Researchers at University of California San Diego School of Medicine used an artificial intelligence (AI) algorithm to sift through terabytes of gene expression data which genes are on or off during infection to look for shared patterns in patients with past pandemic viral infections, including SARS, MERS and swine flu.

Two telltale signatures emerged from the study, published today (June 11, 2021) in eBiomedicine. One, a set of 166 genes, reveals how the human immune system responds to viral infections. A second set of 20 signature genes predicts the severity of a patients disease. For example, the need to hospitalize or use a mechanical ventilator. The algorithms utility was validated using lung tissues collected at autopsies from deceased patients with COVID-19 and animal models of the infection.

These viral pandemic-associated signatures tell us how a persons immune system responds to a viral infection and how severe it might get, and that gives us a map for this and future pandemics, said Pradipta Ghosh, MD, professor of cellular and molecular medicine at UC San Diego School of Medicine and Moores Cancer Center.

From a simple blood draw, gene expression patterns associated with pandemic viral infections could provide clinicians with a map to help define patients immune responses, measure disease severity, predict outcomes and test therapies. Credit: UC San Diego Health Sciences

Ghosh co-led the study with Debashis Sahoo, PhD, assistant professor of pediatrics at UC San Diego School of Medicine and of computer science and engineering at Jacobs School of Engineering, and Soumita Das, PhD, associate professor of pathology at UC San Diego School of Medicine.

During a viral infection, the immune system releases small proteins called cytokines into the blood. These proteins guide immune cells to the site of infection to help get rid of the infection. Sometimes, though, the body releases too many cytokines, creating a runaway immune system that attacks its own healthy tissue. This mishap, known as a cytokine storm, is believed to be one of the reasons some virally infected patients, including some with the common flu, succumb to the infection while others do not.

But the nature, extent and source of fatal cytokine storms, who is at greatest risk and how it might best be treated have long been unclear.

When the COVID-19 pandemic began, I wanted to use my computer science background to find something that all viral pandemics have in common some universal truth we could use as a guide as we try to make sense of a novel virus, Sahoo said. This coronavirus may be new to us, but there are only so many ways our bodies can respond to an infection.

The data used to test and train the algorithm came from publicly available sources of patient gene expression data all the RNA transcribed from patients genes and detected in tissue or blood samples. Each time a new set of data from patients with COVID-19 became available, the team tested it in their model. They saw the same signature gene expression patterns every time.

In other words, this was what we call a prospective study, in which participants were enrolled into the study as they developed the disease and we used the gene signatures we found to navigate the uncharted territory of a completely new disease, Sahoo said.

By examining the source and function of those genes in the first signature gene set, the study also revealed the source of cytokine storms: the cells lining lung airways and white blood cells known as macrophages and T cells. In addition, the results illuminated the consequences of the storm: damage to those same lung airway cells and natural killer cells, a specialized immune cell that kills virus-infected cells.

We could see and show the world that the alveolar cells in our lungs that are normally designed to allow gas exchange and oxygenation of our blood, are one of the major sources of the cytokine storm, and hence, serve as the eye of the cytokine storm, Das said. Next, our HUMANOID Center team is modeling human lungs in the context of COVID-19 infection in order to examine both acute and post-COVID-19 effects.

The researchers think the information might also help guide treatment approaches for patients experiencing a cytokine storm by providing cellular targets and benchmarks to measure improvement.

To test their theory, the team pre-treated rodents with either a precursor version of Molnupiravir, a drug currently being tested in clinical trials for the treatment of COVID-19 patients, or SARS-CoV-2-neutralizing antibodies. After exposure to SARS-CoV-2, the lung cells of control-treated rodents showed the pandemic-associated 166- and 20-gene expression signatures. The treated rodents did not, suggesting that the treatments were effective in blunting cytokine storm.

It is not a matter of if, but when the next pandemic will emerge, said Ghosh, who is also director of the Institute for Network Medicine and executive director of the HUMANOID Center of Research Excellence at UC San Diego School of Medicine. We are building tools that are relevant not just for todays pandemic, but for the next one around the corner.

Reference: 11 June 2021, eBiomedicine.DOI: 10.1016/j.ebiom.2021.103390

Co-authors of the study include: Gajanan D. Katkar, Soni Khandelwal, Mahdi Behroozikhah, Amanraj Claire, Vanessa Castillo, Courtney Tindle, MacKenzie Fuller, Sahar Taheri, Stephen A. Rawlings, Victor Pretorius, David M. Smith, Jason Duran, UC San Diego; Thomas F. Rogers, Scripps Research and UC San Diego; Nathan Beutler, Dennis R. Burton, Scripps Research; Sydney I. Ramirez, La Jolla Institute for Immunology; Laura E. Crotty Alexander, VA San Diego Healthcare System and UC San Diego; Shane Crotty, Jennifer M. Dan, La Jolla Institute for Immunology and UC San Diego.

Funding: National Institutes for Health, UC San Diego Sanford Stem Cell Clinical Center, La Jolla Institute for Immunology Institutional Funds, and VA San Diego Healthcare System

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AI Trained With Genetic Data Predicts How Patients With Viral Infections Including COVID-19 Will Fare - SciTechDaily

Can we reprogram existing life at will?

To synthetic biologists, the answer is yes. The central code for biology is simple. DNA letters, in groups of three, are translated into amino acidsLego blocks that make proteins. Proteins build our bodies, regulate our metabolism, and allow us to function as living beings. Designing custom proteins often means you can redesign small aspects of lifefor example, getting a bacteria to pump out life-saving drugs like insulin.

All life on Earth follows this rule: a combination of 64 DNA triplet codes, or codons, are translated into 20 amino acids.

But wait. The math doesnt add up. Why wouldnt 64 dedicated codons make 64 amino acids? The reason is redundancy. Life evolved so that multiple codons often make the same amino acid.

So what if we tap into those redundant extra codons of all living beings, and instead insert our own code?

A team at the University of Cambridge recently did just that. In a technological tour de force, they used CRISPR to replace over 18,000 codons with synthetic amino acids that dont exist anywhere in the natural world. The result is a bacteria thats virtually resistant to all viral infectionsbecause it lacks the normal protein door handles that viruses need to infect the cell.

But thats just the beginning of engineering lifes superpowers. Until now, scientists have only been able to slip one designer amino acid into a living organism. The new work opens the door to hacking multiple existing codons at once, copyediting at least three synthetic amino acids at the same time. And when its 3 out of 20, thats enough to fundamentally rewrite life as it exists on Earth.

Weve long thought that liberating a subset ofcodons for reassignment could improve the robustness and versatility of genetic-code expansion technology, wrote Drs. Delilah Jewel and Abhishek Chatterjee at Boston College, who were not involved in the study. This work elegantly transforms that dream into a reality.

Our genetic code underlies life, inheritance, and evolution. But it only works with the help of proteins.

The program for translating genes, written in DNAs four letters, into the actual building blocks of life relies on a full cellular decryption factory.

Think of DNAs lettersA, T, C, and Gas a secret code, written on a long slip of crinkled paper wrapped around a spool. Groups of three letters, or codons, are the cruxthey encode which amino acid a cell makes. A messenger molecule (mRNA), a spy of sorts, stealthily copies the DNA message and sneaks back into the cellular world, shuttling the message to the cells protein factorya sort of central intelligence organization.

There, the factory recruits multiple translators to decipher the genetic code into amino acids, aptly named tRNAs. The letters are grouped in threes, and each translator tRNA physically drags its associated amino acid to the protein factory, one by one, so that the factory eventually makes a chain that wraps into a 3D protein.

But like any robust code, nature has programmed redundancy into its DNA-to-protein translation process. For example, the DNA codes TCG, TCA, AGC, and AGT all encode for a single amino acid, serine. While it works in biology, the authors wondered: what if we tap into that code, hijack it, and redirect some of lifes directions using synthetic amino acids?

The new study sees natures redundancy as a way to introduce new capabilities into cells.

For us, one question was could you reduce the number of codons that are used to encode a particular amino acid, and thereby create codons that are free to create other monomers [amino acids]? asked lead author Dr. Jason Chin.

For example, if TCG is for serine, why not free up the othersTCA, AGC, and AGT for something else?

Its a great idea in theory, but a truly daunting task in practice. It means that the team has to go into a cell and replace every single codon they want to reprogram. A few years back, the same group showed that its possible in E. Coli, the lab and pharmaceuticals favorite bug. At that time, the team made an astronomical leap in synthetic biology by synthesizing the entire E. Coli genome from scratch. During the process, they also played around with the natural genome, simplifying it by replacing some amino acid codons with their synonymssay, removing TCGs and replacing them with AGCs. Even with the modifications, the bacteria were able to thrive and reproduce easily.

Its like taking a very long book and figuring out which words to replace with synonyms without changing the meaning of sentencesso that the edits dont physically hurt the bacterias survival. One trick, for example, was to delete a protein dubbed release factor 1, which makes it easier to reprogram the UAG codon with a brand new amino acid. Previous work showed that this can assign new building blocks to natural codons that are truly blankthat is, they dont encode anything naturally anyways.

Chins team took this much further.

The team cooked up a method called REXER (replicon excision for enhanced genome engineering through programmed recombination)yeah, scientists are all about the backcronymswhich includes the wunderkind gene editing tool, CRISPR-Cas9. With CRISPR, they precisely snipped out large parts of theE. coli bacterial genome, made entirely from scratch inside a test tube, and then replaced more than 18,000 occurrences of extra codons that encode for serine with synonym codons.

Because the trick only targeted redundant protein code, the cells were able to go about their normal businessincluding making serinebut now with multiple natural codons free. Its like replacing hi with oy, making hi now free to be assigned a completely different meaning.

The team next did some house cleaning. They removed the cells natural translatorsthe tRNAsthat normally read the now-defunct codons without harming the cells. They introduced new synthetic versions of tRNAs to read the new codons. The engineered bacteria were then naturally evolved inside a test tube to grow more rapidly.

The results were spectacular. The superpowered strain, Syn61.3(ev5), is basically a bacterial X-Men that grows rapidly and is resistant to a cocktail of different viruses that normally infect bacteria.

Because all of biology uses the same genetic code, the same 64 codons and the same 20 amino acids, that means viruses also use the same codethey use the cells machinery to build the viral proteins to reproduce the virus, explained Chin. Now that the bacteria cell can no longer read natures standard genetic code, the virus can no longer tap into the bacterial machinery to reproducemeaning the engineered cells are now resistant to being hijacked by almost any viral invader.

These bacteria may be turned into renewable and programmable factories that produce a wide range of new molecules with novel properties, which could have benefits for biotechnology and medicine, including making new drugs, such as new antibiotics, said Chin.

Viral infection aside, the study rewrites whats possible for synthetic biology.

This will enable countless applications, said Jewel and Chatterjee, such as completely artificial biopolymers, that is, materials compatible with biology that could change entire disciplines such as medicine or brain-machine interfaces. Here, the team was able to string up a chain of artificial amino acid building blocks to make a type of molecule that forms the basis of some drugs, such as those for cancer or antibiotics.

But perhaps the most exciting prospect is the ability to dramatically rewrite existing life. Similar to bacteria, weand all life in the biosphereoperate on the same biological code. The study now shows its possible to get past the hurdle of only 20 amino acids making up the building blocks of life by tapping into our natural biological processes.

Next up, the team is looking to potentially further reprogram our natural biological code to encode even more synthetic protein building blocks into bacterial cells. Theyll also move towards other cellsmammalian, for example, to see if its possible to compress our genetic code.

Image Credit: nadya_il from Pixabay

Originally posted here:
Scientists Used CRISPR to Engineer a New 'Superbug' That's Invincible to All Viruses - Singularity Hub

June 10, 2021

Investments Totaling $250M Have Catalyzed Research and Clinical Trials Across Many Disciplines

By Ariel Bleicher and Cyril Manning

UC San Francisco is launching a new initiative to propel the development of living therapeutics a category of treatments broadly defined as human and microbial living cells that are selected, modified, or engineered to treat or cure disease and bring them quickly to patients.

The Living Therapeutics Initiative (LTI) will bring together UCSFs vast scientific and clinical expertise to accelerate research and quickly advance promising therapies to clinical trials for patients who have few, if any, good treatment options. As a federation of established UCSF initiatives, the LTI will allow disparate research and clinical programs to share information, toolsand platforms. Early this fall, the initiative will launch a $50 million grants program, made possible by philanthropy, to fund UCSF faculty living-therapeutics projects.

The Living Therapeutics Initiative creates a seamless continuum from the earliest stages of discovery all the way through to patient treatment in our hospitals, said UCSF Chancellor Sam Hawgood, MBBS. This process will span discovery, translational development, manufacturing therapeutic products, executing clinical trials, and securing regulatory approval for novel therapeutics. It will transform how we approach some of the most difficult diseases.

The Living Therapeutics Initiative creates a seamless continuum from the earliest stages of discovery all the way through to patient treatment in our hospitals.

Chancellor Sam Hawgood, MBBS

Over the past few years, UCSF has raised philanthropic gifts and made institutional commitments totaling more than $250 million to support living therapeutics-related efforts across the University.

Living therapeutics have been called a new third pillar of medicine, following small-molecule drugs (relatively simple compounds that can be chemically manufactured) and biologics (proteins and other molecules synthesized within microorganisms or cells).

CAR-T-cell therapies, which were among the first living therapeutics, have already proven lifesaving for patients with certain blood cancers. These advances can be replicated in other disciplines, and modification of cells to deliver these therapies is going to become a major new modality for many, many diseases, said Alan Ashworth, PhD, FRS, president of the UCSF Helen Diller Family Comprehensive Cancer Center and chair of the LTI steering committee.

Researchers across UCSF are already building the next generation of cellular therapies to treat diseases including solid tumors, autoimmunity, neurodegeneration, diabetesand infectious diseases. These therapies will be smarter, safer, and more effective than CAR-T, thanks to recent breakthroughs in cell engineering and gene editing.

The whole idea of living therapeutics is to take advantage of normal cellular processes and make them more efficient, said Michelle Hermiston, MD, PhD, clinical director of the UCSF Pediatric Immunotherapy Program. But there often is a big gap between what happens in the lab and what gets to the patient. With the LTI, were leveraging the scientific community at UCSF to bring new and novel therapies to kids and adults that they cant get anywhere else. Were at a point where these therapies are going to revolutionize how we treat disease.

Michelle Hermiston, MD, PhD: With the LTI, were leveraging the scientific community at UCSF to bring new and novel therapies to kids and adults that they cant get anywhere else. Were at a point where these therapies are going to revolutionize how we treat disease. Photo byMarco Sanchez

A number of these therapies could be realized in clinical trials with astonishing speed. One example is CAR-T therapies for solid tumors that have so far proven difficult to treat. Researchers and clinicians at UCSF are working together to develop CAR-T therapies for brain tumors. The science behind these efforts is at an advanced stage, and the cellular product is primed for production in UCSFs new cell-manufacturing facility as soon as it is up and running, said Ashworth.

Heritable disorders caused by single-gene mutations are also a prime target for living therapeutics. Clinical trials of CRISPR therapies for sickle cell disease, for example, are already underway at UCSF Benioff Childrens Hospital Oakland. Researchers are also using CRISPR to cure severe combined immunodeficiency syndrome and repair a genetic mutation in T cells that causes immune deficiency.

Such cell therapies could even be used in utero to treat diseases before birth. Pediatric and fetal surgeon Tippi MacKenzie, MD, is running the worlds first clinical trial using blood stem cells transplanted before birth. In this trial, the cells are donated by the mother and transfused into her fetus to treat alpha thalassemia major, a fatal blood disorder. Future therapies might genetically edit a fetuss own cells to repair the mutation that causes the disease.

Tippi MacKenzie, MD: Right now, UCSF has amazing expertise in the basic science of stem cell biology, and we have world-class clinical capabilities at UCSF Health. The Living Therapeutics Initiative is bringing these pieces together. Photo by Noah Berger

This is a transformational time in medicine, said MacKenzie, co-director of the UCSF Center for Maternal-Fetal Precision Medicine. Right now, UCSF has amazing expertise in the basic science of stem cell biology, and we have world-class clinical capabilities at UCSF Health. The Living Therapeutics Initiative is bringing these pieces together.

Further down the line, cell therapies may be used to restore or regenerate tissues that have been damaged by aging or disease. Such applications might include restoring cardiac function, regenerating neurons, and even engineering immune cells to treat HIV and other infectious diseases, particularly for immunocompromised patients.

Were just at the infancy of cell engineering hacking the genome of cells and getting them to behave in controllable ways, Ashworth said. Its like a computers operating system. The early ones were clunky and didnt work so well, but now theyre incredibly sophisticated. Thats the trajectory were on.

Not all living therapeutics are derived from human cells, however. We now understand that we also have trillions of microbial genomes within us that affect our bodies function, said Susan Lynch, PhD, director of the UCSF Benioff Center for Microbiome Medicine. We can manipulate the composition and activities of these microbial genomes in ways that will lead to better health overall.

Susan Lynch, PhD: We now understand that we also have trillions of microbial genomes within us that affect our bodies function. We can manipulate the composition and activities of these microbial genomes in ways that will lead to better health overall. Photo by Barbara Ries

Faculty members engaged in microbiome research across campus have demonstrated the tremendous potential of microorganisms isolated from the human gut and elsewhere in our bodies as therapies for a wide range of diseases. For example, microbial dysfunction in the infant gut characterized by the enrichment of particular microbial genes and their products drive immune dysfunction and can be used to predict the development of allergy and asthma in childhood.

Perturbed microbial ecosystems across the human body have been linked to autoimmune disease, metabolic syndromes such as obesity and diabetes, skin diseases, and even multiple sclerosis. Gut microbes can also produce and contribute to drug metabolism influencing pharmacologic function and bioavailability, opening up the possibility of microbial pharmacology as a key component of precision patient treatment.

The LTI will connect tools and expertise from across the ecosystem of UCSF initiatives and partner institutions working to advance cell-based therapeutics.

These initiatives and institutions include clinical services at UCSF Medical Center and UCSF Benioff Childrens Hospitals; the Chan Zuckerberg Biohub; the Gladstone-UCSF Institute of Genomic Immunology; the Innovative Genomics Institute; the Parker Institute for Cancer Immunotherapy; and UCSFs Bakar Computational Health Sciences Institute, Bakar ImmunoX Initiative, Benioff Center for Microbiome Medicine, Cell Design Institute, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. Most recently, UCSF announced a partnership with Thermo Fisher Scientific for the co-development of a specialized facility for making cell-based immunotherapies and other cell-therapy products.

In addition to Alan Ashworth as chair, steering committee members include:

Michelle Hermiston, MD, PhD, clinical director of the UCSF Pediatric Immunotherapy Program

Wendell Lim, PhD, chair and Byers Distinguished Professor of cellular and molecular pharmacology;director of the Cell Design Institute

Tippi MacKenzie, MD, co-director of the UCSF Center for Maternal-Fetal Precision Medicine; pediatric fetal surgeon

Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology

Qizhi Tang, PhD, immunologist and Director of the Department of Surgerys Transplantation Research Lab

Jeffrey Wolf, MD, director of the UCSF Helen Diller Family Comprehensive Cancer CentersMyeloma Program

In addition to administering the $50 million in funding through an internal grant process, the LTI steering committee will help with coordination and strategy, such as thinking through regulatory issues, submitting applications to the U.S. Food and Drug Administration, and designing and evaluating clinical trials. Their evaluation of funding proposals will prioritize high-need, high-impact projects designed to lead to clinical trials.

Well be funding new ways of engineering cells for therapeutic benefit as well as the mechanics of getting those cells into the clinic, Ashworth said. Well learn from the clinical trials and then go back into the lab to design better versions of these therapies, iterating rapidly between lab and clinic. Thats at the heart of the Living Therapeutics Initiative.

Original post:
Living Therapeutics Initiative Will Accelerate Development and Delivery of Revolutionary Treatments - UCSF News Services