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New technologies, desires and threats from biological research

Rapid developments in biotechnology, genetics and genomics are undoubtedly creating a variety of environmental, ethical, political and social challenges for advanced societies. But they also have severe implications for international peace and security because they open up tremendous avenues for the creation of new biological weapons. The genetically engineered 'superbug'highly lethal and resistant to environmental influence or any medical treatmentis only a small part of this story. Much more alarming, from an arms-control perspective, are the possibilities of developing completely novel weapons on the basis of knowledge provided by biomedical researchdevelopments that are already taking place. Such weapons, designed for new types of conflicts and warfare scenarios, secret operations or sabotage activities, are not mere science fiction, but are increasingly becoming a reality that we have to face. Here, we provide a systematic overview of the possible impact of biotechnology on the development of biological weapons.

The history of biological warfare is nearly as old as the history of warfare itself. In ancient times, warring parties poisoned wells or used arrowheads with natural toxins. Mongol invaders catapulted plague victims into besieged cities, probably causing the first great plague epidemic in Europe, and British settlers distributed smallpox-infected blankets to native Americans. Indeed, the insights into the nature of infectious diseases gained by Louis Pasteur and Robert Koch in the nineteenth century did not actually represent a great breakthrough in the use of infectious organisms as biological weapons. Similarly, the development of a bioweapon does not necessarily require genetic engineeringsmallpox, plague and anthrax are deadly enough in their natural states. But the revolution in biotechnology, namely the new tools for analysing and specifically changing an organism's genetic material, has led to an increased risk of biowarfare due to several factors. First, the expansion of modern biotechnology in medical and pharmaceutical research and production has led to a worldwide availability of knowledge and facilities. Many countries and regions, where 30 years ago biotechnology merely meant brewing beer and baking bread, have established high-tech facilities for vaccine or single-cell-protein production that could be subverted for the production of biological weapons. Today, nearly all countries have the technological potential to produce large amounts of pathogenic microorganisms safely (). Second, classical biowarfare agents can be made much more efficiently than their natural counterparts, with even the simplest genetic techniques. Third, with modern biotechnology it becomes possible to create completely new biological weapons. And for technical and/or moral reasons, they might be more likely to be used than classical biowarfare agents. These possibilities have generated new military desires around the world, including within those countries that have publicly renounced biological weapons in the past. This paper deals predominantly with the last two factors, and with the use of real-life examples, we shall discuss the possibilities for such military abuse of biotechnology.

The US Army Medical Research Institute of Infectious Diseases in Fort Detrick, Maryland, is the centre of the USA's defensive research on biological weapons. ( (2001) Jan van Aken/Sunshine Project.)

By using genetic engineering, biological researchers have already developed new weapons that are much more effective than their natural counterparts. Countless examples from the daily work of molecular biologists could be presented here, not least the introduction of antibiotic resistance into bacterial pathogens, which today is routine work in almost any microbiology laboratory. Indeed, many research projects in basic science showsometimes unwillingly and unwittinglyhow to overcome current scientific and technological limits in the military use of pathogenic agents. Furthermore, genetic engineering is not merely a theoretical possibility for future biowarfare: it has already been applied in past weapons programmes, particularly in the former Soviet Union. One example is the USSR's 'invisible anthrax', resulting from the introduction of an alien gene into Bacillus anthracis that altered its immunological properties (Pomerantsev et al., 1997). Existing vaccines proved to be ineffective against this new genetically engineered strain.

...genetic engineering will not necessarily have a major role in the early stages of a biowarfare programme

In debates about genetic engineering and biological weapons it is often stated that natural pathogens are sufficiently dangerous and deadly, and that genetic engineering is not necessary to turn them into more effective biological weapons. This is indeed true in that biological weapons can be used without genetic engineeringor, for that matter, without any scientific knowledgeas has been shown by their effective use in past centuries. In fact, genetic engineering does not necessarily have a central role in the early stages of a biowarfare programme. The development of reliable, effective biological weapons requires an intense and resource-demanding research programme that must, step by step, solve increasingly complex problems: the procurement of virulent strains of suitable agents, the mass production of the agents without loss of pathogenicity, and the development of an effective means of delivery. In particular, the third step is very demanding, and has rarely been accomplished, with the exception of the huge former biowarfare programmes in the USA () and the USSR. Even Iraq, after several years of an active biowarfare programme, had developed only rudimentary methods of delivery. From this perspective, genetic engineering is a step taken relatively late in the development of biowarfare potential, which most probably will not be taken before the first, essential steps are solved. Indeed, we know only from the massive biowarfare programme in the former Soviet Union that pathogens have been genetically modified to increase their effectiveness as bioweapons, but there may have been other, so far undetected, attempts elsewhere.

The so-called '8-ball', a 1 million litre steel ball built in 1949 in which the US Army tested the effectiveness of biological weapons. The ball is in Fort Detrick, Maryland, and is a 'historical monument' today. ( (2001) Jan van Aken/Sunshine Project.)

By contrast, it must not be underestimated that hardly any natural pathogens are really well suited to being biowarfare agents from a military point of view. Such a bioweapon must fulfil a variety of demands: it needs to be produced in large amounts, it must act fast, it must be environmentally robust, and the disease must be treatable, or a vaccine must be available, to allow the protection of one's own soldiers. This explains why only a minority of natural pathogens are suitable for military purposes. Anthrax is of course the first choice because the causative agent, B. anthracis, fulfils nearly all of these specifications (). However, potential victims of an anthrax attack can be treated with antibiotics even several days after an infection. Therefore, only a minority of the infected persons will die from an anthrax attack in most instances, as has been shown by the anthrax attacks in 2001 in the USA. However, a very simple genetic intervention could produce much more drastic and deadly results.

Until 1969, the US Army produced anthrax spores for offensive warfare in this building at Fort Detrick, Maryland. ( (2001) Jan van Aken/Sunshine Project.)

In addition, another important restriction of bioweapons might be overcome by genetic engineering techniques in the future. Today, access to highly virulent agents and strains is increasingly regulated and restricted. In particular, smallpox, which was eradicated more than 20 years ago, is officially only stored at two high-security laboratories in the USA and Russia, and it is at present virtually impossible to gain access to these virus stocks. But considering the rapid development of molecular biology, it is only a question of time before the artificial synthesis of agents or new combinations of agents becomes possible. This danger was highlighted last year by a worrying article in Science: a research team at the State University of New York in Stony Brook chemically synthesized an artificial polio virus from scratch (Cello et al., 2002). They started with the genetic sequence of the agent, which is available online, ordered small, tailor-made DNA sequences and combined them to reconstruct the complete viral genome. In a final step, the synthesized DNA was brought to life by adding a chemical cocktail that initiated the production of a living, pathogenic virus.

In principle, this method could be used to synthesize other viruses with similarly short DNA sequences. This includes at least five viruses that are considered to be potential biowarfare agents, among them Ebola virus, Marburg virus and Venezuelan equine encephalitis virus. The first two in particular are very rare viruses that might be difficult to acquire by potential bioweaponeersaccording to rumours, members of the Japanese cult Aum Shinrikyo, famous for the nerve gas attack on the Tokyo subway, tried unsuccessfully to get their hands on Ebola virus during an outbreak in former Zaire in the 1990s. Using the method that has been published for polio, such a group or an interested state could theoretically construct Ebola virus in the laboratory. However, it should be noted that this method is complex, and probably only a few highly trained experts would be able to master this technique, at least for the time being.

The polio virus itself is not an effective biological weapon, but the experiment shows the tremendous potential of genetic engineering and also highlights its problems, particularly when applied to smallpox. The current risk assessments with regard to this virus rate the likelihood of an attack as being rather low, because it is highly unlikelyalthough not completely impossiblethat countries other than Russia and the USA have access to it. If it should become possible to rebuild variola major, the smallpox virus, in the laboratory from scratchand the virus's genome sequence is available from biological databasesthis risk could change greatly. Smallpox is an ideal biological weapon, particularly for terrorist groups, because it is highly infectious and lethal and there is no effective treatment available. The relative safety that can be assumed today will then be gone.

However, the method for creating polio virus artificially cannot be directly transferred to the smallpox virus. The variola genome, with more than 200,000 base pairs, is far bigger than that of polio, and even if it were possible to recreate the full smallpox sequence in vitro, it could not easily be transformed into a live infectious virus particle. But there might be other ways. It would, for example, be possible to start with a closely related virus, such as monkeypox or mousepox, and to alter specifically those bases and sequences that differ from human smallpox. Some months ago, researchers documented for the first time that the sequence of a pathogenicity-related gene from the vaccinia virus could be transformed through the targeted mutation of 13 base pairs into the sequence of the corresponding smallpox gene (Rosengard et al., 2002). It is probably only a matter of time before this technique is applicable to full genomes, and then we shall have to reconsider our current assessment of the smallpox threat. Considering the extreme danger that smallpox poses to a now largely unvaccinated human population, it seems at least questionable to make the smallpox sequence available on the World Wide Web.

However, the genetic enhancement of classical pathogens is only a small part of the broad array of possibilities that new biomedical techniques have created. From the point of view of disarmament, another trend is much more alarming: new types of biological weapons are becoming possible that were entirely fictitious until a few years ago. This is especially true of so-called 'non-lethal' weapons that are designed for use outside classical warfare. The danger is that these new possibilities generate desires even in countries that previously renounced the use and development of classical biological weapons.

The global norm against biological weapons, laid down in the 1925 Geneva Convention and the 1972 Biological and Toxin Weapons Convention, clearly contributed to the fact that few countries have been engaged in research into offensive biowarfare during recent decades. This moral barrier seems to be lower for 'non-lethal' weapons that are targeted against materials or drug-producing plants. Indeed, today's technical possibilities are creating a new interest in this area that might be leading to a new biological arms race. In the following paragraphs, we document three real examples of biological and chemical weapons development that are now being pursued by democracies in the Western world. All three examples have been researched and extensively published by the Sunshine Project (further reading is available at http://www.sunshine-project.org).

The US military has repeatedly discussed possible uses of biotechnology for warfare scenarios, including the development of material-degrading microorganisms to destroy fuel, constructional material or stealth paints (Strategic Assessment Center of Science Applications International Corporation, 1995; US Army War College, 1996). This idea is based on the fact that natural microorganisms are able to degrade nearly every material and are already being used to detoxify environmental pollution. The natural organisms are rather slow-acting and unreliable, but, with the help of genetic engineering, the development of much more effective organisms might become possibleprobably effective enough to be used as biological weapons (Sayler, 2000). The specific interest of military researchers in material-degrading microbes is due to the synergistic effects of two concurrent developments: first, the military, particularly in the USA, has a renewed interest in these non-lethal weapons for use in mediasensitive mili-tary operations so that visible civilian victims can be avoided; second, rapid developments in biotechnology provide the

Considering the extreme danger that smallpox poses to a now largely unvaccinated human population, it seems at least questionable to make the smallpox sequence available on the World Wide Web

technological basis to change natural microorganisms into anti-material microbes. New technological possibilities met new military concepts in the USA and led to a renewed interest in weapons that, until recently, had been banned and rejected.

In 1998, it became public that the US Naval Research Laboratory in Washington DC was developing genetically engineered fungi with offensive biowarfare potential. They isolated natural microorganisms that degrade a variety of materials, such as plastics, rubber and metals, and used genetic engineering to make them more powerful and focusedone of these genetically engineered microbes can destroy military paints in 72 hours. The principal investigator at the Naval Research Laboratory, James Campbell, described possible applications of this technology in his presentation at the 3rd Non-Lethal Defense Symposium in 1998. Among them were microbial derived or based esterases [that] might be used to strip signature-control coatings from aircraft, thus facilitating detection and destruction of the aircraft (www.dtic.mil/ndia/NLD3/camp.pdf). This work is purportedly defensive in nature, although no threat has been articulated, and continuing research by the US Navy and Army continues to strive towards taking these weapons from the laboratory to the field. Just a few years later, in 2002, several research proposals by the US military that were clearly offensive in nature became public.

New technological possibilities met new military concepts in the USA and led to a renewed interest in weapons that, until recently, had been banned and rejected

About a decade ago, the USA also increased their efforts to identify microorganisms that kill drug-producing crops; by the late 1990s, this research focused largely on two fungi. The testing of one, Pleospora papaveracea, against opium poppy, was conducted in Tashkent, Uzbekistan, with financial and scientific support from the USA, and was completed in 2001. Pathogenic Fusarium oxysporum strains developed in the USA to kill coca plants were scheduled for field tests in Colombia in 2000, but international protests halted this project. These fungi provide a quintessential example of the hostile use of biological agents. In Colombia, the biggest areas of coca and opium poppy cultivation are in combat zones, and the 'War on Drugs' is part of the country's continuing armed conflict. These biological agents are lowering the political threshold for the use of biological weapons and are likely to have tremendous environmental and health impacts. The pursuit of crop-killing fungi as weapons would be a further slide down a slippery slope that, by following the same logic, could easily lead to the use of other plant pathogens, animal pathogens or even non-lethal biological weapons against humans (van Aken & Hammond, 2002).

The third example is not about biological weapons but new types of chemical, or rather biochemical, weapons. As in the other examples, the revolution in biomedicine created new desires in the East and the West, and there are already new weapons under development that violate international treaties. This area came under the spotlight of the international media after the use of psychoactive substances in the Moscow hostage crisis last year, causing the death of more than 170 people. These supposedly 'non-lethal' chemical weapons had been developed as early as the 1950s, particularly a substance called 'BZ', known in the US army as 'sleeping gas'. But BZ caused very different effects in different individuals and was considered to be unreliable, leading to its banishment from the US chemical arsenal in the late 1960s. Today, however, modern neurobiology provides comprehensive knowledge about a broad range of neuroreceptors and manifold psychoactive substances that make 'non-lethal' chemical weapons attractive for the military once more. For instance, the US Marine Corps recently investigated the potential military usefulness of calmatives such as benzodiazepines and 2-adrenoreceptor agonists. However, the identification of suitable substances is only one part of the renewed chemical weapons research in the USA. Recently published documents show that the US military forces are also developing new delivery devices for chemicals with a range of more than 2.5 kma distance that makes sense only for warfare scenarios as opposed to police operations, in which ranges from 10 to 50 m for tear gas grenades are common. The Chemical Weapons Convention prohibits any use of chemicals, including 'non-lethal' chemicals, in warfare situations. Even the use of tear gas is prohibited because of the enormous danger of escalation. In a specific combat situation, the attacked side will be unable to identify the nature of the chemical used and might feel tempted to retaliate in kind with potentially lethal chemicals.

Molecular biology and genetic engineering are still in their infancy, and more technical possibilities will arise in the years to comefor military abuse too (Fraser & Dando, 2001). More efficient classical biowarfare agents will probably have only a marginal role, even if the genetically engineered 'superbug' is still routinely featured in newspaper reports. More likely and more alarming are weapons for new types of conflicts and warfare scenarios, namely low-intensity warfare or secret operations, for economic warfare or for sabotage activities. To prevent the hostile exploitation of biology now and forever, a bundle of measures must be taken, from strengthening the Biological and Toxin Weapons Convention to building an awareness in the scientific community about the possibilities and dangers of abuse. Any kind of biotechnological or biomedical research, development or production must be performed in an internationally transparent and controlled manner. In cases in which military abuse seems to be imminent and likely, alternative ways to pursue the same research goal have to be developed. Furthermore, as we mentioned above with regard to the smallpox genome sequence, it might also be necessary to apply restrictions to certain research and/or publications.

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Genetic engineering and biological weapons

After exhausting all available options, doctors approached David Bennett Sr with a last-ditch effort to save his life receive a heart transplant from a gene-edited pig. Three days after the transplant, David remains in stable condition, a positive sign that some experts suggest may foreshadow a new era of organ transplantation.

The transplantation of organs from one species to another, known as xenotransplantation, has been the target of medical curiosity for centuries. In 1905, a French scientist attempted to transplant slices of rabbit kidney into a child suffering from chronic kidney disease. Although unsuccessful, this procedure was followed by decades of attempts to transfer organs from lambs, pigs, and primates into human patients.

Scientists would discover that xenotransplantation frequently triggers deadly immune responses in organ recipients. The presence of foreign animal cells sets off a cascade of molecular signals that can kill patients in a matter of days or even minutes.

Advancements in genetics and immunology have uncovered the genes, proteins, and molecular pathways linked to organ rejection. In parallel, rapid improvements in gene-editing technologies like CRISPR have given scientists the ability to precisely edit dozens of sequences across an animals genome. In theory, targeted genetic changes could camouflage foreign organs and prevent a deadly immune response, a proposition that multiple companies are pursuing.

In October 2021, surgeons at New York University's Langone Health completed a proof-of-concept experiment by attaching a pig kidney to a brain-dead human body. The organ continued to function normally for two days post-treatment. The kidney came from the Virginia-based regenerative medicine company Revivicor. A year prior, Revivicor had received regulatory approval to genetically-engineer pigs for both food and medical uses.

The issue, however, is that pigs produce a sugar in their cells, which causes an immune response in humans during an organ transplant. By eliminating that sugar through genetic engineering, Revivicor created organs capable of evading an immune response.

On January 7 2022, xenotransplantation took another monumental leap forward with the successful transferring of a gene-edited pig heart into a living human. This time Revivicor provided a heart from a donor pig, engineered to have 10 genetic alterations. They eliminated three genes responsible for organ rejection within the pig's genome while introducing six human genes to help the patients body accept the new heart. They knocked out one additional gene to prevent the pig heart from growing too large.

Scientists are hesitant to draw conclusions from this procedure since the surgery was not part of a formal clinical trial and the patient was on novel immunosuppressive drugs. Further monitoring and evaluation of the patients health and recovery will reveal whether this one-off experiment is a glimpse of whats to come. Companies like eGenesis and Qihan Biotech see this as a step in the right direction and are moving their xenotransplantation research closer to the clinic.

Thousands of people die every year waiting for an organ transplant. Demand for organs outpace supply. Where precious organs are available, the distance between donor and recipient can create huge hurdles. Xenotransplantation is, therefore, an applauded technological innovation, but the benefits are not without concern.

David Bennett Srs heart transplant has renewed debates on the ethics of using animals for organs. Pigs are historically the donors of choice thanks to their human-sized organs, short gestation periods, and the opinion that pigs are less ethically fraught than primates. Some animal activists contest these arguments, arguing that pigs shouldnt be engineered or used as organ donors.

Instead of xenotransplantation, experts suggest alternatives for society and governments to address organ donation shortages. One long-fought policy change involves switching organ donation systems from opt-in to opt-out. Some countries, like the USA, give citizens a choice to become organ donors. Others, like the UK, automatically enrol people with the option to opt-out of the programme. This simple change can dramatically increase the number of available donors and shorten the long waiting list.

Next-generation artificial organs may one day act as an alternative to human organ donation. Compared to earlier generations, which use mechanical pumps, advances in 3D printing and tissue engineering are propelling the creation of new artificial hearts made of flesh and blood. Even with an emerging class of organs that blur the line between artificial and natural, there will still be patients who may not meet eligibility requirements, leaving a demand for xenotransplantation.

Written by

Kevin Doxzen, Hoffmann Fellow, Precision Medicine and Emerging Biotechnologies, World Economic Forum

The views expressed in this article are those of the author alone and not the World Economic Forum.

Excerpt from:

Gene-edited pig heart transplanted into a human patient - World Economic Forum

Gene therapy is a lot like landing a Mars rover.

Hear me out. The cargoa rover or gene editing toolsis stuffed inside a highly technical protective ship and shot into a vast, complex space targeting its destination, be it Mars or human organs. The cargo is then released, and upon landing, begins its work. For Perseverance, its to help seek signs of ancient life; for gene editors, its to redesign life.

One critical difference? Unlike a Mars missions seven minutes of terror, during which the entry, descent, and landing occur too fast for human operators to interfere, gene therapy delivery is completely blind. Once inside the body, the entire flight sequence rests solely on the design of the carrier spaceship.

In other words, for gene therapy to work efficiently, smarter carriers are imperative.

This month, a team at Harvard led by Dr. David Liu launched a new generation of molecular carriers inspired by viruses. Dubbed engineered virus-like particles (eVLPs), these bubble-like carriers can deliver CRISPR and base editing components to a myriad of organs with minimal side effects.

Compared to previous generations, the new and improved eVLPs are more efficient at landing on target, releasing their cargo, and editing cells. As a proof of concept, the system restored vision in a mouse model of genetic blindness, disabled a gene associated with high cholesterol levels, and fixed a malfunctioning gene inside the brain. Even more impressive, its a plug-and-play system: by altering the targeting component, its in theory possible for the bubbles to land anywhere in the body. Its like easily rejiggering a Mars-targeting spaceship for Jupiter or beyond.

Theres so much need for a better way to deliver proteins into various tissues in animals and patients, said Liu. Were hopeful that these eVLPs might be useful not just for the delivery of base editors, but also other therapeutically relevant proteins.

Overall, Liu and colleagues have developed an exciting new advance for the therapeutic delivery of gene editors, said Dr. Sekar Kathiresan, co-founder and CEO of Verve Therapeutics, who was not involved in the study.

We already have families of efficient gene editors. But carriers have been lacking.

Take base editing. A CRISPR variant, the technology took gene editing by storm due to its precision. Similar to the original CRISPR, the tool has two components: a guide RNA to hunt down the target gene and a reworked Cas protein that swaps out individual genetic letters. Unlike Cas9, the CRISPR scissors, base editing doesnt break the DNA backbone, causing fewer errors. Its the ultimate genetic search and replace, with the potential to treat hundreds of genetic disorders.

The problem is getting the tools inside cells. So far, viruses have been the go-to carrier, due to their inherent ability to infect cells. Here, scientists kneecap a viruss ability to cause disease, instead hijacking its biology to carry DNA that encodes for the editing components. Once inside the cell, the added genetic code is transcribed into proteins, allowing cells to make their own gene editing tools.

Its not optimal. Viruses, though efficient, can cause the cells to go into overdrive, producing far more gene editing tools than needed. This stresses the cells resources and leads to side effects. Theres also the chance of viruses tunneling and integrating into the genome itself, damaging genetic integrity and potentially leading to cancer.

So why not tap into a viruss best attributes and nix the worst?

eVLPs are like their namesakes: they mimic viral particles that are efficient at infecting cells, but cut out the dangerous parts: DNA. Picture a multi-layered pin cushion, but with an empty cavity to hold cargo.

Unlike viruses, these bubbles dont carry any viral DNA and cant cause infections, potentially making them far safer than viral carriers. The downside? Theyre traditionally terrible at carrying cargo to its targets. Its akin to a spaceship with awful homing machinery that crashes into other planets and causes an unexpected wave of disaster. Theyre also not great at releasing the cargo even on the target site, trapping CRISPR machinery inside and making the whole gene-editing fix moot.

In the new study, Lius team started by analyzing those pain points. By limiting proteins inside the eVLPs that act as the carriers safety belts, they found, its easier for the cargothe base editor proteinsto release. How they packed the cargo inside the particle bubbles also made a difference. The balance between the twoseat belt to protein passengersseems to be key to protecting the cargo but allowing them to quickly bail when needed. And finally, dotting the outer shell of the spaceship with specific proteins helps the spaceship navigate towards its designated organ.

In other words, the team figured out the rules of the game. Now that we know some of the key eVLP bottlenecks and how we can address them, even if we had to develop a new eVLP for an unusual type of protein cargo, we could probably do so much more efficiently, said Liu.

The result is that a carrier can pack 16 times more cargo and up to a 26-fold increase in gene editing efficacy. Its a fourth-generation carrier, said the authors.

After first testing their new molecular spaceship in cultured cells in the lab, the team moved on to treating genetic disorders. They targeted three different biological planetsthe eye, liver, and brainshowcasing the flexibility of the new carrier.

In mice with an inherited form of blindness, for example, the carrier was loaded with the appropriate gene editing tools and injected into a layer of tissue inside the eye. In just five weeks, the single injection rebooted retinal function to a point thatbased on previous studies from the same labcan restore the mices ability to see.

In another study, the team focused on a gene that often leads to brain disorders. Because of a tough barrier between the brain, blood, and other tissues, the brain is a notoriously difficult organ to access. With the new eVLP spaceship, the gene editors smoothly sailed through the barrier. Once inside brain cells, the tools had a roughly 50 percent chance of transforming damaged genes.

As an additional proof of concept, the new carriers honed in on the livers of mice with cholesterol problems. One injection amped up the mices ability to produce a protective molecule that thwarts heart disease.

Gene editing has always been haunted by the ghost of off-target effects. Using viruses to deliver the tools, for example, runs those risks as they last a long time, potentially overwhelming cells.

Not so for the new eVLPs. Because theyre completely engineered, they carry zero viral DNA and are safer. Theyre also highly programmablejust a few changes to the targeting proteins can shift them towards another docking location in the body.

For the next step, the team is engineering better seat belt proteins inside the carriers for different moleculeseither gene editors or therapeutic proteins such as insulin or cancer immunotherapies. Theyre also further unpacking what makes eVLPs tick, aiming for next-generation carriers that can explore every nook and cranny of our bodies complex universe.

Image Credit: nobeastsofierce/Shutterstock.com

Excerpt from:

New Virus-Like Particles Can Deliver CRISPR to Any Cell in the Body - Singularity Hub

A key breakthrough came in the early 2000s, when Japanese researchers hit on a simple formula to turn any type of tissue into powerful stem cells, similar to ones in an embryo. Imaginations ran wild. Scientists realized they could potentially manufacture limitless supplies of nearly any type of cellsay, nerves or heart muscle.

In practice, though, the formula for producing specific cell types can prove elusive, and then theres the problem of getting lab-grown cells back into the body. So far, there have been only a few demonstrations of reprogramming as a way to treat patients. Researchers in Japan tried transplanting retina cells into blind people. Then, last November, a US company, Vertex Pharmaceuticals, said it might have cured a mans type 1 diabetes after an infusion of programmed beta cells, the kind that respond to insulin.

The concept startups are pursuing is to collect ordinary cells such as skin cells from patients and then convert these into hair-forming cells. In addition to dNovo, a company called Stemson (its name is a portmanteau of stem cell and Samson) has raised $22.5 million from funders including from the drug company AbbVie. Cofounder and CEO Geoff Hamilton says his company is transplanting reprogrammed cells onto the skin of mice and pigs to test the technology.

Both Hamilton and Lujan think there is a substantial market. About half of men undergo male-pattern baldness, some starting in their 20s. When women lose hair, its often a more general thinning, but its no less a blow to self-image.

These companies are bringing high-tech biology to an industry known for illusions. There are plenty of bogus claims about both hair-loss remedies and the potential of stem cells. Youve got to be aware of scam offerings, Paul Knoepfler, a stem-cell biologist at UC Davis, wrote in November.

JIYOON LEE AND KARL KOEHLER, HARVARD MEDICAL SCHOOL

So is stem-cell technology going to cure baldness or become the next false hope? Hamilton, who was invited to give the keynote at this years Global Hair Loss Summit, says he tried to emphasize that the company still has plenty of research ahead of it. We have seen so many [people] come in and say they have a solution. That has happened a lot in hair, and so I have to address that, he says. Were trying to project to the world that we are real scientists and that it's risky to the point I cant guarantee its going to work.

Right now, there are some approved drugs for hair loss, like Propecia and Rogaine, but theyre of limited use. Another procedure involves cutting strips of skin from someplace where a person still has hair and surgically transplanting those follicles onto a bald spot. Lujan says in the future, hair-forming cells grown in the lab could be added to a persons head with a similar surgery.

I think people will go pretty far to get their hair back. But at first it will be a bespoke process and very costly, says Karl Koehler, a professor at Harvard University.

Hair follicles are surprisingly complicated organs that arise through the molecular crosstalk between several cell types. And Koehler says pictures of mice growing human hair aren't new. Anytime you see these images, says Koehler, there is always a trick, and some drawback to translating it to humans.

Koehlers lab makes hair shafts in an entirely different wayby growing organoids. Organoids are small blobs of cells that self-organize in a petri dish. Koehler says he originally was studying deafness cures and wanted to grow the hair-like cells of the inner ear. But his organoids ended up becoming skin instead, complete with hair follicles.

Koehler embraced the accident and now creates spherical skin organoids that grow for about 150 days, until they are around two millimeters across. The tube-like hair follicles are clearly visible; he says they are the equivalent of the downy hair that covers a fetus.

One surprise is that the organoids grow backwards, with the hairs pointing in. You can see a beautiful architecture, although why they grow inside out is a big question, says Koehler.

The Harvard lab uses a supply of reprogrammed cells established from a 30-year-old Japanese man. But its looking at cells from other donors to see if organoids could lead to hair with distinctive colors and textures. There is absolutely demand for it, says Koehler. Cosmetics companies are interested. Their eyes light up when they see the organoids.

More here:

Going bald? Lab-grown hair cells could be on the way - MIT Technology Review

An estimated 37,470 animal, plant, and fungi species are now listed as threatened (vulnerable, endangered, critically endangered) by the International Union for the Conservation of Nature (IUCN) Red List (downloaded August 2021) with most known species (72%) still to be assessed (1). Species listing on the IUCN Red List is rigorous, with multiple assessments, reviews, and consistency checks to ensure robustness of the global list (1). However, global biodiversity is not evenly spread across the globe, with just 17 megadiverse countries home to 60 to 80% of all life on earth (2). As a result, the responsibility of conserving much of the worlds biodiversity tends to fall upon these few nations, 15 of which are classified as developing economies by the United Nations (3). The range of threats contributing to the global biodiversity crisis (4) are broad, including habitat loss and fragmentation, invasive pest species, disease, and climate change (5). As the human population continues to increase and encroach on the natural world, a 10-year program has commenced (6)The United Nations Decade of Ecosystem Restoration 20212030to help slow biodiversity loss. Fragmentation and modification of habitat reduces population size and connectivity for many species and threatened species are typically found in small, isolated populations susceptible to genetic risks and other stochastic processes (7). Conservation practitioners are more frequently using conservation translocations as a restoration tool for maintaining populations of threatened fauna and flora (8, 9). Yet, translocations can further entrench small population risks because when managing a species in a fragmented landscape, behind a fence, or on an island, natural gene flow is reduced (7). As a result, genetic management is becoming integral to the conservation of an ever-greater number of species.

Genomes, and their associated downstream applications, are powerful tools for discovery of new knowledge around species behavior and biology. They can improve our understanding of species taxonomy, provide information regarding past and future evolutionary processes, and complement current ecological survey and study methods (10). In 2018, of the 13,500 animal species on the IUCN Red List, less than 0.8% of species had published genomes on the National Center for Biotechnology Information (11); in the past 3 y this has increased slightly to 2.4% of the 15,521 listed threatened species. Although there is an increase in global genome consortia, such as the Earth Biogenome Project (10, 12), the Vertebrate Genome Project (13), and the Global Invertebrate Genomics Alliance (14), that are creating genomes for nonmodel species, genomic resources for some of our most critically endangered species are still lacking. Furthermore, developing reference genomes for species does not impact their conservation on their own, but rather it is the downstream applications and tools that use reference genomes that can significantly improve species conservation.

A recent review by Supple and Shapiro (15) highlighted that the transition to genomic technologies is only just beginning and that there needs to be an expansion in the available datasets so researchers can ask different questions applicable to conservation. Here, we reviewed the conservation-focused peer-reviewed literature to explore the trends in increasing use of genomic data in studies regarding the management of threatened or endangered species (see SI Appendix for methodological details). We identified a total of 498 papers containing a variety of sequencing methods and types of studies: 263 (52.8%) used either microsatellites, SNPs, or whole genome data, to address population genetics/genomics; and 89 (17.9%) were some form of review (SI Appendix, Table S1). Of the 212 papers that used nuclear DNA to address population genetics/genomics, there has been a marked decrease in the use of microsatellites and an increase in the use of SNPs since 2010 (Fig. 1). As expected, with genome technologies becoming more prominent in nonmodel species after 2010, there was an increase in using next-generation sequencing to improve the development of microsatellite markers (20152020) and an increased use of thousands of SNPs to improve genome-wide diversity studies (Fig. 1). More recently (since 2017) there has been a steady increase in the number of studies using resequenced whole genomes (Fig. 1). Although this is not a fully comprehensive search of all the conservation genomics/genetics works currently published, we find that even in the absence of available reference genomes for threatened species, there has been a sustained uptake of other genomic approaches in conservation genetic studies of threatened species, with many leading to explicit conservation recommendations (see refs. 1517 for more comprehensive reviews).

As Supple and Shapiro (15) (and others) point out, the suite of genomic tools available to researchers to understand both genome-wide and functional diversity within and between species and populations, can be greatly expanded when reference genome information is available, enabling more precise targeting of conservation measures (11, 15, 16). Indeed, we know that conservation practitioners use genetic information in their decision-making (SI Appendix, Table S2), particularly when it comes to managing threatened species in small populations within fragmented landscapes (18). However, the use of big data genomic approaches presents challenges for practitioners to access and interpret the available information.

Australia is one of the 17 megadiverse nations. Separating from other continents over 42 to 53 million y ago (19, 20) means many of the species in Australia are unique, with 87% of mammals, 45% birds, 93% reptiles, 94% amphibians, and 92% of plants endemic to the island continent (21). However, many Australian species have seen marked declines since European settlement in 1788, with 1,774 species (480 animals; 1,294 plants, as of 2016) listed as threatened under the Australian Environment Protection and Biodiversity Conservation Act (22). Various recovery and other conservation plans have been put in place by the Australian, State, and Territory Governments with actions to address threats and support the long-term recovery of these species. Globally, Australia has the worst record of mammal extinctions in the world. Multiple species have faced population declines of over 90% in the past two decades (23). The loss of Australian mammal species is largely due to predation by introduced species and changes to fire regimes (23, 24), with our first mammal extinction attributed to anthropogenic climate change declared in 2016 (25). Apart from managing species in often increasingly fragmented landscapes, to address the challenges of rapidly declining populations, many threatened species are increasingly being managed in large, fenced areas, in zoological/botanic garden insurance populations, and on offshore islands. Consequently, genetic diversity and gene flow are reduced for many species and this needs to be accounted for in ongoing management actions.

Conservation biologists and practitioners have a range of technological tools at their disposal to address the various challenges of conserving biodiversity (26). However, for many conservation practitioners there is often an implementation gap between research and development of new tools and their application in conservation practice (27). One such research implementation gap that has been widely discussed is the use of genomics and associated tools for conservation of threatened species (2830). Although recent reviews (see refs. 15 and 3133) discuss the value of genomes for conservation and protection of biodiversity, as sequencing technology improves, there are increasing requirements around genome quality, bioinformatic knowledge, and handling of big data. This creates an ever-widening researchimplementation gap between the creation of genomic resources by genome biologists and bioinformaticians and the application of these resources in conservation management by conservation practitioners.

Bioplatforms Australia (Bioplatforms), a nonprofit organization that supports Australian Life Science research by investing in state-of-the-art infrastructure and expertise in genomics, proteomics, metabolomics, and bioinformatics, has invested in a number of genome initiatives over the past 10 y, producing genomic resources for Australian species (Table 1). The focus of many of these initiatives has been on reference genome production, comparative genomics, and phylogenomics to resolve species taxonomy for conservation application. Building on the success of these programs, the mission of the Threatened Species Initiative (TSI), launched in May 2020, is to bridge the implementation gap between the production of genomic resources and their application in conservation management (https://threatenedspeciesinitiative.com/). From the outset, TSI has been developed in direct consultation with governmental threatened species managers and other conservation practitioners, around their needs and knowledge gaps (SI Appendix, Table S2). It brings together genome biologists, population biologists, bioinformaticians, population geneticists, and ecologists with conservation agencies across Australia, including government, zoos, botanic gardens, and nongovernment organizations (NGOs). Our objective is to create a foundation of genomic data to advance our understanding of representative Australian threatened species, in addition to fast-tracking genomic information to conservation end-users through online resources and open-access data. We aim to empower conservation practitioners to leverage genomic information to tackle critical biological and conservation issues, including genetic data to inform translocations, captive breeding, seed banking, and ongoing population management.

Environmental genome initiatives that have been supported by Bioplatforms Australia that have produced genomic resources for Australian wildlife and plant species

Studies from New Zealand/Aotearoa (28) and Australia (34) show that conservation practitioners know the value of using genetic data in conservation decision-making, but access to easily interpretable information is lacking. In Australia, projects such as Devil Tools & Tech (34) and Restore & Renew (35) have shown that by creating partnerships between academic researchers and conservation practitioners, the latest genome technologies and techniques can be applied in real-time to conservation decision-making. It was the success of these programs with specific species and their philosophy of open access to the latest research data that led to the development of the TSI. TSIs goal is to undertake applied research that has direct management applications, while ensuring the research is innovative and novel for peer-review publication and to attract competitive research funding.

Our approach to engineering and building a bridge for the current genomic researchimplementation gap is threefold: 1) use genome sequencing technologies that meet the needs of the conservation end-users while maximizing the limited conservation resources available (both funding and sample access), so genomic data can be developed for as many threatened species as possible; 2) develop an on-line interface where TSI project teams can obtain protocols and use a set of established bioinformatic tools and workflows to provide genetic outputs in a standardized reporting format for conservation practitioners; and 3) open-data access, where genomic data will be open access but other related metadata may be restricted due to threatened species and indigenous sensitivities (36). To ensure seamless delivery of the larger project, a pilot phase was commenced in August 2020, to test and bed down workflows and pipelines to ensure outputs were fit-for-purpose for conservation management and decision-making. Eight species (two birds: eastern bristlebird, Dasyornis brachypterus and orange-bellied parrot, Neophema chrysogaster; two marsupials: eastern barred bandicoot, Perameles gunnii, and western barred bandicoot, Perameles bougainville; two mammals: ghost bat, Macroderma gigas and Hastings River mouse, Pseudomys oralis; one fish: swan galaxias, Galaxias fontanus; and one plant: native guava, Rhodomyrtus psidioides) were selected for the pilot phase through consultation with the Australian, State, and Territory threatened species managers. Note, the Australian Amphibian and Reptile Genomics (AusARG) project commenced at the same time as the TSI and is undertaking similar activities for reptiles and amphibians, so these taxa were not included in the initial TSI pilot phase. The species were grouped into five scenarios to enable comprehensive testing of the different stages of the TSI conservation genomics pipeline: 1) the species has no reference genome, no population genetic data; 2) the species has closely related species with a reference genome, but no population genetic data; 3) the species has no reference genome, and population genetic data exists; 4) the species has a reference genome, or conspecific genome, some population genetic data, and is subject to conservation action which mixes genetically distinct populations; and 5) the species has no reference genome, but short-read data exists, and some population genetic data exists.

This pilot phase was followed by a Request for Partnership round in early 2021, and with a second scheduled for early 2022. In the Request for Partnership academic researchers are encouraged to select species from a preselected list of threatened species, which has been prioritized by the Australian Federal, State, and Territory government agencies. Initially it was anticipated that the current TSI funding (AUD$1.4M) would be able to provide genomic resources for between 40 and 50 threatened plant, animal, and invertebrate species over its 3-y lifespan. In 2021, this goal was superseded, with 61 species currently supported by the program from across Australia (Fig. 2 and SI Appendix, Table S3), representing extinct in the wild (n = 3), critically endangered (n = 16), endangered (n = 17), vulnerable (n = 15), and data-deficient species (n = 9). Note, one least concern species is supported to investigate its value as a genetic rescue surrogate for a critically endangered species. Participating project teams are encouraged to leverage other funding opportunities using TSI resources as seed funding; this will see a multiplier effect from the base investment and provide genomic resources for more species. Of the 61 species projects, there are over 130 project team members representing government (46%), academia (35%), and nongovernment/conservation organizations (19%). All participating project teams are encouraged to work with local Aboriginal nations where possible and provide tangible on-ground conservation outcomes as part of their projects.

Species involved in the TSI by: (A) geographical location, noting some species are found in more than one State or Territory; (B) IUCN threat status: extinct in the wild (EW), critically endangered (CR), endangered (EN), vulnerable (VU), least concern (LC), data deficient (DD); and (C) taxa. Base Australia map by Free Vector Maps (https://freevectormaps.com/).

There are more than 30 genomes of Australian species, with 40 draft genomes in development through the Bioplatforms Australia initiatives. These genomes have used a variety of sequencing technology over the years, including whole-genome shotgun approach with Sanger sequencing [e.g., Tammar wallaby, Macropus eugenii (37)]; Illumina platform [e.g., Tasmanian devil, Sarcophilus harrisii (38)]; PacBio RS II platform with Illumina HiSeq [e.g., koala, Phascolarctos cinereus (39)], and 10X Genomics linked-read sequencing on NovaSeq. 6000 [e.g., brown antechinus, Antechinus stuartii (40)]. Some of these genomes may be now classified as low-quality by todays genome standards, but their conservation application has been significant. For example, the original 2012 Tasmanian devil genome (38) (Table 2) has been used with much success for the management of both wild and captive populations of this endangered species (see full review, ref. 11)]. The Tasmanian devil genome allowed for the development of conservation-based tools, such as species-specific microsatellite markers, characterization of immune gene families, blocking primers for use in metagenomics studies, as a few examples (11). The 2018 koala genome (39) (Table 2), is permitting a large-scale genomic survey of the species to understand both genome-wide and functional diversity in light of the recent Australian megafires, which saw more than 126,000 km2 of habitat burned (41). This genomic survey will inform potential future management actions around habitat restoration and translocations for a globally recognized species. Other draft genomes for the woylie [Bettongia penicillate ogilbyi (42)] have been used in real-time (as the genome was assembled) to inform management actions and translocation success for both the woylie (43), and other cogeneric species (16), such as the boodie (Bettongia lesueur). It should be noted that most of these genomes are not chromosome length assemblies, although the recently released koala chromosome assembly (https://www.dnazoo.org/assemblies/Phascolarctos_cinereus, January 2021) has improved the 2018 assembly (Table 2). During the 17 y between the human genome being published (44, 45) and the chromosome-scale, haplotype-resolved assembly being released (46), the original genome exponentially changed human medicine and our understanding of Homo sapiens. As a result, the TSI Steering Committee has opted to fund long-read genome data [HiFi reads of PacBio Sequel II system (47)] with associated species-specific transcriptome data for more species to meet conservation needs, rather than focusing on producing chromosome-length assemblies for a few species. Project teams are encouraged to seek funding to facilitate chromosome-length assemblies in the future using HiC (48) technology. Appropriately collected and stored tissue samples are being archived where possible within Australian museum collections to ensure future assemblies use the same specimen (49).

Assembly features of Tasmanian devil (38), koala (39) and Hi-C scaffolded koala genomes (dnazoo.org)

Sampling requirements for high-quality genomes can be extremely difficult to meet for threatened species, particularly those that are listed as critically endangered (49, 50). Many long-read technologies require nonfragmented DNA, which is most easily obtained from tissue samples that are flash-frozen or freshly collected. While relatively large amounts of fresh, preferably young, leaves are required for the high molecular weight DNA extraction needed for assembling a plant genome, collecting leaf tissue for genotype by sequencing is less stringent and requires significantly smaller amounts of silica-dried tissue (and can even work from herbarium specimen). Given the static nature of plants, and the small population size of many of the most threatened species, sometimes most living individuals can be sampled (51). For animal species, however, collecting fresh tissue samples that need to be flash-frozen from cryptic species is more problematic. It is also impractical in a large geographic country like Australia 7.69 million km2, with a relatively small human population (25.4 million), where access to liquid nitrogen in remote locations is logistically challenging and transport networks from remote locations are limited, resulting in difficulties transporting samples to laboratory facilities in a timely manner. Furthermore, many Australian animal species are small, and so blood volumes greater than 100 to 500 L may not be achievable.

Although sequencing costs in the United States, Europe, and China are relatively low, the nature of distance and small turnover in other parts of the world means that discounted sequencing costs tend not to be available for many. Of the 17 megadiverse nations (2), the United States has the cheapest sequencing. To ensure the full value of genomic resources for the conservation of global biodiversity, it is important to invest in local conservation communities and empower them to develop resources within country. For many threatened and endemic species, sending samples to the United States, Europe, and China may be also be constrained by international (e.g., CITES) and national (e.g., United States Endangered Species Act; Australian Environment Protection and Biodiversity Conservation Act) biosecurity, trade regulations, and permit requirements. Furthermore, for many Indigenous and First Nations peoples the natural world, and their affiliation with it, holds cultural significance, meaning that movement of samples, or even extracted DNA, across international borders is often restricted. This brings to the fore potential issues with sampling and the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization (52, 53). Globally we need to embed indigenous principles into genomic research (36, 54), and be able to facilitate genome projects within nations, often where sequencing is not cheap. This requires us to rethink what kinds of genomes we are seeking to produce to effect change in conservation practice and ensure the genomic resources, and associated downstream tools that are created, are utilized to their full potential (50).

TSI is also producing supporting population genetic data (for up to 190 individuals) for species that require it to inform conservation management action (Fig. 3). This will not cover all the population genetic data that will be required for some species, but rather is a launchpad for coinvestment into using genetic data for conservation management. Reduced representation sequencing (RRS) has been selected for population genetic data, although it does have limitations for some population analyses, such as runs of homozygosity (RoH), identification of alleles within species genes, or effective population sizes. For these analyses, whole-genome resequencing (WGS) is needed but is also currently costly for many taxa with larger genomes (e.g., mammals, amphibians). Either double-digest RADseq (55) (ddRAD) or Diversity Arrays Technology (56) (DArTseq), have been selected as the sequencing methods of choice for TSI population genetics, as both are readily available within Australia from commercial providers and will ensure that the bioinformatic workflows are useful across the range of taxa to be undertaken in this project. Our current workflow can either align RRS data to a reference genome or be used de novo (57). Using species-specific transcriptome data to annotate the genomes allows for conservation managers to have access to functional data, particularly around gene families that are not conserved between species, such as the immune genes.

Components and the interoperable framework of the TSI. Currently, smaller working groups are supporting the development of workflows and protocols for sample collection and storage, bioinformatics, and standardized reporting.

To facilitate the long-term uptake of genetic data into population monitoring and management, TSI is also trialing the use of low-density SNP arrays, where reduced subsets of informative SNP loci identified through the above WGS and population genomic approaches are selected and optimized for high-throughput automated genotyping. SNP arrays can be flexibly designed to contain loci targeted to specific conservation applications: for example, to ascertain population structure and monitor neutral and adaptive genetic diversity (5860), assess parentage and kinship (61, 62), and monitor introgression/hybridization (63). Besides the initial investment in SNP discovery and multiplex primer design, downstream genotyping costs are highly affordable (e.g., MassARRAY iPlex system AUD$11 per sample per 50-plex) with minimal requirements for data analysis, making the routine genetic analysis of populations accessible to a wider array of end-users. Furthermore, SNP genotyping systems, such as MassARRAY, are suitable for application with noninvasive samples (scats, hair) (64), expanding the utility of the method in wildlife monitoring scenarios. We advocate for developing arrays and calling SNPs against reference genomes to ensure future use of the data as SNP locations will be known. As more high-quality reference genomes become available and sequencing costs reduce, WGS will become the norm. In the interim however, using RRS data aligned to a draft reference genome can permit a wide-range of conservation actions for a species [see Brandies etal. (11)].

A key aim of the TSI is to develop an online platform, an applied conservation genomics hub, to empower nongeneticists to be able to use these genomic resources in their conservation decision-making. The TSI is committed to developing such a platform (Fig. 3). The Hub will host protocols for sample collection and storage, in addition to a suite of existing analytical pipelines and workflows [e.g., STACKS (57), dartR (65), Sequoia (66)] with a user-friendly interface that has point-and-click options, rather than a command-line interface. The outputs from these workflows can be used to answer some of the most common conservation management questions (SI Appendix, Table S2). Users will be able to manipulate their data for their specific species, but the output report will be standardized, with different modules for different management questions. The report will be in a simple, consistent format to ensure that conservation practitioners are receiving the same information for their species in a standardized way so they can become familiar with summary methods for genetic data. Reports will include standard genetic metrics (such as heterozygosity, inbreeding, relatedness) in addition to an appendix with sequencing methods used, number of filtered SNPs, filtering used, and compute requirements for the datasets. Standardizing the reporting will assist with reproducibility over time. Users who are creating the reports will also have the option to add more outputs/variables if they so desire. By standardizing the output report, we aim to further promote the education of the conservation practitioners in the use of genetic data in the management practice and encourage the uptake of longer-term genetic monitoring in-line with the Convention of Biological Diversity targets (67, 68). This is perhaps TSIs biggest innovation, because while techniques can change and initial interpretations might be complex, once baseline genomic information is developed and there is standardized management reporting, cheap, effective, long-term monitoring tools can become a reality.

We fully recognize that this online platform and associated standardized reporting will not be a simple task to achieve, as there are many nuances in the interpretation of genetic data for management purposes. However, with the ever-widening gap between genome biologists and conservation practitioners, we need to develop solutions to bridge this divide. Not knowing how to interpret and use the information, nor how it is generated or who to contact, are a few of the reasons that have been flagged by conservation practitioners for why they are not routinely using genetic data in their management practice (28). The platform will be a living, iterative system, which we anticipate will start small and grow with time, use, need, and technological development. TSI has recognized that we need to start to fill this niche, as the gap between the genome biologists and the conservation practitioners is widening each year as the costs of sequencing reduce, bioinformatics becomes more challenging, and the need for genomic resources for conservation management increases.

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After much of Los Angeles went dark in the spring of 2020 amid the growing SARS-CoV-2 threat, two UCLA scientists and their small teambegan working late nights on the fifth floor of the Gonda (Goldschmied) Neuroscience and Genetics Research Center, developing technology that would pave the way for the UCLA community to safely return to campus.

The safer-at-home orders had shut down all but the few core campus activities and services deemed essential. While that meant the suspension of most laboratory research, it didnt apply to a new project led by Valerie Arboleda M.D. 14,Ph.D. 14, assistant professor of pathology and human genetics, and Joshua Bloom 06, a research scientist in human genetics and an adjunct professor in computational biology. Through their collaboration with Octant Bio, a biotech company founded and incubated at UCLA; faculty in UCLAs departments of human genetics and computational medicine; UCLA Health; and other academic institutions across the country, their research ultimately found its way from the high-tech lab Arboleda and Bloom named SwabSeq to vending machines across campus.UCLA faculty, staff and students returning last fall were able to easily access the free COVID-19 test kits, with picking up a testas simple as grabbing a snack: Users simply register for the SwabSeq test by scanning a QR code with their smartphone, retrieve the kit and collect their saliva sample, then deposit the kit in a drop box next to the machine. An email or text notifies them when they can access a secure website for their result.

Diagnosing COVID-19 typically involves polymerase chain reaction (PCR) testing, but as a tool for mass screening of asymptomatic individuals, the approach is limited in its capacity. To run tens of thousands of tests simultaneously, SwabSeq harnesses the power of next-generation DNA sequencing a revolutionary technology thats come of age in the last 15 years and enables the processing of millions of DNA fragments at a time. The testing platform also bypasses a step typically required in the PCR method that of extracting RNA from samples, which can take days to process.

Im thrilled that SwabSeq helped put us back on campus and that my students and I are able to come into the lab.

Valerie Arboleda

SwabSeq attaches a piece of DNA that acts like a molecular barcode to each persons sample, enabling the labs scientists to combine large batches of samples in a genomic sequencing machine. Viewing the barcodes in the resulting sequence, the technology can quickly identify the samples that have the coronavirus that causes COVID-19. SwabSeq can return individual test results in about 24 hours, with highly accurate results the false-positive rate is just 0.2%.

Michal Czerwonka

Rachel Young, laboratory supervisor and clinical laboratory scientist for the COVID-19 SwabSeq lab

SwabSeq has now tested more than half a million specimens from UCLA, as well as from a handful of other universities in Southern California and from the Los Angeles Unified School District. A $13.3 million contract recently awarded by the National Institutes of Health sets the stage for an expansion of SwabSeqs efforts.

This is an innovative use of genomic sequencing for COVID-19 testing that is uniquely scalable to thousands of samples per day, [and that is] sensitive and fast a combination that is challenging to find in diagnostic testing, Arboleda says. Its not cost-effective as a test for a few people, or if you have someone in the hospital who needs an immediate result, but its very effective as a screening tool for large asymptomatic populations.

Neither Arboleda nor Bloom could have predicted they would one day find themselves leading a major element of UCLAs research response to a once-in-a-century pandemic.

Arboleda entered the David Geffen School of Medicine at UCLA intending to become a full-time clinician, but when she took a year off from her medical school studies to work in a lab, she found her true calling. She enrolled in the UCLA Medical Student Training Program, graduating in 2014 with both an M.D. and a Ph.D. in human genetics. As a faculty member, she now devotes about 80% of her time to research, with much of the focus on rare genetic syndromes.

Bloom, trained as a geneticist and a computational biologist, has used model systems such as yeast to develop experimental and computational methods for identifying the heritable genetic factors underlying gene expression differences and other complex traits in large populations. Ive worked on some really abstract problems. Diagnostic testing in a pandemic is definitely not something I thought Id ever be involved in, he says, smiling.

Michal Czerwonka

A machine in the SwabSeq laboratory

Like most of their UCLA colleagues and much of the rest of the world, Bloom and Arboleda saw their work routines upended by the pandemic. Bloom was grappling with the new reality when he received a call from Sri Kosuri, a UCLA assistant professor of chemistry and biochemistry and co-founder/CEO of Emeryville, California-based Octant Bio, the startup where Bloom was a consultant and where early pilot studies for SwabSeq were conducted.

He suggested we could turn the drug-screening technology Octant was using into a COVID test, and asked if I could help with the computational work, Bloom recalls. There were other people at UCLA who were also thinking that with all these smart people here, we should be able to develop a test. From there we began to have large group meetings involving multiple universities sharing information.

When Arboleda heard about the nascent project from a faculty colleague, she knew she could be helpful. In addition to the expertise in molecular biology she could apply to setting up the experiments, her training in pathology gave her the experience with regulatory matters that would need to be addressed once the test was developed. She agreed to collaborate with Bloom, who used his expertise in informatics to optimize the automated DNA sequencing process toward the goal of producing accurate diagnostic readouts.

The two spent a good part of April and May 2020 in the lab. We would do the assay and put it on the sequencer, then Josh would analyze it as soon as it came off the machine, Arboleda says. Based on that, the next day we would adjust a couple of parameters and rerun the experiment.

PreCOVID-19, she had become accustomed to a supervisory role as a principal investigator overseeing a team of scientists. I hadnt gone back to the lab in a while, she says. It was a wild two months, where I felt like a grad student again!

The number and pace of the iteration cycles a new one every 24 hours made this research project unlike any other Bloom had seen. The sequencing technology enables that, because you can tweak a bunch of things and get readouts for them all at once, he says.

But more than that, he credits the speed with which SwabSeq moved from concept to reality to an all-hands-on-deck approach befitting the urgency of the need. We had senior faculty, including department heads, engaged and excited to help, Bloom says.

One of those department heads isEleazar Eskin,chair of the Department of Computational Medicine,a departmentaffiliated with both UCLA Samueli School of Engineering and the medical school. He hascoordinatedlogistics and business operations to ensure that the lab operates efficiently and remainsflexibleenough toadapt to changing circumstances, such asthe appearance of theomicron variant of the virus.Eskinalso built the custom software for SwabSeq'slab-information management system.

Adds Arboleda: Everyone knew it was important and contributed in whatever way would support the mission, whether it was getting space, fundingor institutional review board approvals. And since only people who were doing COVID work could come to campus, I had people on my team who said, OK, Ill put on a mask and do whats needed.

Michal Czerwonka

Hard at work in the SwabSeq lab

The SwabSeq lab now occupies an entire floor in the Center for Health Sciences South Tower. The space is divided into three rooms, each dedicated to a portion of the test. One room is for handling samples; a second is used as a clean room and storage area; and a third, its walls lined with high-level sequencers, is for post-PCR sequencing. All over, freezers and refrigerators store enough reagents for millions of tests. The lab isnt necessarily a one-off Arboleda notes that the technology can be applied to general infectious disease testing and surveillance. Its flexible protocol can rapidly scale up testing and provide a solution to the need for population-wide testing to stem future pandemics, she says.

For now, aside from regular meetings to discuss SwabSeq development and high-level technical issues, the scientists have returned to the work they were doing before everything changed in March 2020. Im thrilled that SwabSeq helped put us back on campus and that my students and I are able to come into the lab, Arboleda says. Now if someone tests positive, no one worries because that person can stay home, and we know we can all easily get tested.

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And unlike a prison, a mink shed has no plumbing. We focus a lot on the respiratory transmission among people, Jonathan Epstein, a zoonotic-disease ecologist, says, but its important to remember that this is also a GI-tract virus, and its shed in the stool. While we flush our own infected excreta down porcelain toilets, the excreta of mink collects under their cages in dank mounds in which coronavirus can remain infectious for days, long enough to be aerosolized when farmworkers shovel it away.

Its probable that the factory-farm conditions that minks are subjected to make them especially susceptible to microbial pathogens. Notwithstanding their undeniably adorable exteriors alert, wide-set eyes, dainty, partly webbed paws and long furry bodies mink are not sociable herd animals like cows, sheep, chickens and pigs, who have been under human domestication for thousands of years, exchanging microbes back and forth with one another and with us. They are solitary, meat-eating predators, unaccustomed to life in intimate proximity to other individuals. Just how the stress of crowding affects mink is unknown, though it is thought to suppress their immune systems. Farmed mink are famously vulnerable to pathogens such as distemper and influenza. Mink farmers must pump them up with vaccinations to keep them alive for the handful of months it takes for them to grow thick fur.

I was told by Michael Whelan, then a mink-industry spokesman, that farmers in the United States had developed strict biosecurity measures to prevent microbial transmission between humans and animals on mink farms. Livestock operations such as poultry farms, for example often require that workers wear Tyvek suits, masks and bootees and shower-in and shower-out of the fully sealed sheds where captive animals are kept. And yet many of the mink farms I visited in Utah didnt even have adequate fencing around their borders. The rickety perimeter gate around one farm I saw was open to passing traffic, including the cows in an adjacent clearing, the deer of which nearby roadway signs warned and a band of feral cats that slinked onto the farms gravel lot just yards from the doorless mink sheds.

Unlike in Europe, health officials in the United States did not conduct active surveillance on mink farms for coronavirus, relying instead on mink farmers to self-report outbreaks. Publicly, industry representatives said they took the risk of coronavirus incursions seriously, but privately, many were almost dismissive about the threat the virus posed. One mink farmer, Joe Ruef, described coronavirus in mink as a nonevent when we spoke by phone. The industry trade group, Fur Commission USA, called it a supposed public health threat, in an email to its members that was leaked to activists and shared with me. And when word got out that I was visiting Utah mink farms, Fur Commission USA sent out a security alert to its members, with a photograph of my rental car and its license plates. DO NOT let her on to your property, and under no circumstances allow her near the mink sheds, it read, because any pictures or documented cases of ranches that are not following the recommended biosecurity protocols could damage our efforts to defend the US producers.

As a relatively small industry that sells most of its animal products overseas as garments rather than as food, mink farms have escaped most regulatory oversight. Federal laws that pertain to animals like the Animal Welfare Act and the Humane Slaughter Act do not cover animals on fur farms. Few states require mink farms to be licensed or inspected; none require veterinary oversight. Like most states, Utah has no regulations on fur farming at all. Even the minimal containment strategies devised for infected mink farms proved difficult to implement. In Utah, mink farmers were fairly resistant to having anyone come onto their facilities, the Utah state veterinarian Dean Taylor told me. In internal correspondence acquired through public-records requests, Utah health department officials discussed an infected farm that the department was not permitted to access even for testing. Unregulated, secretive mink farms, Han says, are not that different, if you think about it, from these captive wildlife farms that we hear about in Asia.

On the 12 mink farms that reported outbreaks, health officials implemented quarantines, testing protocols and trapping programs to capture and test nearby animals. Unlike in Europe, there were no culls of susceptible or infected mink. While in 2014 and 2015 the U.S.D.A. paid $200 million to compensate farmers for culling 50 million farmed birds to short-circuit an outbreak of avian influenza, the agency had no budget to do the same to prevent coronavirus from exploding on mink farms.

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Animals Infecting Humans Is Scary. Its Worse When We Infect Them Back. - The New York Times

China has unveiled its lists of the top-10 scientific advances in China and the world for 2021, as selected by members of the Chinese Academy of Sciences (CAS) and members of the Chinese Academy of Engineering (CAE).

Academicians from the CAS and CAE hold Chinas highest national academic titles in science and engineering.

Among the scientific breakthroughs listed, Chinas progress on its first solar exploration task stands out.

The China National Space Administration released new images taken by the countrys first Mars rover Zhurong, including the landing-site panorama, the Martian landscape and a selfie of the rover, signifying the complete success of Chinas first Mars exploration mission.

Other advances include progress on long-term stays on Chinas space station, research into synthesizing starch from carbon dioxide, the lunar samples brought back by the Change-5 mission, the route to de novo domestication of wild allotetraploid rice, as well as the prevention and control of the agricultural pest Bemisia tabaci.

Topping the list of the worlds top-10 scientific advances is the development of the first living robots with the ability to reproduce. The millimeter-sized living machines, called Xenobots 3.0, are neither traditional robots nor a species of animal, but living, programmable organisms.

Other notable advances include research on the accurate prediction of protein structures, a genetic engineering technique for genetic diseases, using human pluripotent stem cells to grow sesame-seed-sized heart models, and the recreation of the early structures of the human embryo from stem cells.

The selection of the top-10 scientific advances in China and the world has been hosted by the CAS and CAE on 28 occasions, playing a positive role in popularizing the latest sci-tech developments at home and abroad.

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China reveals lists of top global, Chinese scientific advances for 2021 - Macau Business

Researchers from the Indian Institute of Technology Mandi and The International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, have identified phytochemicals in the petals of a Himalayan plant that could potentially be used to treat COVID-19 infections.

The research team's findings have been recently published in the Biomolecular Structure and Dynamics journal. The research was led by Dr Shyam Kumar Masakapalli, Associate Professor, BioX Centre, School of Basic Science, IIT Mandi, Dr Ranjan Nanda, Translational Health Group and Dr Sujatha Sunil, Vector-Borne Disease Group, International Centre for Genetic Engineering and Biotechnology, New Delhi.

Two years into the COVID-19 pandemic, the researchers are trying to understand the virus's nature and discover new ways to prevent the infection. While vaccination is one route to providing the body with fighting power against the virus, there is a worldwide search for non-vaccine medicines that can prevent viral invasion of the human body. These medicines use chemicals that either bind to the receptors in our body cells and prevent the virus from entering them or act on the virus itself and prevent its replication inside our bodies.

Masakapalli says, "Among the different types of therapeutic agents being studied, phytochemicals - chemicals derived from plants - are considered particularly promising because of their synergistic activity and natural source with fewer toxicity issues. We are hunting for promising molecules from the Himalayan flora using multi-disciplinary approaches."

The petals of the Himalayan Buransh plant, scientifically called Rhododendron Arboreum, are consumed in various forms by the local population for their varied health benefits. IIT Mandi and ICGEB set out to scientifically test the extracts containing different phytochemicals, focusing on the anti-viral activity. The researchers extracted the phytochemicals from the Buransh petals and performed biochemical assays and computational simulation studies to understand their anti-viral properties.

Ranjan Nanda says, "We have profiled and investigated the phytochemicals of Rhododendron Arboreum petals sourced from Himalayan flora and have found it to be a promising candidate against the COVID virus."

Extracts from these petals were rich in quinic acid and its derivatives. Molecular dynamics studies showed that these phytochemicals have two effects against the virus. They are bound to the main protease - an enzyme that plays a vital role in viral replication - and the Human Angiotensin-Converting Enzyme-2 (ACE2) that mediates viral entry into the host cells.

The researchers also showed through experimental assays that non-toxic doses of the petal extracts can inhibit COVID infection in Vero E6 cells (cells derived from the kidney of an African green monkey that is commonly used to study infectivity of virus and bacteria) without any adverse effects on the cells themselves.

Sujatha Sunil says, "A combination of the phytochemical profiling, computer simulations and in vitro anti-viral assays showed that the extracts from the Buransh petals inhibited the replication of the COVID virus in a dose-dependent manner."

The findings support the urgent need for further scientific studies to find specific bioactive drug candidates from R. Arboreum, in vivo and clinical trials against COVID-19. The research team also plans to carry out additional studies to understand the precise mechanism of inhibition of COVID-19 replication by specific phytochemicals from Buransh petals.

**

The above article has been published from a wire source with minimal modifications to the headline and text.

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Flower Petals of Himalaya's Buransh Tree Has Phytochemicals That Can Help Fight COVID-19, Say Researchers | The Weather Channel - Articles from The...

CINCINNATI The Bengals ended their playoff drought on Saturday night when they beat the Raiders 26-19. It's Cincinnati's first postseason win since Jan. 6, 1991. Get head coach Zac Taylor's reaction, plus hear from Joe Burrow, Ja'Marr Chase, C.J. Uzomah and Sam Hubbard below.

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Watch: Bengals React to Playoff Win Over Raiders - Sports Illustrated