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The concept of de-extinction has been around for many years. Once considered a fanciful idea, recent advancements in technology - notably CRISPR - have made bringing back extinct animals such as mammoths an extremely feasible proposition that investors are willing to put their money into, with an aim of reversing and preventing biodiversity loss. The idea of bringing back extinct animals was first explored in the 20th century through a technique known as back-breeding, which involves the application of selective breeding - similar to that of traditional selective breeding to create an animal with certain desired traits - to resurrect ancestral traits that have been lost over time through evolution. While back-breeding is still one of the main techniques used, the first ‘successful’ de-extinction came via cloning. In 2003, scientists used a cloning technique adapted from Dolly the Sheep - the world’s first ever mammal cloned from an adult somatic cell - to create a clone of the last living bucardo, named Celia, who died in 2000. After implanting the nuclei from Celia’s cells into goat eggs and implanting the eggs into 57 goat surrogates, seven goats became pregnant, with six suffering miscarriages. A cesarean section was performed on the remaining goat and the clone survived for ten minutes before dying from respiratory failure due to her lung having grown a sizeable extra lobe. So far, this has been the only successful de-extinction, but even then, the science proved not to be advanced enough for the clone to survive. Now, the newest method being explored for de-extinction is the gene editing technology known as CRISPR - specifically CRISPR/Cas9 - which is still fairly new to the scene, having first been used as a gene-editing tool in 2012. Not only is CRISPR viewed as one of the most promising methods for tackling a range of diseases, it also appears to be producing positive results when it comes to de-extinction. Science behind using CRISPR for de-extinction CRISPR is an engineered cellular technology that has an RNA guide that is programmed to target specific areas on a genome, with the Cas9 protein acting as scissors. It essentially adds or deletes genetic information, allowing scientists to edit DNA. The first step in using CRISPR for de-extinction is sequencing the extinct animal’s genome, as this will provide a blueprint for it. Sequencing the genome will determine the order of the four bases, or chemical building blocks (A, C, G, and T), that make up the DNA molecule. Scientists also need to get hold of the genome of its closest living relative in order to achieve this. “If you know the sequence of the genome of your extinct animal, and if you have the genome of its relative, you can look for the differences and just use CRISPR to edit the differences - that’s the basic idea,” said Professor Tom Gilbert, evolutionary biologist at the University of Copenhagen. To do this, scientists compare the genomes of the extinct animal and its living relative and insert critical parts of the extinct animal’s genome into the genome of its relative. For example, in the case of the mammoth, its cold-resistant traits need to be inserted into the Asian Elephant genome. However, in reality, it is a lot more complicated than that due to the fact that ancient DNA is very fragmented, having been broken down over time by bacteria and exposure to UV light. The shorter the fragments, the more difficult it becomes. Once the extinct animal’s crucial traits have been inserted into its relative’s genome, a CRISPR/Cas9 complex containing RNA needs to bind to the identified gene in the genome of the relative and cut into the double strands of its DNA, allowing scientists to eventually create a hybrid version of the extinct animal. But, as promising as the technology is, using CRISPR for de-extinction does ultimately have its limitations, in the sense that it can’t bring back an exact replica of an extinct species. These limitations were laid out in the Christmas Island rat study in 2022. “The study was to show how, for various reasons, if you try and bring something back, what you end up with is not really what you lost to start with, it’s some kind of hybrid version, which is fine,” said Gilbert, who co-authored the study. The truth is that gene editing technology is not advanced enough yet to bring back an exact replica in a timely manner. It would take hundreds of years to change all of the differing sequences to the extinct animal’s DNA. Gilbert said that he isn’t against de-extinction, but that he wants people to understand that it doesn’t mean bringing back a full version of an extinct animal. “My worry is that if someone gives a company a whole lot of money to bring back a mammoth, and the end product isn’t a mammoth, they won’t be happy, and the last thing the world needs is more people not trusting in science,” he said. Current CRISPR de-extinction projects: resurrecting the wooly mammoth, the thylacine and the dodo If you’re looking for proof of the allure de-extinction currently holds on investors, then Colossal Biosciences, which is at the forefront of the current scientific landscape surrounding de-extinction, is the perfect example. It secured $150 million in Series B financing two years after the company’s initial launch in 2021, and is involved in ongoing projects to resurrect the wooly mammoth, the thylacine and the dodo using CRISPR. The return of the mammoth with CRISPR is Colossal’s landmark project. Given that the species died out around 4,000 years ago, it seemed unlikely it could be brought back. But scientists managed to recover DNA from mammoth fossils frozen in the Arctic tundra, in Siberia, in 2021. Now, Colossal is working on splicing bits of this DNA into the genome of its closest relative, the Asian elephant, which shares 99.6% of its DNA. Colossal also announced in January 2023 that it has launched a project to bring back the iconic dodo, with the help of University of California Santa Cruz professor and lead palaeogeneticist at the company, Beth Shapiro, who led the team that sequenced the dodo’s genome for the first time in March 2022. But at this moment in time, it’s the project to de-extinct the lesser-known thylacine - a marsupial apex predator from Australia - that shows the most promise, given it died out less than 100 years ago, meaning its DNA is more accessible and the leftover fragments are longer. The project is led by the Thylacine Integrated Genetic Restoration Research (TIGRR) Lab at the University of Melbourne, who partnered with Colossal last year. Geneticist Professor Andrew Pask, Head of TIGRR, managed to sequence the thylacine’s genome in 2017 using an extremely well-preserved sample. “Museums Victoria in Australia had one pouch young (pup) that was placed into ethanol when it was collected more than 100 years ago. This was unusual - most go into formalin - but the ethanol preserved the DNA better, making the genome sequencing tractable for this species,” said Pask. TIGRR also has access to a platinum-level genome for the closest living relative to the thylacine; the fat-tailed dunnart. The two species share 95% of their DNA, meaning the dunnart can provide the cells and genomic blueprint to create a functional thylacine genome. There is still a long way to go, though. “The sheer scale of the number of edits which need to be made is the bulk of the work here. We also need to develop assisted reproductive technologies (ART) for marsupials; things such as embryo transfers, IVF, stem cells,” said Pask. However, he stated that the partnership with Colossal will help to advance the thylacine de-extinction quest: “The partnership with Colossal brings together an incredible team of dedicated biologists all working on the same goal – of recreating the thylacine. The DNA editing technologies leveraged by Colossal will greatly accelerate the project.” A conservation solution or an ethical concern? Depending on who you talk to, de-extinction can either be viewed as a solution to biodiversity loss and act as a progressive conservation tool, or it can be seen as an unnecessary distraction from current conservation efforts and could have a negative impact on current ecosystems. The former is the primary reason behind the recent push for de-extinction; it can potentially provide an opportunity to bring back the animals that were driven to extinction by humans - rather than through natural, evolutionary causes - resulting in the removal of key balancing factors within specific ecosystems. In theory, re-introducing certain extinct species to their natural environment will favorably impact biodiversity because of this. The thylacine was one such species forcibly removed through human acts that played an integral part in its ecosystem. “The thylacine was completely unique among living marsupials. Not only did it have its iconic wolf-like appearance, but it was also our only marsupial apex predator. Apex predators form extremely important parts of the food chain and are often responsible for stabilizing ecosystems,” explained Pask. In fact, human interference is the root cause of most modern extinctions, which is a trend that is becoming increasingly more noticeable. According to a report released in October 2022, the planet’s wildlife populations have decreased by around 69% since 1970 due to things like rainforest destruction, pollution, overfishing and trophy hunting. De-extinction could also be used for the conservation of existing species, through the use of freezing and biobanking stem cells, which can then be used to repopulate an area with an endangered species. However, there are also multiple ethical concerns surrounding de-extinction, with some scientists and conservationists arguing that the habitat of species’ brought back to life will no longer exist, and they might not be able to survive by themselves in the wild, leading to them ending up in cages and zoos. Another major concern is whether they might upset existing ecosystems and alter food chains if they are re-introduced into the wild. There are also fears de-extinction might undermine conservation efforts for existing animals by diverting funds away from well-known conservation techniques, like the creation of protected areas and the management of small animal populations to help them survive. Phil Brooke, research and education manager at Compassion in World Farming, said: “De-extinction is not a good solution. It is likely to involve procedures that cause suffering to the animals involved and is unlikely to produce a range of animals with the genetic diversity required to ensure long-term survival. Above all, it is a distraction from the real challenge, which is that we must act quickly to stop even more extinctions of the animals we currently have.” There is no precedent for bringing an extinct animal back to life for long enough to witness the effect it has on the ecosystem it is re-introduced into, so it’s difficult to say yet whether de-extinction will have an overall positive or negative impact. But, ultimately, scientists hope that CRISPR will prove to be the solution to both de-extinction and the conservation of existing species. “It is through great partnerships like ours with Colossal that de-extinction will soon become another tool in our conservation tool kit, and one that will be used to restore lost biodiversity and ecosystems - something which is becoming more and more critical with our changing planet,” said Pask.

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