It took 4,000 years, but they are almost here. Back. Somewhere in the Arctic tundra, perhaps on some deserted Siberian island, emulating Nublar from Jurassic Park, would be the ideal scenario to soon host the resurrection of an icon of the Ice Age: the mammoth. Science says it has just taken a, of course, giant step, after the chance discovery of fossilized chromosomes of a woolly mammoth that died 52,000 years ago in the Siberian permafrost.
The chromosomes are a million times longer than most ancient DNA fragments found to date, providing information on how the mammoth's genome was organized within its living cells. An unprecedented level of structural detail, made possible because the mammoth was naturally subjected to a lyophilization process shortly after death. Its DNA was preserved in a state similar to glass, as if a billionaire had paid for a luxury preservation for a potential resurrection.
So far, all mammoth cloning projects have faced difficulties at every step. The first: the need to find an intact entire chain of DNA. This new discovery, the results of which have just been published in the journal Cell, is so well preserved that researchers were able to infer for the first time genes related to the woolly nature or cold tolerance of the mammoth. "It means we are one step closer to assembling the genomes of extinct ancient species, with significant implications for de-extinction," says M. Thomas Gilbert, a paleogenomic researcher at the University of Copenhagen and the Norwegian University of Science and Technology, as well as a study co-author.
Once the DNA is recovered, it would need to be fused with an Asian elephant egg, the closest living relative to mammoths, sharing 99.6% of its genetic code. Then insert it into the uterus of an African elephant female, the closest in size, and if successful, 22 months later, something resembling a mammoth calf would be born.
The biotechnology company Colossal claims we could see a baby mammoth by 2028, after successfully converting cells from modern Asian elephants into stem cells with the potential to differentiate into all the different types of cells that make up their bodies.
Juan Antonio Rodríguez, a researcher at the National Center for Genomic Analysis in Barcelona (Spain) and at the University of Copenhagen, Denmark, is not so sure: "My personal conclusion is that we should dedicate resources to not decimating and protecting existing biodiversity, instead of spending millions on resurrecting something very large and complicated. We wouldn't know the consequences this would have on the ecosystem and animal welfare. How will it fit into the ecosystem? Definitely, 3D structure is necessary; a step up the ladder, but not the only one. I think they could generate a mamophant, an elephant with some mammoth genes here and there, but far from a real mammoth, which I don't know if we will see in our lifetime. Also, many specimens would be needed to produce a stable population over time."
Fossil chromosomes are a new and powerful tool for studying the history of life on Earth because they allow for the complete DNA sequence assembly of extinct creatures, providing insights that were previously impossible. This is because typical ancient DNA fragments rarely exceed 100 base pairs, or 100 letters of the genetic code, much smaller than the complete DNA sequence of an organism, which often has billions of letters. In contrast, fossil chromosomes can span hundreds of millions of genetic letters.
Legs of a young female woolly mammoth killed by a saber-toothed tiger 39,000 years ago.Love Dalen
Researchers analyzed dozens of samples over five years before finding this specimen in northeast Siberia in 2018. "We knew that tiny fragments of ancient DNA can survive for long periods of time. But what we found here is a sample where the three-dimensional arrangement of these DNA fragments froze in place for tens of millennia, thus preserving the structure of the entire chromosome," said Dr. Marcela Sandoval-Velasco, from the Center for Evolutionary Hologenomics at the University of Copenhagen and lead co-author of the new study.
To reconstruct its genomic architecture, researchers extracted DNA from a skin sample taken behind the ear, using a method called Hi-C. "Imagine you have a 3-billion-piece puzzle, but you don't have a final image of the puzzle to work with. Hi-C allows you to have an approximation of that image before starting to put the puzzle pieces together," explains Marc A. Marti-Renom, ICREA research professor and structural genomic researcher at the National Center for Genomic Analysis (CNAG) and the Center for Genomic Regulation (CRG) in Barcelona.
The Hi-C analysis was combined with DNA sequencing to identify interacting sections and create an ordered map of the mammoth genome, using that of current elephants as a template. The analysis revealed that woolly mammoths had 28 chromosomes. The same as current Asian and African elephants. Surprisingly, the fossilized mammoth chromosomes also retained a wealth of details. Researchers were able to identify active and inactive genes within the cells and discovered that mammoth skin had genetic activation patterns different from those of its closest relative, the Asian elephant, including those related to its woolly nature and cold tolerance. "It was extremely exciting to be able to count the chromosomes of an extinct creature for the first time. It's not usually possible to have so much fun just counting from one to 28," notes Juan Antonio Rodríguez.
However, researchers were left with an enigma: how could ancient chromosome DNA fragments survive for 52,000 years with their three-dimensional structure intact? In 1905, Albert Einstein published a classic paper calculating how quickly tiny particles, like DNA fragments, tend to move through a substance. "Einstein's work makes a very simple prediction about chromosome fossils: under normal circumstances, they shouldn't exist, and yet: here they are. It's a mystery of physics!," points out Olga Dudchenko, assistant professor of molecular and human genetics at the Center for Genome Architecture at Baylor College of Medicine and lead researcher at the Theoretical Biological Physics Center at Rice University.
Leg of a woolly mammoth in a permafrost environment.Love Dalen
To explain this apparent contradiction, researchers realized that the chromosome fossils were in a very special state, very similar to the state of molecules in glass, something that was not so far-fetched. Many civilizations developed ways to induce a glassy transition in their food as a way to preserve it, through a combination of cooling and dehydration. This resulted in foods like beef jerky, which are more fragile than the original foods but last much longer. Basically, researchers discovered that the chromosome fossils had been trapped inside a piece of lyophilized woolly mammoth jerky.
"We confirmed this theory by conducting experiments with old, lyophilized beef jerky, which is much easier to find than woolly mammoth jerky," explained Dr. Cynthia Pérez Estrada, lead co-author of the study and researcher at the Center for Genome Architecture and the Theoretical Biological Physics Center at Rice University. "We shot it with a shotgun, ran it over with a car, and each time, the jerky broke into pieces, as if it were glass, but on a nanometer scale, the chromosomes were intact, unchanged. That's why these fossils can survive, and why they were there 52,000 years later, waiting for us to find them."
Although the method used in this study is based on exceptionally well-preserved fossils, researchers are optimistic that it could also be used to study other ancient DNA specimens, including Egyptian mummies.
"Museum mummy samples, if well-preserved, could provide us with information on gene activation profiles that were occurring at the time of death, allowing us to understand environmental conditions, for example," explains Juan Antonio Rodríguez. "If we talk about mummies of things other than humans, like collections of animals in museum basements, again if the tissue samples have undergone this glassy state transition we mentioned, it would allow us to investigate and use these samples to generate, for example, reference genomes for extinct species, or use the information for species conservation."