science Watch / Saul Scheinbach
De-Extincting the Woolly Mammoth
“This is a new type of fossil, and its scale dwarfs that of individual ancient DNA fragments—a million times more sequence." – E. Lieberman Aiden
Adult male woolly mammoth. Leonello Calvetti Stocktrek Images
The woolly mammoth (Mammuthus primigenius) appeared in Eurasia about a million years ago. It entered North America via the Siberian land bridge roaming the northern half of the continent for over half a million years. It was the Pleistocene epoch (2.5 million-12,000 years ago) a time of extreme cold. Nevertheless, mammoths could withstand temperatures as low as -50oC (-58oF) persisting even when an ice sheet 2,000 feet thick covered New York City 24,000 years ago. But the planet began warming and mammoths went extinct 4,000 years ago. Paleontologists are still debating whether it was the warming planet or hunting by humans that caused the mammoth’s extinction. Meanwhile, others are working to restore the species to its natural habitat, the tundra, through a process called “De-extinction.” (See: 2013, De-Extinction at https://www.hras.org/past-sciencewatch-articles.)
About 30 years ago scientists realized emerging biotechnologies could resurrect extinct species. To de-extinct a species you need to sequence its genomic DNA which rapidly degrades after death. But well-preserved mammoth carcasses in melting permafrost yield ancient DNA fragments for reassembling the 3.4 billion subunit genome. In 2021 a company, “Colossal,” was founded to de-extinct the woolly mammoth.
Scientist examine 52,000-year-old woolly mammoth skin after it was excavated from permafrost. Love Dalén/ Stockholm
Colossal has been identifying mammoth genes that control cold-adaptive traits like long hair, small ears, insulating fat and mammoth hemoglobin (Hb) which unlike elephant Hb can function in extreme cold. Mammoths share 99.6% of their DNA with the Asian elephant (Elephas maximus). So, Colossal plans to splice these genes into the Asian elephant genome using the gene editing technique CRISPR. (See: 2019, The End of Malaria? at https://www.hras.org/past-sciencewatch-articles.) Using Asian elephant stem cells, they will test mammoth gene function in vitro. Next, all working genes get spliced into a stem cell nucleus, fused with an Asian elephant egg and implanted into an elephant surrogate to produce a “functional mammoth.”
A breakthrough study published in the July 11, 2024 issue of Cell will doubtlessly aid Colossal’s endeavor. An international research team analyzed skin collected from a woolly mammoth so well preserved that cell nuclei retained their 3-D genome architecture. The skin came from a 52,000-year-old carcass in Siberia that experienced freezing and desiccation causing the chromosomes to form a glasslike state. “Basically, the chromosomes were trapped inside a piece of freeze-dried woolly mammoth jerky for 50,000 years,” said team member Erez Lieberman Aiden. Mammoth DNA fragments extracted previously were barely a hundred DNA sub-units long. This mammoth’s “fossil” chromosomes are hundreds of millions of sub-units long yielding a sequencing road map unimaginable until now. It’s like trying to reassemble a shredded book from phrases or sentences to now having the pages.
Using a software program, PaleoHi-C, which reassembles DNA fragments, the team put the genome “pages” in their proper order and determined the spatial arrangement of the mammoth’s chromosomes. The Hi-C analysis, combined with DNA sequencing, revealed that mammoths, like modern elephants, have 28 chromosomes. Chromosomes contain a single long strand of DNA looped over itself. PaleoHi-C identified which DNA loops were in close proximity to each other and contained genes likely to interact.
Furthermore, chromosomal regions align into compartments based on gene activity. So, the team could establish which genes were active or not. A comparison with the Asian elephant’s 3-D genome architecture indicated which genes were expressed differently in mammoths. For example, when a gene regulating skin and hair growth is turned off excess hair growth occurs in humans and sheep. That gene was inactive in the mammoth but active in the Asian elephant. In all 800 skin genes exhibited differing elephant to mammoth activity profiles.
Colossal claims it will de-extinct the mammoth in 3-5 years. However, some question the wisdom of bringing back an animal absent for thousands of years. Will functional mammoths be healthy or will they suffer from abnormalities and die before maturity? Will they be fertile? Will they survive on a warming planet? Is it even ethical to bring them back?
Questions aside, Colossal is forging ahead. We may soon see how functional their functional mammoth is.
Saul Scheinbach