These chimeric mice are made up of some cells with a rat chromosome University of Yamanashi
The de-extinction company Colossal Biosciences could be about to get leapfrogged. It might be possible to resurrect mammoth chromosomes in living cells after scientists transferred a chromosome from a rat that has been deep-frozen for more than a year into living mouse cells. They then generated entire mice in which some of their cells contain an added rat chromosome.
“Once we have refined the technique, we’ll start testing it on elephant cells,” says at Yamanashi University in Japan. “If we succeed in introducing elephant chromosomes into mouse embryonic stem cells, we definitely want to try it with mammoths.”
The team’s immediate aim is to study the activity of genes from extinct animals in living ones, which could reveal far more than just analysing genetic sequences. But the work could also help with conservation and de-extinction efforts. For instance, we have frozen tissue from a bird called the Hawaiian poʻouli that went extinct in 2004. A quirk of biology means chromosome transfer would be essential to bring it back to life.
The genomes of animals are divided into pieces known as chromosomes. When cells divide, these long strands of DNA get folded up very tightly and take on the classic cylinder shape pictured in textbooks. These condensed chromosomes, as they are called, can be made visible in living cells without damaging them, for instance, by adding pigments to antibodies that bind to the proteins around which DNA is wrapped.
Wakayama’s technique involves extracting the nucleus of a cell and injecting it into an egg to trigger chromosome condensation. This is similar to the nuclear transfer technique used in cloning – Wakayama was the first to clone mice using this technique, soon after the birth of Dolly the sheep.
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The egg with the added nucleus is then injected with enzymes that help separate the chromosomes. Next, a single chromosome is extracted with a microscopic hollow needle and injected into a second egg. If this egg develops into an embryo, all the cells in the embryo – known as embryonic stem cells – will contain the added chromosome.
After developing the technique by adding extra mouse chromosomes, Wakayama then tried it with rats genetically modified to fluoresce green. He extracted blood cells from the tail of one of these rats, which had been deep-frozen for more than a year, and successfully generated mouse embryonic stem cells containing an extra chromosome from the genetically modified rat.
These cells were then injected into normal mouse embryos and implanted into female mice, producing chimeric animals in which some of the cells contain the rat chromosome. These animals look like normal mice, but under UV light, some of these cells fluoresce green like those of the original rat.
The team has attempted to create mice in which all cells contain the extra rat chromosome, but haven’t yet been successful. What’s more, for now, the technique is working only with rat chromosome 9 – if other chromosomes are added, the eggs don’t develop into embryos. “We are currently trying various methods to improve the success rate,” says Wakayama.
The cells glowing green in this mouse pup contain a rat chromosome University of Yamanashi
It’s possible this is because the activity of genes on other rat chromosomes disrupts embryonic development. If so, the team might have to try deactivating genes on the added chromosome in a similar manner to the way in which one of the two X chromosomes in the cells of female mammal cells is deactivated. But Wakayama hopes this will not be necessary.
His team has already obtained samples of frozen elephant tissue from a zoo for testing. Wakayama is also talking to a team that from a 28,000-year-old mammoth called Yuka about trying this with mammoth chromosomes.
Simply trying to clone mammoths from these cells would never work because there is far too much DNA damage. But Wakayama hopes it might be possible to retrieve individual chromosomes, allowing them to be studied in living cells.
“Even just one successful transfer is a very cool start,” says at the non-profit wildlife conservation group Revive & Restore in the US. “In passerine birds, there could be a big value in this work.” That’s because in passerine birds – a large group that includes more than half of all bird species – the cells that form body tissues such as skin and muscles lose a chromosome. This extra chromosome is retained only in the reproductive cells that form the egg and sperm.
Because the Hawaiian poʻouli was a passerine bird and only non-reproductive male tissue was frozen, bringing it back would require adding two chromosomes from closely related species – the chromosome found only in reproductive cells and the W chromosome found only in female birds. “It would produce partial hybrids, but it would allow for the revival of the species,” says Novak.
Wakayama isn’t the first to create living animals with extra chromosomes. In 2022, another team in Japan in order to study Down’s syndrome. However, the technique involved extensive genetic modifications that wouldn’t be desirable or possible for conservation applications.
Extra reproductive chromosomes may be far more widespread than we recognise, says Novak, which means many of the tissues being frozen by biobank projects may be missing them.
Journal reference:
Scientific Reports
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