With curious eyes, a furry snout, and lush skin, the mouse – nicknamed Xiao Zhu, or Little Bamboo – sits gracefully on a stalk of bamboo, beautifully posing for the camera. But this mouse does not exist in nature.
Made in a lab in Beijing, Xiao Zhu pushes the boundaries of what’s possible for genetic engineering and synthetic biology. Instead of harboring the usual 20 pairs of chromosomes, a mouse and its siblings have only 19 pairs. Two pieces of different chromosomes were artificially fused together in a daring experiment that wondered: Instead of modifying single DNA letters or multiple genes, could we reset the rules of the existing genetic game in bulk, while shuffling huge blocks of genetic material at the same time?
It’s the starting idea. If the genome is a book, gene editing is like transcription editing — changing a typo here and there, or fixing multiple grammatical errors with carefully crafted edits.
Engineering at the chromosome level is a whole different beast: It’s like rearranging multiple paragraphs or transposing entire sections of an article, while simultaneously hoping the changes add capabilities that can be passed on to the next generation.
Reprogramming life is not easy. Xiao Zhu’s DNA is built from genetic letters that have already been improved upon by eons of evolutionary pressure. Not surprisingly, manipulating the well-established genome book often leads to unviable lives. So far, only yeast has survived the reorganization of its chromosomes.
The New studypublished in SciencesThe technology made it possible for mice. The team artificially fused parts of the mice’s chromosomes. One fused pair made of the four and the fifth chromosomes was able to support the embryos that developed into healthy mice – albeit with rather strange behaviour. Remarkably, even with this tectonic shift to their normal genes, mice can breed and pass their engineered genetic quirks to second generation offspring.
“For the first time in the world, we have achieved complete rearrangement of chromosomes in mammals, and made new advances in synthetic biology,” He said Study author Dr. Wei Li at the Chinese Academy of Sciences.
In a way, the technology mimics the evolution at the speed of a neck break. Based on existing data on mutation rates, the type of genetic exchange presented here would generally take millions of years to achieve naturally.
Studying is not perfect. Some of the genes in the engineered mice were abnormally tuned, resembling a pattern typically seen in schizophrenia and autism. And although the mice grew to adulthood and could give birth to healthy young, the birth rate was much lower than their non-engineered counterparts.
However, studying is a wonderful experience, He said Evolutionary biologist Dr. Harmit Malik at the Fred Hutchinson Cancer Center in Seattle, who was not involved in the study. We now have this ‘beautiful toolkit’ to address the outstanding questions of genetic alterations on a larger scale, which may shed light on chromosomal diseases.
Wait, what are chromosomes again?
The work takes advantage of the genetic rulebook of long-term evolution to build new species.
Let’s go back. Our genes are encoded in the double helix strands of DNA, which are like ribbons that float inside the cell. It is not a space saver. The natural solution is to wrap each string around a protein roller, like sliced prosciutto rolled over a mozzarella stick. Additional twists pack these structures into tiny balls — picture beads on a string — and then twist into chromosomes. Under a microscope, it mostly looks like the letter X.
Each type carries a specific number of chromosomes. Human cells – excluding sperm and eggs – contain 46 individual chromosomes arranged in 23 pairs, inherited from each parent. In contrast, lab mice contain only 20 pairs. The complete set of chromosomes is called the karyotype, derived from the Greek word for “nucleus” or “seed”.
Mixing and matching chromosomes has always been part of evolution. According to current estimates, rodents in general accumulate approximately 3.5 chromosome rearrangements every million years. Some sections are omitted, while others are randomly repeated or shuffled. For primates, the rate of change is about half that. Shifting around parts of chromosomes might seem drastic for any animal, but when viable, the changes pave the way for the development of completely different species. Our second chromosome, for example, was fused from two separate taxa, but the disc is not found in gorillas, our close evolutionary cousin.
The new study aimed to do one better than evolution: Using genetic engineering, I wondered, could we condense millions of years of evolution into just a few months? It’s not just about scientific curiosity: Chromosomal diseases underlie some of our toughest medical puzzles, like childhood leukemia. Scientists previously launched chromosome rearrangements using radiation, but the results were not easy to control, making it impossible for the animals to give birth to new offspring. Here, synthetic biologists have taken a more targeted approach.
The first step is to find out why chromosomes are resistant to significant changes in their organization. As it turns out, significant hiccups in swapping — or merging — chromosome segments is a biological anomaly called imprinting.
We receive chromosomes from both parents, with each group containing similar genes. However, only one group is operated. How the imprinting process works remains a mystery, but we know that it impairs the ability of embryonic cells to develop into multiple types of mature cells and limits their ability to genetically engineer.
back in 2018, The same team found that deleting three genes could nullify the biochemical fingerprinting program in stem cells. Here, they used these “unlocked” stem cells to graft genetic chromosome pairs together.
They first set their eyes on chromosomes I and II, the two largest in a mouse genome. Using CRISPR technology, the team sliced the chromosomes, allowing them to swap out genetic pieces and remodel them into stable genetic constructs. Then cells containing the chromosome change were injected into the oocytes – oocytes. The resulting embryos were transplanted into surrogate mice to mature further.
The swap was fatal. The artificial chromosome, with the second chromosome followed by the first, or 2+1, killed the developing fetus just 12 days after conception. The same fused chromosomes in the opposite direction, 1 + 2, had better luck, resulting in a live pup with only 19 pairs of chromosomes. The young mice were abnormally large for their size, and in many tests they appeared more anxious than their normal peers.
The second chromosome fusion experiment fared better. Chromosomes 4 and 5 are smaller in size, and the resulting embryo – aka 4 + 5 – developed into healthy young mice. Although they also lacked a pair of chromosomes, they looked surprisingly normal: they weren’t restless, they had an average body weight, and when they matured, they gave birth to young ones that also lacked a pair of chromosomes.
In other words, the team engineered a new karyotype in a mammalian species that can be passed down through generations.
A whole new world in synthetic biology?
For Malik, it’s all about the scale. By overcoming the imprinting problem, “the world is their oyster as far as genetic engineering” He said to me the scientist.
The team’s next goal is to use the technology to solve challenging chromosomal diseases rather than design mutant species. Artificial evolution is hardly around the corner. But the study shows the amazing ability to adapt mammalian genomes.
“One goal of synthetic biology is to create complex multicellular life using tailored DNA sequences,” the authors wrote. “The ability to manipulate DNA at significant levels, including at the chromosome level, is an important step toward this goal.”
Image Credit: Chinese Academy of Sciences