With curious eyes, a hairy nose and lush fur, this rat, called Kodake (小竹), perches quickly on a bamboo stalk and poses cutely for the camera. However, this rat does not exist in nature.

Made in a Beijing lab, Xiao Zhu pushes the boundaries of what is possible in genetic engineering and synthetic biology. Instead of the normal he possessing 20 pairs of chromosomes, mice and their sibling cohorts have only 19 of hers. Her two chunks of different chromosomes were artificially fused in a daring experiment. Rather than fine-tuning individual DNA letters or multiple genes, can an existing genome his playbook be massively re-tuned to simultaneously shuffle large blocks of genetic material?

It’s a moonshot idea. If the genome is a book, gene editing is like copy editing. Change typos here and there or fix multiple grammatical errors with carefully placed tweaks.

Chromosome-level engineering is an entirely different beast. It’s like reordering multiple paragraphs or moving entire sections of an article, all while hoping the changes add functionality that will carry over to the next generation.

Reprogramming your life is not easy. Xiao Zhu’s DNA structure is built from genetic letters already optimized by years of evolutionary pressure. It’s no surprise that tinkering with established genome books often renders life unviable. So far, only yeast have survived chromosomal rearrangement.

New research published in chemistry, enabled mouse technology. The team artificially fused chunks of mouse chromosomes. His one fusion pair, made from chromosomes 4 and 5, was able to support embryos developing into healthy mice. Remarkably, even with this tectonic shift to normal genetics, mice were able to reproduce the engineered genetic specificity and pass it on to the second generation of offspring.

“For the first time in the world, we have achieved a complete chromosomal rearrangement in a mammal, providing a new breakthrough in synthetic biology,” said study author Dr. Wei Li of the Chinese Academy of Sciences.

In some ways, this technique mimics evolution at breakneck speed. Based on existing data on mutation rates, it would generally take millions of years for gene swaps of the type introduced here to be naturally accomplished.

Research is not perfect. Some genes in the engineered mice are aberrantly regulated, resembling patterns commonly seen in schizophrenia and autism. Mice were able to grow to adulthood and give birth to healthy offspring, but birth rates were much lower than their unmanipulated peers.

Still, the study is a masterpiece, said Dr. Hermit Malik, an evolutionary biologist at Fred Hutchinson Cancer Center in Seattle. He was not involved in the research. We now have this ‘beautiful toolkit’ that could address unsolved questions about genomic alterations at scale and shed light on chromosomal diseases. rice field.

Wait, what are chromosomes again?

The study draws on evolutionary theory’s long-standing genetic playbook for building new species.

Back up. Our genes are encoded in ribbon-like DNA double helices that float inside our cells. Not space efficient. Nature’s solution is to wrap each strand around a spool of protein, like a slice of prosciutto wrapped around a stick of mozzarella. With a further twist, these structures are packed into tiny packs (pictured beads attached to a string) that wrap around the chromosome. Under the microscope they look almost like the letter X.

Each species has a certain number of chromosomes. All human cells, with the exception of sperm and eggs, carry her 46 individual chromosomes, arranged in 23 pairs, inherited from each parent. In contrast, laboratory mice have only 20 pairs. A complete set of chromosomes is called a karyotype, derived from the Greek words “kernel” or “seed.”

Chromosome mixing and matching has long been part of evolution. Current estimates indicate that rodents generally accumulate about 3.5 chromosomal rearrangements every million years. Some segments are deleted and others are duplicated or shuffled. For primates, the rate of change is about half that. Moving chunks of chromosomes may seem drastic for any animal, but when feasible, the change paves the way for evolution into an entirely different species. For example, our second chromosome was fused from her two separate chromosomes, a tweak that is absent in our close relative, the gorilla.

New research aimed to do something better than evolution. Could genetic engineering be used to condense millions of years of evolution into just a few months? Just for scientific curiosity. not. Chromosomal disorders underlie some of the most difficult medical conundrums, such as childhood leukemia. Scientists have previously used radiation to induce chromosomal rearrangements, but the results could not be easily controlled, preventing the animals from producing new offspring. Here, synthetic biologists have taken a more targeted approach.

The first step is to figure out why chromosomes resist large changes in organization. After all, the big problem with swapping or fusing chunks of chromosomes is a biological quirk called imprinting.

We receive chromosomes from both parents and each set contains similar genes. However, only one set is on for her. How the imprinting process works remains a mystery, but it is known to impair the ability of embryonic cells to develop into multiple types of mature cells, limiting the potential for genetic engineering.

In 2018, the same team found that deleting three genes could disable the imprinting biochemical program of stem cells. Here, we used these ‘unlocked’ stem cells to genetically piece together two chromosome pairs.

They first focused on chromosomes 1 and 2, the two largest chromosomes in the mouse genome. The team used his CRISPR to chop up chromosomes so that clumps of genes could be exchanged and reshaped into stable genetic constructs. Cells containing the chromosomal alterations were then injected into oocytes (egg cells). The resulting embryos were transferred to surrogate female mice for further maturation.

Swap was fatal. An artificial chromosome, Chromosome 2 followed by her Chromosome 1, or 2 + 1, killed the developing fetus just 12 days after conception. Her two identical chromosomes fused in opposite directions, 1 + 2, were lucky and produced live pups with only 19 chromosome pairs. Baby mice were unusually large for their size and appeared more anxious than their normal peers in some tests.

The second chromosomal fusion experiment went well. Chromosomes 4 and 5 were much smaller in size and the resulting embryos (called 4 + 5) grew into healthy mouse pups. A chromosome pair was also missing, but it looked surprisingly normal. They were less anxious, had average weights, and when they reached maturity gave birth to puppies that also lacked a pair of chromosomes.

In other words, the team designed new karyotypes for mammalian species that could be passed on from generation to generation.

A whole new world of synthetic biology?

For Malik, scale is everything. By overcoming the imprinting problem, “the world is their oyster as far as genetic engineering is concerned,” he said. the scientist.

The team’s next goal is to use this technology to solve difficult chromosomal disorders rather than engineering mutants. Artificial evolution is just around the corner. However, this study demonstrates the surprising adaptability of mammalian genomes.

“One of the goals of synthetic biology is to use engineered DNA sequences to generate complex multicellular organisms,” the authors write. “Being able to manipulate DNA on a large scale, including at the chromosomal level, is an important step towards this goal.”

Image credit: Chinese Academy of Sciences