March 2, 2024

Synthetic biology is already rewriting life.

In late 2023, scientists revealed yeast cells with half their genetic blueprint replaced by artificial DNA. It was a “watershed” moment in an 18-year-long project to design alternate versions of every yeast chromosome. Despite having seven and a half synthetic chromosomes, the cells reproduced and thrived.

A new study moves us up the evolutionary ladder to designer plants.

For a project called SynMoss, a team in China redesigned part of a single chromosome in a type of moss. The resulting part-synthetic plant grew normally and produced spores, making it one of the first living things with multiple cells to carry a partially artificial chromosome.

The custom changes in the plant’s chromosomes are relatively small compared to the synthetic yeast. But it’s a step towards completely redesigning genomes in higher-level organisms.

In an interview with Science, synthetic biologist Dr. Tom Ellis of Imperial College London said it’s a “wake-up call to people who think that synthetic genomes are only for microbes.”

Upgrading Life

Efforts to rewrite life aren’t just to satisfy scientific curiosity.

Tinkering with DNA can help us decipher evolutionary history and pinpoint critical stretches of DNA that keep chromosomes stable or cause disease. The experiments could also help us better understand DNA’s “dark matter.” Littered across the genome, mysterious sequences that don’t encode proteins have long baffled scientists: Are they useful or just remnants of evolution?

Synthetic organisms also make it easier to engineer living things. Bacteria and yeast, for example, are already used to brew beer and pump out life-saving medications such as insulin. By adding, switching, or deleting parts of the genome, it’s possible to give these cells new capabilities.

In one recent study, for example, researchers reprogrammed bacteria to synthesize proteins using amino acid building blocks not seen in nature. In another study, a team turned bacteria into plastic-chomping Terminators that recycle plastic waste into useful materials.

While impressive, bacteria are made of cells unlike ours—their genetic material floats around, making them potentially easier to rewire.

The Synthetic Yeast Project was a breakthrough. Unlike bacteria, yeast is a eukaryotic cell. Plants, animals, and humans all fall into this category. Our DNA is protected inside a nut-like bubble called a nucleus, making it more challenging for synthetic biologists to tweak.

And as far as eukaryotes go, plants are harder to manipulate than yeast—a single-cell organism—as they contain multiple cell types that coordinate growth and reproduction. Chromosomal changes can play out differently depending on how each cell functions and, in turn, affect the health of the plant.

“Genome synthesis in multicellular organisms remains uncharted territory,” the team wrote in their paper.

Slow and Steady

Rather than building a whole new genome from scratch, the team tinkered with the existing moss genome.

This green fuzz has been extensively studied in the lab. An early analysis of the moss genome found it has 35,000 potential genes—strikingly complex for a plant. All 26 of its chromosomes have been completely sequenced.

For this reason, the plant is a “broadly used model in evolutionary developmental and cell biological studies,” wrote the team.

Moss genes readily adapt to environmental changes, especially those that repair DNA damage from sunlight. Compared to other plants—such as thale cress, another model biologists favor—moss has the built-in ability to tolerate large DNA changes and regenerate faster. Both aspects are “essential” when rewriting the genome, explained the team.

Another perk? The moss can grow into a full plant from a single cell. This ability is a dream scenario for synthetic biologists because altering genes or chromosomes in just one cell can potentially change an entire organism.

Like our own, plant chromosomes look like an “X” with two crossed arms. For this study, the team decided to rewrite the shortest chromosome arm in the plant—chromosome 18. It was still a mammoth project. Previously, the largest replacement was only about 5,000 DNA letters; the new study needed to replace over 68,000 letters.

Replacing natural DNA sequences with “the redesigned large synthetic fragments presented a formidable technical challenge,” wrote the team.

They took a divide-and-conquer strategy. They first designed mid-sized chunks of synthetic DNA before combining them into a single DNA “mega-chunk” of the chromosome arm.

The newly designed chromosome had several notable changes. It was stripped of transposons, or “jumping genes.” These DNA blocks move around the genome, and scientists are still debating if they’re essential for normal biological functions or if they contribute to disease. The team also added DNA “tags” to the chromosome to mark it as synthetic and made changes to how it regulates the manufacturing of certain proteins.

Overall, the changes reduced the size of the chromosome by nearly 56 percent. After inserting the designer chromosome into moss cells, the team nurtured them into adult plants.

A Half-Synthetic Blossom

Even with a heavily edited genome, the synthetic moss was surprisingly normal. The plants readily grew into leafy bushes with multiple branches and eventually produced spores. All reproductive structures were like those found in the wild, suggesting the half-synthetic plants had a normal life cycle and could potentially reproduce.

The plants also maintained their resilience against highly salty environments—a useful adaptation also seen in their natural counterparts.

But the synthetic moss did have some unexpected epigenetic quirks. Epigenetics is the science of how cells turn genes on or off. The synthetic part of the chromosome had a different epigenetic profile compared to natural moss, with more activated genes than usual. This could potentially be harmful, according to the team.

The moss also offered potential insights into DNA’s “dark matter,” including transposons. Deleting these jumping genes didn’t seem to harm the partially synthetic plants, suggesting they might not be essential to their health.

More practically, the results could boost biotechnology efforts using moss to produce a wide range of therapeutic proteins, including ones that combat heart disease, heal wounds, or treat stroke. Moss is already used to synthesize medical drugs. A partially designer genome could alter its metabolism, boost its resilience against infections, and increase yield.

The next step is to replace the entirety of chromosome 18’s short arm with synthetic sequences. They’re aiming to generate an entire synthetic moss genome within 10 years.

It’s an ambitious goal. Compared to the yeast genome, which took 18 years and a global collaboration to rewrite half of it, the moss genome is 40 times bigger. But with increasingly efficient and cheaper DNA reading and synthesis technologies, the goal isn’t beyond reach.

Similar techniques could also inspire other projects to redesign chromosomes in organisms beyond bacteria and yeast, from plants to animals.

Image Credit: Pyrex / Wikimedia Commons