by Megan Molteni: Tessera Therapeutics is developing a new class of gene editors capable of precisely plugging in long stretches of DNA—something that Crispr can’t do…
CRISPR’S POTENTIAL FOR curing inherited disease has made headlines, including at WIRED, for years. ( Here, here, here, and here.) Finally, at least for one family, the gene-editing technology is turning out to deliver more hope than hype. A year after 34-year-old Victoria Gray received an infusion of billions of Crispr’d cells, NPR reported last week that those cells were still alive and alleviating the complications of her sickle cell disease. Researchers say it’s still too soon to call it a cure. But as the first person with a genetic disorder to be successfully treated with Crispr in the US, it’s a huge milestone. And with dozens more clinical trials currently in progress, Crispr is just getting started.
Yet for all its DNA-snipping precision, Crispr is best at breaking DNA. In Gray’s case, the gene editor built by Crispr Therapeutics intentionally crippled a regulatory gene in her bone marrow cells, boosting production of a dormant, fetal form of hemoglobin, and overcoming a mutation that leads to poor production of the adult form of the oxygen-carrying molecule. It’s a clever way around Crispr’s limitations. But it won’t work for a lot of other inherited conditions. If you want to replace a faulty gene with a healthy one, you need a different tool. And if you need to insert a lot of DNA, well, you’re kind of out of luck.
Not anymore, says Geoffrey von Maltzahn, the CEO of a new startup called Tessera Therapeutics. The company, founded in 2018 by Boston-based biotech investing powerhouse Flagship Pioneering, where von Maltzahn is a general partner, emerged from stealth on Tuesday with $50 million in initial financing. Tessera has spent the past two years developing a new class of molecular manipulators capable of doing lots of things Crispr can do—and some that it can’t, including precisely plugging in long stretches of DNA. It’s not gene editing, says von Maltzahn. It’s “gene writing.”
“Simplistically, we think of it as a new category,” says von Maltzahn. “Gene writing is able to make either perfect deletions or simple base pair changes, but its wheelhouse is in the full spectrum, and in particular the ability to make large alterations to the genome.”
To get beyond simplistics, to understand how gene writing works, you have to take a deep dive into the history of an ancient, invisible battle that’s been raging for billions of years.
For nearly as long as there have been bacteria, there have been viruses trying to attack them. These viruses, called phages, are like strings of malicious computer code trying to hack into a bacterial genome to trick it into making more phages. Every day, phages invade and blast apart huge quantities of the world’s bacteria (up to 40 percent of the bacterial population in the oceans alone). To avoid the unrelenting slaughter, bacteria have had to constantly evolve defense systems. Crispr is one of them. It’s a way for bacteria to steal a bit of a phage’s code—its DNA or RNA—and store it in a memory bank, like a primordial immune system. It’s the longest-running arms race in the history of Earth, says Joe Peters, a microbiologist at Cornell University: “That level of evolutionary pressure has driven an incredible amount of novelty in molecular mechanisms for manipulating DNA and RNA.”
But bacteria haven’t just had to contend with foreign viral invaders. Their genomes are also under perpetual assault from within. Through the millennia, as bacteria have been swapping bits of DNA with each other, trying to stay ahead of the next wave of phage attacks, some of those genes evolved the ability to move around and even replicate independently of the rest of their original genome. These so-called “mobile genetic elements,” or MGEs, carry self-contained code for the machinery to either cut and paste or copy and paste themselves into a new locality, either within their host or into nearby bacteria.
That can spell real trouble for the bacteria on the receiving end of this gene shuffle. If those MGEs insert themselves into critical gene regions, it’s bye-bye bacteria. “You can think about MGEs the same way you can think about mutations,” says Peters. “We wouldn’t have evolved without them, but 99.99999 percent of them are bad. Bacteria are trying at any cost to stop MGEs from destabilizing their genome.”
The Nobel Prize-winning botanist Barbara McClintock discovered the first known class of MGEs, called transposons, or “jumping genes,” in maize in 1931. Her technique for staining the plant’s chromosomes allowed her to see when chunks from one would jump to another. But for many decades, the purpose of all these repeated sections of self-rearranging DNA eluded scientists. Some went so far as to dub the MGE-heavy sections of the human genome “junk DNA.” It was hard to get funding to study it. But little by little, researchers like Peters discovered that MGEs in bacteria were actually highly-evolved systems for recognizing DNA, writing it, and moving it around. In fact, Crispr itself appears to have evolved from a self-synthesizing transposon, as NIH researchers Eugene Koonin and Kira Makarova described in 2017. (Crispr codes for a protein that cuts specific, recognizable pieces of DNA stored in its genetic memory bank. The transposons allowed Crispr to start amassing that memory bank in the first place.)
Earlier that year, Peters and Koonin published a paper describing how this evolution can sometimes come full circle. They found one type of transposon that had stolen some Crispr genes to help it move between bacterial hosts. They realized that these molecular tools for cutting, copying, and pasting were constantly being shuttled between MGEs, phages, and bacteria to be used alternately as a means of offense or defense. At the end of that paper, Peters and Koonin wrote that these systems could “potentially be harnessed for genome-engineering applications.”
Not long after, Peters says, he started getting calls from commercial interests. One of them was from Jake Rubens, Tessera’s Chief Innovation Officer and co-founder. In 2019, the company began a sponsored research collaboration with Peters’ Cornell lab around the discovery of new MGEs with genome engineering potential. (Tessera also has other research partnerships, but company officials have not yet disclosed them.)
MGE’s come in a few flavors. There are transposons, which can cut themselves out of the genome and hop into a different neighborhood. Retrantransposons make a copy and shuttle that replica to its new home, expanding the size of the genome with each duplication. They both work by having special sequences on either end that define their boundaries. In between are genes for making proteins that recognize those boundaries and either excise them out in the case of transposons, leaving a gap. Or in the case of retrotransposons, copy them, via an RNA-intermediate, into new locations. There are other classes, too, but these are the two that Tessera executives are interested in. That’s because you can add a new string of code between those sequences—say a healthy, non-mutated version of a disease-causing gene—and let the MGE’s machinery do the work to move that therapeutic DNA into a patient’s chromosomes.
For the past two years, the company’s team of bioinformaticians have been mining public databases that house the genome sequences of hundreds of thousands of bacterial species that scientists have collected from all over the world. In those reams of genetic data, they’ve been prospecting for MGEs that might be best suited for making these kinds of therapeutic DNA changes.
So far, company scientists have identified about 6,000 retrotransposons (what Tessera calls RNA writers) and 2,000 transposons (DNA writers) that show potential. Tessera’s team of 35 scientists have been conducting experiments in human cells to understand how exactly each one works. Sometimes, a promising, naturally-occurring gene writer will get tweaked further in Tessera’s lab, to be more precise or go to a different location. The company hasn’t yet demonstrated that any of its gene writers can eliminate an inherited disease. But in mouse models, the team has consistently been able to use them to insert lots of copies of a large green fluorescent protein gene into the animals’ genomes as a way of proving that they can reliably place designer DNA.
Now, scientists have been making animals artificially glow for decades. What’s different about Tessera’s method is that company’s scientists only need to inject a bit of RNA to make it happen. That little package of RNA has all the information it needs to recruit the necessary enzymes to make a new molecule of DNA that codes for the green fluorescent protein and then insert it into the mouse’s chromosomes.
That’s a big deal because two of the largest hurdles in genetic medicine have long been how to deliver a DNA-altering tool to the right cells, and altering enough of them that it works. Traditional gene therapy relies on ferrying the healthy gene in hollowed-out viruses that can’t fit big pieces of DNA. These treatments can only be given once, because people’s bodies develop immune responses to the viral shell. Scientists using Crispr have run into these same issues. This is why the first successes have been with disorders in which you can edit cells outside the body and then infuse them back in, like with sickle cell disease, and cancer. Outside the body, scientists can inject Crispr’s component parts directly into cells instead of relying on a viral vector.
But being able to integrate new DNA into the genome of a living animal from just a direct shot of RNA has never been done before. “As far as we know, that’s the first time anyone has ever shown it’s possible to do that with something that big—not just in genetic medicine, but it’s a first for molecular biology,” says Rubens.
The ability to inject just a piece of RNA, similar to the approach taken by one of the leading Covid-19 vaccinemakers, Moderna, could make it easier for researchers to go after genetic conditions in which the treatment involves adding big chunks of reparative genetic code. “This is a really interesting approach and it absolutely deserves pursuit,” says Fyodor Urnov, a gene editing expert and scientific director of UC Berkeley’s Innovative Genomics Institute. (In recent months, Urnov has helped transform IGI into a full-time Covid-19 testing operation; he says Tessera officials approached him recently about joining their board but that he lacked the bandwidth to participate, despite his excitement.)
Still, he says it’s too early to tell if gene writing will wind up being superior to Crispr or its more precise next-generation cousin prime editing, or any other of the new gene editing technologies currently in development. “What I’ve learned from three decades in this field is that only the clinic can tell you what tech will ultimately be the best way forward for a given disease,” he says.
For Tessera, any such human trials are likely still at least a year away. The company is just starting to build out an early manufacturing team. And so far, its officials have been tight-lipped about what diseases they plan to go after first, saying only that they will likely be rare genetic conditions. “We want to direct our attention right now to a bake-off of as many variations and engineered constructs as we can create,” says von Maltzahn. The company’s internally-developed RNA writers are the furthest along, he says. But their goal is to arrive at a suite of molecular machines capable of addressing many human diseases before moving into the clinic. “We think with almost virtual certainty that genetic medicine will be one of the most extraordinary new categories of medicine for the next couple of decades,” says von Maltzahn.
The field is certainly accelerating; Gene therapy took decades of research before the first human trials. It took Crispr 7 years. For gene writing, we may not have that long to wait.