This Startup Is Rewriting The Language Of Life To Make Smart Biologics

Synthetic biology has brought many breakthroughs to the biotherapeutics space over the last decade. The dropping cost of sequencing and precision genome editing has paved the way for personalized medicine. At the same time, generative AI technology has enabled the designing of antibodies with a much higher clinical success rate. Yet, scientists’ ingenuity is still challenged by the laws of biology. All biologics are susceptible to unpredictable degradation rates and immune responses, in addition to being constrained to the 20 natural amino acids that make up these therapeutics.

But now, one company is challenging that paradigm. Pearl Bio, a synthetic biology company backed by Khosla Ventures, has recently emerged from stealth mode with a hefty IP portfolio of 24 patents that protect their groundbreaking technology: a generically recoded organism. With it, Pearl Bio is creating entirely new classes of materials for smart biologics.

Pearl’s genetically recoded organism, combined with the engineered translational machinery of the cell, breaks the rules of life by enabling the incorporation of building blocks beyond the 20 amino acids that exist in nature. This technology can disrupt the medical paradigm by producing novel chemistries that solve existing challenges in the immunotherapeutics space and pave the way to completely new materials.

What is a Genetically Recoded Organism (GRO)?

Pearl’s cornerstone technology is a genetically recoded organism (GRO), which heralds a new era of synthetic biology. The rules of life are written in a four-letter genetic code: A, T, C, and G. These letters form three-letter words—called codons—that encode the amino acids which make up the tissues and enzymes of all living beings. However, biology is not perfect: there are 64 possible combinations of ATCG but only 20 amino acids. This phenomenon is known as “redundancy.”

The idea of using those redundant codons for a practical purpose has been around for a while. “It dates back to the late 2000s. I was working as a postdoc in George Church’s lab, together with Michael Jewett,” recalls Farren Isaacs, Co-founder and Science Advisor at Pearl Bio. “We were always the first people to get to the lab in the morning. There was no one around at that time, and we would brainstorm ideas.”

Isaacs and Jewett, Pearl Bio’s other Co-founder and Science Advisor, were working on the bleeding edge of synthetic biology at that time: “I was recoding genomes, and Michael was engineering ribosomes. We realized that when you put those two technologies together, you have the ability to basically repurpose the genetic code and the translational machinery of any cell to produce entirely new materials,” says Isaacs.

In 2013, scientists from the Isaacs lab managed to free up one of those three-letter combinations by editing the entire E. coli genome. Now the missing codon could be assigned to code for anything else, such as non-natural amino acids, which do not occur in any living beings. By introducing these new-to-nature building blocks, you could make proteins that are impervious to degradation, target specific tissues and disease states, and attach highly specialized payloads.

“That could lead to fundamentally new kinds of therapeutics that have longer stability and reduced immunogenicity,” says Isaacs.

A New Way to GRO

Years went by, but Isaacs, Church, and Jewett kept working on tweaking the technology to improve and expand on what it could do. In 2020, the two decided to co-founder Pearl Bio together with Amy Cayne Schwartz, Chief Operating Officer & Chief Business Officer, and George Church and Jesse Rinehart of Yale as Science Advisors. Pearl Bio was officially financed and launched in Q3 of 2021.

“This is something that we’ve been incubating over many years: developing the technology, de-risking proof of concept, and filing IP,” says Isaacs. “With platform technology companies, you want to be poised to advance product development from day one.”

And Pearl Bio was. They had been working to secure an impressive portfolio of 19 patents to corner the market of multi-functionalized biologics. The newly issued U.S. patent 11,649,446 gives Pearl Bio the exclusive license for engineering programmable biologics by encoding synthetic chemistries and now brings their total patent figures to 24.

When the paper describing the first GRO was published in 2013, the technology and the strain were released publicly. But just like the first version of iOS, there were many things that needed to be improved to make the strain better suited for commercial applications. For example, the initially published version only had one codon freed up, which meant that it could only encode one alternative amino acid. Pearl took this concept further and now also holds exclusive rights to a newly developed GRO with two open coding channels to endow multi-functionality into protein therapeutics.

“Another key piece of IP is the orthogonal tethered ribosomes. This allows Pearl to engineer the ribosome to work efficiently with exotic substrates beyond L-alpha amino acids, opening access to new classes of therapeutic biomaterials. This capability holds promise to transform biopharmaceutical development,” says Jewett.

Other companies have also taken a stab at challenging the paradigm within the biotherapeutics space. For example, Ambrx, a clinical-stage biopharmaceutical company using an expanded genetic code technology, IPO’d for $126 million in 2021. However, Ambrx’s technology does not use genetically recoded organisms. Synthorx is another synthetic genome company in this space which was acquired by Sanofi for $2.5 billion in 2019. Their Expanded Genetic Alphabet technology that adds a novel DNA base pair can be used to create optimized biologics.

What distinguishes Pearl Bio is that they hold a number of broad-blocking patents giving Pearl the exclusive right to encode synthetic amino acids using engineered synthetases and translation machinery to drive multi-site incorporation of synthetic amino acids and other building blocks with site-specificity at high yield and purity.

Schwartz thinks this technology is poised to overcome a lot of the shortcomings of current biologics on the market: “For example, optimizing the drug-antibody ratio has been a defining challenge because when you attach the drug to natural amino acid residues, you are limited in the number and specific location since multiple lysines, for example, are found in a given protein and are critical for its function. Thus, approaches that attach to natural amino acids are constrained, lead to heterogeneous products, and typically ablate protein function. By contrast, Pearl can attach up to 50 synthetic amino acids at monomeric precision to tune therapeutic properties while preserving protein sequence and function.”

Such precision enables the programmability of a therapeutic window with a half-life of up to three weeks to address specific disease indications or patient populations. “With this, we have the opportunity to advance both best-in-class and first-in-class therapeutics to address critical unmet needs and solve challenges plaguing the biologics industry,” says Schwartz.

The Future of Biotherapeutics

Pearl has positioned itself as the leader in this new field thanks to advancing technology and staking the IP landscape. They have developed exclusive next-generation multifunctional capabilities, such as adding synthetic monomers, multiple types of modifications, and multiple locations.

“It’s exciting to see ideas from whiteboards over 15 years ago realized in technologies that are now poised to transform the therapeutic landscape and evolve novel biomaterials. Pearl is pioneering a new era of biotherapeutic design by enabling access to new disease targets and evolution of entirely new classes of molecules,” says Church.

“Today, we can access two distinct functionalities. With our Series A funds, we will advance the technology to access three or more distinct functionalities,” says Schwartz. “We are excited to drive next-generation molecules to the clinic to change the therapeutic landscape with the evolution of smart programmable biologics.”

Thank you to Katia Tarasava for additional research and reporting on this article. I’m the founder of SynBioBeta and some of the companies I write about are sponsors of the SynBioBeta conference and weekly digest.