Synthetic Biology Matures, Promising Affordable And Personalized Treatments
Executive Summary
Advances in synthetic biology are moving biopharma closer to a world where treatments can be tailored while remaining cost-effective.
The idea of manipulating biology to produce therapeutics is not new. In 1978, Eli Lilly and Company and Genentech, Inc. developed the first recombinant DNA human insulin by inserting the human gene for insulin into a strain of Escherichia coli. Early versions of monoclonal antibodies were also made using transgenic mice.
Now, however, the field of synthetic biology is at an inflection point, yielding new ways of altering the highest-order organism: humans. From startups to big pharma, companies are pioneering DNA synthesis approaches, developing new ways of reading genetic material and finding novel targets, and incorporating artificial intelligence into their processes. The field of “SynBio” could soon yield the holy grail of biopharma: affordable and tailor-made cellular and genetic medicines.
"The broad activity of trying to design a cell or a genetic circuit or a biological therapeutic is still very expensive." - John Cumbers
According to John Cumbers, a molecular biologist and founder and CEO of SynBioBeta, the sector's premier conference, unlike many established engineering disciplines that are by now reliable, robust and repeatable, biology has resisted conquest by human ingenuity.
“There are certain slivers of biology that are [reliable and repeatable], but the broad activity of trying to design a cell or a genetic circuit or a biological therapeutic is still very expensive and it still takes tens of millions of dollars and a number of years to develop,” he told In Vivo.
But companies in the SynBio space are developing increasingly reliable ways of engineering cells, producing disease models and creating robust biological paradigms.
Starting From The Ground Up
Take for example Molecular Assemblies, Inc., a San Diego-based startup. The company has developed a DNA synthesis technology that the company’s chief technology officer, Phil Paik, says can produce longer chains of DNA with higher accuracy than currently used chemical-based synthesis.
“With the conventional chemical process, to make a 200-nucleotide long piece of DNA – which is really the limit of what you can make with that process – you’ll only get 40% of the product that you want and the other 60% will basically be junk,” Paik told In Vivo.
Using enzyme-based synthesis, his company can produce 300-nucleotide-long DNA strands with 80-85% purity. Employing enzymes rather than chemicals can also increase the complexity of DNA sequences.
“DNA likes to fold over on itself and if it finds a complementary sequence, it will actually create a secondary structure,” Paik explained. “It’s really difficult to write through something that’s folded over on itself and bound to itself. What we have done is created a way to write at very high temperatures, which basically melts away those secondary structures.”
Technical innovations like this could ultimately reduce the price tag of costly gene therapies, which are often attributed to high manufacturing costs.
“When you get DNA of low quality, you have to repeat your experiments, or you have to adjust the sequences and have them remade, and of course this impacts the cost to the patient,” Paik said.
Improving Stem Cell Development
In the cell therapy field, a Cambridge-based startup, bit.bio, is touting a faster and more reliable process to program pluripotent stem cells (PSCs). Founder and CEO Mark Kotter, who was previously an academic neurosurgeon and stem cell biologist, said he wanted to address some of the pitfalls of prevailing approaches to cell reprogramming.
“Typically, companies recapitulate what happens during embryonic development, instructing cells down developmental pathways by using chemicals,” Kotter explained to In Vivo.
PSCs live in an epigenetic landscape that stochastically dictates their cell identity, determining how they move through their developmental trajectory.
“You can visualize this stem cell on top of a mountain, and as it rolls down to the valley, on the trajectory between a stem cell and a brain cell, there are a lot of branch points, and development takes time, half a year to get to certain cell types,” said Kotter.
For the past 25 years, stem cell biologists have used chemicals to influence cell development at those branch points, but that approach is complex and inefficient, he said.
Rather than influencing cell development chemically, bit.bio targets gene regulatory networks to control the identity of the PSC. Using machine learning, the company analyzes the unique 20,000-gene composition of a given human cell type, identifies the 10,000 genes that determine the function of that specific cell type, the 2,000 transcription factors that control those genes, and the 1 to 6 transcription factors responsible for defining the identify of each cell type, sub-cell type or cell state. The basis of the bit.bio platform is controlling those few genetic transcription factors by using an inducible “genetic switch” placed in the stem cell genome.
The company’s most advanced program, bbHEP01, is a preclinical-stage hepatocyte cell therapy targeting acute liver diseases. Bit.bio has six other earlier-stage programs, including one in partnership with BlueRock Therapeutics LP for the discovery and manufacture of iPSC-derived regulatory T cells. BlueRock intends to use those to develop therapeutics for unspecified autoimmune disorders. Bit.bio also manufactures a variety of cell types for research purposes, from neurons to muscle cells and cell models for diseases like Duchenne muscular dystrophy.
Kotter claims bit.bio’s cell therapies will be up to two orders of magnitude cheaper than current cell therapies, because it can reprogram cells at industrial scale within days at exceptional purity and consistency.
"The moonshot we’ve formulated is to be able to produce not only any human cell type, but any human cell state as well." - Mark Kotter
“So, that means not hundreds of thousands, but single-digit thousands per patient dose, which is what the world needs,” he said.
For its partners, bit.bio has introduced three new cell types a year, and Kotter said he can accelerate that speed of production by an order of magnitude, assuming the company receives the funding needed to do so.
“The moonshot we’ve formulated is to be able to produce not only any human cell type, but any human cell state as well,” he added.
Gene Editing With No Off-Target Effects
Prime Medicine, Inc., which raised $151.3m in a public offering in February, has moved further along the treatment development continuum with a platform featuring prime editing, the in vivo gene editing technique that has garnered awards. The company uses a guide RNA to find the specific spot in a cell’s DNA that needs to be repaired, while a protein attached to the guide RNA – known as the prime editor – writes the new DNA sequence in the targeted spot.
Four years after its founding in 2020, Prime Medicine already has a program entering the clinic and over nine others moving along in earlier stages.
In January, the company received FDA Orphan Drug Designation for PM359, its gene therapy for chronic granulomatous disease, a life-threatening disease presenting in childhood. The company plans to initiate a Phase I/II study of the drug in the first half of 2024, with initial clinical data anticipated in 2025. PM359 addresses the single-point mutation in the p47phox protein responsible for the disease using autologous hematopoietic stem cells modified ex vivo.
The study will include three cohorts, each chronologically staggered and each successive group including younger patients. That design will allow safety data to emerge. It is a cautious approach given the novelty of the treatment.
Jeremy Duffield, chief scientific officer at Prime Medicine, told In Vivo the company is presenting preclinical data at the American Society of Gene and Cell Therapy annual conference showing that the treatment repairs patient neutrophils in vivo at scale and with very high efficiency, and that it has an “incredibly favorable safety profile from our extensive off-target studies.”
The company is also presenting posters and talks at the ASGCT meeting on its proprietary delivery systems, including its lipid nanoparticle systems, which can carry both large and small RNA cargo a systemic injection.
Prime Medicine has assets in various stages of development for hematological, immunological, liver, ocular, and neuromuscular indications, but plans to expand to immunological diseases, infectious diseases, and to eventually target genetic risk factors for common diseases.
“The Prime Medicine technology can fix mutations in any disease essentially, and in any part of the body,” said Duffield.
As the company moves towards an increasingly precision-medicine-based approach, Duffield hopes regulators will be amenable to a streamlined process based on the modular therapeutic platforms the company is building.
“The concept with the modular platforms is that you build a system, develop the components, do the CMC [chemistry, manufacturing and controls] and establish a regulatory path with the system, but then to make a new product, you simply swap out one of the RNA and put another in instead, leaving all the other components the same,” he said.
That approach, he hopes, could lead to a simpler regulatory pathway, assuming the toxicology profile of the modular treatment can be standardized. If regulators are open to that approach, the cost of their gene therapy could be driven down.
Big Pharma’s Interest In SynBio
Big pharmas like Roche Holding AG are entering the SynBio sphere, with the Swiss major hiring SynBio researchers from academia “to ensure leadership in research and practical applications, most immediately the company’s cell and gene therapy offerings,” said Sylke Poehling, SVP, global head of therapeutic modalities, Roche pRED (Pharma Research and Early Development).
In addition to using advanced technologies, the company is adopting a SynBio mindset, changing the way their staff work. Specifically, Poehling highlighted the company’s use of Design-Build-Test-Learn (DBTL) cycles in CGT development. The approach yields highly controllable biological and biochemical pathways, she said, and these pathways can then be used to design synthetic cells or therapeutics that have very specific features and functionalities. Combining AI with DBTL cycles further boosts Roche’s ability to optimize CAR-T cells and gene therapy designs, Poehling said.
“Our goal is to develop an automated, platform-centric approach with simplified and standardized procedures, potentially enhancing productivity, increasing throughput, and shortening project cycle times,” she said.
Big pharma companies may not be ready to add SynBio infrastructure and skillsets in-house, Poehling said, but early adopters of SynBio-based processes like DBTL stand to gain broadly. And integrating the broad range of data types that big pharma can access– from disease biology to clinical experience and safety and toxicology data – can be an asset to the overall R&D process.
“By adopting an expanded scope of DBTL cycles, pharma companies can create a more holistic and informed approach to drug development, leading to innovations that are not only technically feasible but also clinically relevant and safe for patients,” she said.
The Varied SynBio Landscape
In terms of external partnerships and investments, Poehling said big pharmas and investors alike face the same challenge: the number of startups is high, novel technologies are varied, and the field is evolving rapidly.
“Questions such as, ‘Is this the pivotal moment we’ve been waiting for”, ‘Will this technology become obsolete soon?’ and ‘How can we best integrate various technologies to fulfill our strategic objectives?’ are common,” Poehling said.
For those at a loss of where to start looking at SynBio companies, Ginkgo Bioworks earlier this year introduced the Ginkgo Technology Network, gathering over 25 SynBio partners representing an array of capabilities, from AI to genetic medicine, biologics and manufacturing.
“There are a number of companies with fantastic technologies, and what we’re doing with this network is offering them an opportunity to work with Ginkgo,” John Androsavich, vice president of business development and head of In Vivo biotherapeutics, told In Vivo. “We have a large sales team and we are great at creating collaborations. That can be a force multiplier for some of these smaller companies who maybe only have one or two business development folks.”
SynBio And AI/ML
As in most other industries, the cutting edge of SynBio resides in the space where generative AI is added to the mix. In this case, adding generative AI to biology helps conceptualize and build proteins that have never existed in nature.
“It’s not just manipulation or tweaks of existing biology, it is really de novo biology,” emphasized Androsavich.
With what Androsavich claimed is the deepest metagenomic database in the world, Ginkgo Bioworks has been modifying RNA to be more stable and less immunogenic, “but the big question, when it comes to RNA, is can we find a sequence that hasn’t existed in nature and that gives us the better physical chemical properties that we would desire in a drug.”
“One of the ways we can try to do that is through machine learning models that allow us to test a certain amount of that RNA, and then the model can lead us to additional therapeutic or sequence hypotheses that we can proceed to validate and confirm,” he said.
The company has used AI and ML to engineer novel enzymes that can place organic solvents in biological catalysis, and the same can be done for therapeutic enzymes, Androsavich said. And while de novo enzyme engineering is possible and has been done, “Given the amount of metagenomic diversity we have in our datasets, oftentimes we can find an enzyme that already exists in nature” that serves the client’s purpose and may need to me slightly modified.
“Nature in many ways has given us the starting point for most things we want to do,” Androsavich said.
The Rate-Limiting Variable: Financing
The rate-limiting factor in terms of the industry realizing its potential may be financing.
“High interest rates continue to depress venture capital investment,” said SynBioBeta’s Cumbers. “A lot of the companies that are pre-revenue in particular are struggling to raise money right now.”
Marcus Gstottner, CEO of early-stage SynBio startup, clock.bio, and an entrepreneur in residence at BlueYard Capital, agreed that SynBio companies are suffering from a paucity of funding. Part of the reason for this “SynBio winter” is that hype from 7-8 years ago is only now beginning to materialize in the form of meaningful science, he said. However, he is also hearing growing optimism that a “SynBio spring” is just around the corner.
“Wherever we are, good ideas and robust scientific approaches will stick around until it’s summer again,” he told In Vivo.
Reading The Story Of Genetic Rejuvenation
Gstottner believes his company – which was in stealth mode until 2023 and is now raising seed financing –is one that will make it through the financing winter. The Vienna-based startup forcibly ages human PSCs and reads the genetic transformation that subsequently unfolds. Unlike somatic cells – which are stem cells that have reached their differentiated state– PSCs in their undifferentiated state are not subject to the same wear and tear of aging. When they are forced to age, as the clock.bio platform can do, they ultimately return to their original state.
"We’re entering an amazing decade of biology." - John Cumbers
“Aging shows itself in the accumulation of epigenetic noise and error over time, and in an inability to defend against negative external impact,” said Gstottner. “That applies to all somatic cells, but stem cells have the ability to resist aging.”
The company uses CRISPR to screen large samples of hPSCs throughout this process of aging and rejuvenation. The hypothesis, which they have yet to prove, is that reading the genetic story of a cell’s rejuvenation can identify potential therapeutics for age-related diseases.
“As we screen these events using CRISPR, we can decode which parts of the genome are at work in self-rejuvenation, and those parts of the genome might well be relevant targets for age-related disease,” said Gstottner.
The Decade Of Biology Is Upon Us
While financing hardships may be upon SynBio, as it is for biotech more broadly, the value of SynBio’s outputs will become apparent soon.
“We’re entering an amazing decade of biology – and probably a century of biology – as well,” SynBioBeta's Cumbers said.
Ginkgo Biowork’s Androsavich echoed this, noting that, “All of the main tools are here, which wasn’t the case five or 10 years ago.”
“We can now manipulate and edit DNA, the cost of synthesizing DNA to build whole chromosomes is cheap, and compute power is enormous,” he said. “I think what we’ll see two, five, 10 years down the line will be absolutely incredible.”