Cell and gene therapies may be the most anticipated invention of this century. For many people, these breakthroughs cannot come fast enough: cell therapies could offer hope for people with fast-progressing cancers, cure genetic diseases like sickle cell anemia, and possibly even treat common conditions like heart disease and diabetes. However, progress is slow and the cost of a single treatment can run up to $3.5 million, making them inaccessible to most patients. I spoke with Behzad Mahdavi, the new head of Biopharma Manufacturing & Life Sciences Tools at Ginkgo Bioworks, who will be giving a talk at SynBioBeta 2023, the Global Synthetic Biology Conference, to understand what needs to be done to make these life-saving therapies more affordable.
The traditional pharma drug development model is in part to blame for the high price tag. The industry is heavily regulated, so implementing any changes takes a long time and requires a lot of upfront investment. Innovations may save money in the long run, but onboarding new technologies involves some risk, and it is hard to know how much of a cost benefit they can provide. This is why most pharmaceutical companies focus on process and operational improvements, which can increase efficiency by 10-20%. But making cell and gene therapy treatments more affordable demands leap-frog advancements on the biology side to lower the price by orders of magnitude: “Improvements on manufacturing side only produce marginal gains,” says Mahdavi. “We need to come back to biology and have a better understanding of how it works. Synthetic biology is helping us do that.”
Ginkgo Bioworks has made its name as a synthetic biology platform that helps their customers develop bio-based products using engineered organisms. Ginkgo has partnered with companies covering a wide range of markets from flavors and fragrances to food colorants, cultured cannabinoids, skincare ingredients, materials, and more. But the synthetic biology company does not want to limit itself to ingredients. Ginkgo has expanded their platform into the vast biotherapeutics space, hence Mahdavi’s appointment. Mahdavi comes to Ginkgo with an impressive track record of commercializing novel therapies. Most recently, he served as the VP of Global Open Innovation at Catalent Pharma Solutions and prior to that as the VP of Strategic Innovation at Swiss manufacturer Lonza for almost 14 years. Now Mahdavi sees a lot of potential to revolutionize the industry through the marriage of biopharma and synthetic biology. “Pharma has an established model – and it’s good at what it does. But the real improvements are to be made on the biology side,” thinks Mahdavi. “This requires a better understanding of biology and higher-throughput methods for cell engineering.”
Ginkgo’s platform is a full-stack solution for therapeutic cell engineering. Their multi-story lab spaces – called “foundries” – are Ginkgo’s biological factories equipped with robots and cutting-edge instruments that enable high-throughput cell engineering. This means that Ginkgo can screen hundreds of thousands of cells and molecular compounds to identify the most promising drug candidates that are also the most cost-effective to produce at scale. For example, in their partnership with Aldevron, Ginkgo was able to increase their output by a factor of 10 using cell engineering and biological process improvement. “That means if you want to build a plant [for that product], you can build a plant that’s 10 times smaller, just by having improvements in biology,” says Mahdavi.
Ginkgo has already demonstrated initial success with its platform. During the COVID-19 pandemic, Ginkgo created a public health initiative, Concentric by Ginkgo, that provided testing services to help track emerging infection hotspots. On the vaccine development side, Ginkgo worked with Moderna to rapidly discover optimal processes for production mRNA vaccines. Beyond COVID-19, Ginkgo has recently announced other biopharma partnerships with Optiva, Selecta, and Merck, as well as acquisition of Circularis, a proprietary RNA screening platform.
A major focus of Mahdavi’s work is the potentially curative (and highly lucrative) field of cell and gene therapies. One of the first cell therapies to receive FDA approval were CAR T cell therapies for leukemia, lymphoma, and myeloma. In this breakthrough treatment, the patient’s immune cells are taken from their own blood and changed in the lab by adding a receptor that can target and destroy cancer cells. This requires making precise genetic changes to living cells, which is not that easy. This is why CAR T treatments cost, on average, between $700,000 and $1 million, and most of the cost today come from manufacturing those modified CAR T cells. We have come a long way in our ability to engineer cells. Yet cellular architecture is still a black box, which makes building these new modalities so challenging.
Currently over 1,000 cell and gene therapy clinical trials registered with ClinicalTrials.gov, but only 14 have been approved to date. The majority of those trials are still in Phases 1 or 2, which means that they are still far from commercialization. Given how low the success rate of the FDA approval pipeline is, these potential cures will likely never make it to market. This is why investing at the early stages to discover the best possible targets is so important for developing successful therapies: “We are focused on manufacturing in an optimal way, but not manufacturing the most optimal drug,” says Mahdavi. Synthetic biology tools and workflows are designed to manage the complexity of biology, increasing the chances of success when it comes to developing cell-based therapies that work.
There have been substantial advances in high-throughput tools to engineer biology that could bring down the cost and timeline of developing new cell and gene therapies. Ginkgo has demonstrated that they can build around 10,000 CAR T cell libraries and see which ones are the most promising candidates. For example, they found a sub-group of cells that are much more resistant to exhaustion and could potentially be used to develop treatments for solid tumors. Taking advantage of the high-throughput cell engineering combined with bioinformatics can improve the number of shots-on-goal for each new target: “Ten years ago, to say ‘I’m going to look at 10,000 CAR T constructs’ was a dream, but today to look at even 1 million constructs is not an obstacle,” said Mahdavi.
For biopharma companies, this type of high-throughput scale is a lot harder to accomplish without investing heavily in the latest technologies to update their entire R&D infrastructure. This is why partnering with synthetic biology companies that have the specific expertise in this area could bring substantial savings for biopharma. “At the end of the day it is about how you get the optimal product and optimal manufacturing conditions in the shortest period of time – and this is what Ginkgo brings to biopharma,” said Behzad. He envisions that synthetic biology could disrupt biopharma’s drug development pipeline in a systematic way and help bring life-saving therapies to people much faster.
Thank you to Katia Tarasava for additional research and reporting on this article. I’m the founder of SynBioBeta, and some of the companies that I write about, including Ginkgo Bioworks, are sponsors of the SynBioBeta conference and weekly digest.