With a new way to write DNA, Mike Kamdar and his team at Molecular Assemblies are poised to disrupt just about any industry you can imagine.
Most of us don’t realize how much biotechnology touches every part of our daily lives, from the medicines we use to the food we eat to even the fashions we wear. Much of the material world is built with biology, a trend that is sure to continue.
But how do we actually build with biology?
The answer is DNA synthesis. The building blocks of all life are composed of four chemical nucleotides, nicknamed A, C, T, and G. String these same four letters together in different ways and you get either a banana, a monkey, bacteria that make banana scent, or something in between.
And as DNA synthesis gets cheaper and cheaper, biological engineers are coming up with more and more clever ways to put DNA to good use. Some you might expect, such as in the life sciences where it can make futuristic cancer drugs and personalized medicine. Others are a little more surprising, such as how the chemical industry is turning to biology as the preferred method to manufacture high-performance bio-electronics for the phones in our pockets.
And at the heart of the billion-dollar DNA synthesis industry is a focused team of innovators led by Mike Kamdar, CEO of San Diego-based Molecular Assemblies.
Phosphoramidite synthesis: The heart and soul of the biotech industry
Molecular Assemblies began more than 30 years ago when Bill Efcavitch and Curt Becker, then early founders at the pioneering biotech company Applied Biosystems, commercialized the first practical method of synthesizing DNA. Known as phosphoramidite synthesis, this chemical-based method was a huge breakthrough and remains the industry standard for making DNA today. It led to a wide range of tools and technologies using DNA and helped spawn the biotech industry as we know it.
But even then Efcavitch and Becker recognized its inherent limitations. Specifically, the chemicals used in the process damaged the DNA even as it was being made, limiting the lengths and the quality of DNA that could be synthesized.
“The chemical method used to synthesize DNA today is absolutely marvelous,” says Efcavitch, an incredibly likeable guy who seems more like a favorite uncle than a scientific legend. “But once you start building DNA longer than about 100 nucleotides, your productivity drops off pretty rapidly, and that hasn’t changed for several decades.”
There are two more big challenges with today’s phosphoramidite synthesis. First, it produces significant volumes of toxic chemical waste. Second, it often requires post-synthesis purification and processing.
So in 2013 Bill and Curt founded Molecular Assemblies to create a new approach to DNA synthesis. Their aim was the holy grail of DNA: enzymatic synthesis.
How enzymatic DNA synthesis works
To create these long strings of A, C, T and G, you need an enzyme called a polymerase to add the correct letter one after the other. With traditional DNA synthesis, you need a specific polymerase for each of the letters, and the start-stop between each added letter involves an extra chemical step. But Molecular Assemblies works with a biological polymerase that can attach any of the four letters. The polymerase (in this case, terminal deoxynucleotidyl transferase, or TdT) is engineered to attach whatever nucleotide it’s supplied with, and then stop and protect its work. The reaction tube is washed of nucleotides, and the system is primed for the next round, adding whatever nucleotide you supply it with next. Wash, rinse, repeat.
This method is extremely precise, allowing it to make really long strands. This is something that chemical synthesis struggles with, especially as strands become longer and longer, and the odds of an error somewhere along the way increase.
Making enzymatic synthesis a commercial reality
Here’s where Mike Kamdar comes in. In 2016, Molecular Assemblies recruited him to become President, CEO and Board Member. An industry veteran with expertise in business development and finance, he had done $1 billion in business deals and raised more than $400 million from venture capital and public markets. Kamdar also sits on the boards of Genoa Pharmaceuticals (a company he co-founded), Medipacs (Chairman), Prime Genomics, and Vault Pharma.
At Molecular Assemblies, his job was nothing short of building the first company to make enzymatic synthesis a commercial reality.
In his short time at the helm, Kamdar has raised close to $20 million, hired 18 people, and doubled the company’s footprint in a brand-new, five-story building in San Diego. He recently closed the company’s Series A, and has assembled a who’s who of biotech for the company’s board of directors, including Helge Bastian (M2GEN, formerly Thermo Fisher), Todd Peterson (The Allen Institute, formerly Synthetic Genomics), and David Hwang (Agilent Technologies).
“Nucleic acid synthesis has been core to Agilent’s contribution to the advancement of the life science industry, and the enzymatic synthesis of DNA is poised to further enable a next generation of important nucleic acid-based products.”
— Darlene J.S. Solomon, Ph.D., Chief Technology Officer and Senior Vice President, Agilent Technologies
Disrupting industries from health to electronics
Now, Kamdar has set a bold vision for the future of DNA synthesis. “The thing that inspired me was the broad application for the technology,” Kamdar says.
First, he hopes that his company will transform the life sciences industry, including things like much-anticipated CRISPR gene-editing therapies, cutting-edge CAR-T cancer treatments, and the emerging DNA/RNA vaccine space—made all the more urgent in light of the coronavirus pandemic and the efforts of Moderna and others to create the world’s first mRNA vaccines.
But Kamdar has good reason to believe the impacts will go much, much farther. Take industrial sectors like chemicals and materials. A new McKinsey report suggests that as much as 60 percent of the physical inputs to the global economy could be produced biologically. Most anything made with petrochemistry—your carpets, cosmetics, and contact lenses, to name a few—could soon be made with biology. Not necessarily because it’s greener, but because you can engineer biology to make things more economically and more precisely.
All the world’s data in a shoebox
One of the more fascinating and less intuitive applications of DNA synthesis is data storage.
DNA is the most compact and durable information storage molecule that exists in our world. Depending who you ask, you could store all the world’s information in a shoebox or a teaspoonful of DNA. In a beautiful demonstration of the feasibility of enzymatic synthesis, Molecular Assemblies announced in 2018 that it has successfully completed an end-to-end run to store and retrieve digital information in DNA using enzymatic DNA synthesis.
“To our knowledge, we are the first industry group to store and retrieve digital information in DNA using enzymatic synthesis in a cost-effective, sustainable, and scalable way,” says Kamdar.
There are good reasons to believe that the future will be written in DNA. The world is producing more digital information than can be efficiently stored. DNA represents an essentially limitless hard drive in nearly zero space. You could think of DNA data storage as your “golden backup.” It might take a day or two to retrieve a complete restore, but it will always and forever be a lossless, failsafe backup, capable of recording anything and everything you could ever want.
And with enzymatic synthesis, that vision is a little closer to reality.
The great synthesis race is on
Kamdar, Efcavitch, and the rest of the Molecular Assemblies team have been working on enzymatic DNA synthesis as long as anyone, and they have a formidable patent war chest for their efforts. But they are by no means the only company that recognizes the potential of this technology. DNAScript, Evonetix, Nuclera, Ansa Biotechnologies, and Kern Systems are all working to make enzymatic synthesis a commercial success.
“There will be more than one enzymatic synthesis company,” says Kamdar. If you look at the market for traditional chemical synthesis, he says, there are also many players, including Twist Bioscience, Agilent Technologies, Thermo Fisher, Danaher, IDT, Synbio-tech, and more. “We believe the same to be true for enzymatically derived DNA.”
Perhaps more importantly, Kamdar says that Molecular Assemblies is going a different route with its platform-independent technology.
“We don’t want to create a desktop device,” says Kamdar. “We want to be the ink in a lot of DNA printers.”
He adds: “We anticipate being at a commercial level by next year.”
While Kamdar is confident in Molecular Assemblies’ place in the future landscape, he says that the biggest new threat to the entire synthesis industry is COVID-19.
“All of us have to maintain productivity to advance technology, generate partnerships, and raise capital,” he says, but doing so is difficult while adhering to government-mandated guidelines for social distancing, shifts in work practices, and so on, not to mention the uncertainty that coronavirus is creating in private and public capital markets. The kinds of problems the DNA business is best at solving—biological ones—can also create business problems of their own.
The future of DNA is unimaginably cool
I am a biotech-optimist, but even for me it’s difficult to fathom the ultimate impact that enzymatic DNA synthesis could have on the world.
Take, for example, two very cool, far-out applications of DNA synthesis that I haven’t even mentioned. One is nanotechnology, the folding of DNA to create precise 2D & 3D shapes as useful nanoscale construction materials. The other is DNA electronics, the merging of microchip technology with genetic chemistry to create the next era in computer science. They sound like science fiction now, but let’s ask Kamdar about them in ten years.
There is a bioindustrial revolution happening right now, one that stands to have a direct annual global impact of $2 trillion to $4 trillion in 2030-40. One of the driving forces of the new bioeconomy is cheap DNA sequencing (reading), which has been decreasing at a rate faster than Moore’s Law. Enzymatic synthesis could have the same kind of impact on DNA writing—with exponential effect on just about every industry you can imagine.
Follow me on twitter at @johncumbers and @synbiobeta. Subscribe to my weekly newsletters in synthetic biology Thank you to Kevin Costa for additional research and reporting in this article. I’m the founder of SynBioBeta, and some of the companies that I write about—including Molecular Assemblies—are sponsors of the SynBioBeta conference and weekly digest. I am also an operating partner at DCVC, which has invested in Molecular Assemblies. Here’s the full list of SynBioBeta sponsors.