An interview with Brad Zamft, PhD
Brad Zamft is a physicist turned synthetic biology researcher. He initiated and led a project at X — Alphabet’s “Moonshot Factory” — that sits at the intersection of agriculture, machine learning, and synthetic biology. Since his ambitious PhD, Brad has worked in top teams across many dimensions of the innovation economy. He was an AAAS and ARPA-E Fellow, a Program Officer at the Bill & Melinda Gates Foundation, and the CSO of TL Biolabs.
Talking with Brad is always a pleasure as one finds themselves rapidly navigating scales: from the nanometer to the kilometer, from the cent to the 8-figure project pitch. In this conversation hosted by Homeworld’s Executive Director Dan Goodwin, we explore Brad’s background, topics that get him excited in synbio (e.g., plants), ways to boot-up new ideas, more.
Listen to the full conversation on Spotify or Apple Podcasts. Read on for snippets from the episode (lightly edited for clarity).
How did you get into biology?
I’m originally from Westchester County, New York. I thought I wanted to be like Einstein, like the next theoretical physicist — so that’s how I entered my undergrad. I also thought I wanted to be a tenured professor. That was sort of my goal for life. I applied for physics programs while I was finishing up undergrad, but I then took a year off, traveled around, and thought about it a lot. I realized that I am certainly no Einstein, and that I like helping people, so maybe I’ll just become a doctor.
And then while I was on that year off, I got accepted at the Berkeley physics program, Cal Physics. It was an opportunity not to pass up. I thought, what I’ll do is I’ll get my master’s in physics there, and I’ll take undergraduate biology courses to go to medical school so that I don’t have to pay for it. That was the beginning of my journey into biology.
How did you become a synthetic biology researcher?
[While I was a physics PhD student], I met Carlos Bustamante, who’s a professor at Berkeley. I started brainstorming with him and it was a realization that we can engineer biology. My PhD project was mostly trying to make a free-living organism out of mitochondria [Context from Homeworld: This is a wild synthetic biology challenge to reverse the endosymbiosis of billions of years of evolution, which would also be a major demonstration of genetic editing technology].
So I spent a long time in graduate school really trying to engineer life. [I was] still thinking that my goal was to become a tenured faculty member. After I left Berkeley, I was in George Church’s lab, at that time as a postdoc. But I also was super involved in politics, so I decided to apply for a AAAS fellowship.
I got into AAAS and decided to take the year and learn about policy in Washington D.C. That got me more towards applied work at scale — giving grants and working on tech to market commercialization.
Through AAAS, I realized that there was a world out there beyond academia. I was at ARPA-E for two and a half years. That was actually the formative time where I realized that synthetic biology needs to be applied towards agriculture. I worked on biofuels and robotic phenotyping of plants.
I realized all of the cool stuff that I was doing in George Church’s lab could be applied. What I work on now is changing the scale of plant biology such that you can have [productive] plant synthetic biology.
So that’s really how I went from theoretical physicist to academic biologist to what I am now: I would say I’m an applied entrepreneurial biologist. There’s a lot of physicists in molecular biology and there’s a lot of neuroscientists that go into climate biology. I think it’s much easier to go from quantitative to more applied, than the other way around.
Why are plants so much harder in synthetic biology than yeast?
Ninety-nine percent of the problem is that they’re slow, and they’re low throughput.
Progress depends on how many experiments you can do, and the speed of your learning cycle is exponentially dependeng on time. The doubling time E. coli is 20 minutes and maize is four months, so we have a problem.
Furthermore, the transformation and regeneration tools are not really there, so the vast majority of crops, and even specific genotypes of crops, are recalcitrant to transformation and regeneration.
Regeneration might not even be a term that people understand if they’re working with yeast or E. coli. The way the majority of transformation happens in, let’s say corn or soy, you have artisans look at morphological characteristics of embryonic tissue in plants. They excise that tissue and place it onto media full of hormones that’s largely empirically derived.
It takes weeks — months, even — to get those things to have the proper developmental characteristics that they could be infected by Agrobacterium tumefaciens (the major plant engineering vector) or be shot with biolistic pellets. And then after you’ve made some edits, there’s the process of regenerating that tissue into a full plant … so you first try to get it to root again with hormones, then you try to get it to shoot. These things take months. They’re manual and done by individuals with decades of experience.
Even when this does work, it’s genotype dependent, so it doesn’t work in all species or even within different genotypes of the same species.
There’s some exceptions here. Arabidopsis thaliana is the one that is really easy to transform, which is why we see it so much in academia. Tobacco and its cousins are relatively easy. But generally, it’s nothing like yeast synthetic biology where you could make a library of a million different vectors, transform it, do selections, and then the next day or the next week you’ve done a thousand experiments.
What is the state of the art in plant engineering?
I think it’s probably the Agrobacterium transformation.
There was a big breakthrough around 10 years ago on using developmental regulators — developmental genes — to turn on these developmental processes for regeneration. The two most famous ones today are WUSCHEL (WUS) and BABY BOOM (BBM). These are two plant genes that when you express them in the right amount at the right time, you get conversion to a pluripotent callus, which then can be easily turned into a plant.
There’s an interesting market and business limitation to plant engineering, too. It is very expensive to do, and you’ll hear people in the world of agriculture say that the only things that matter are corn and soy. The vast majority of focus and money that flows around the agricultural system is on those two crops, and this makes sense. But this also means that there isn’t really a democratization of plant biotechnology toward anything besides these two giant crops that are managed by giant companies.
Why is it important to genetically engineer plants at all?
Half of the terrestrial land mass is agriculture. If you want to talk about scale, if you want to talk about having an impact — plants really are the biggest lever that you can push.
If you get the genetics right — and this is my whole thesis — you’ve got something powerful. Sure, there’s a lot that can be done with management, agronomics, things like that. But if you get the genetics right, you have a seed that you can then reproduce — it’s called bulking. You can turn that single seed into billions of seeds, and those seeds can be planted around the world.
Then plants just need sunlight, macronutrients, and water. And now you have your factory, or you have your carbon sequestration machine, or you have whatever scaled around the world in terms of impact.
Note that a quarter of all anthropogenic greenhouse gas emissions is from the agriculture sector. So there’s huge sequestration potential, but there’s also huge mitigation and reduction potential. And then, of course, because this is a climate-focused conversation, we can focus on those other things. Nitrogen, carbon, water, ninety-two percent of freshwater consumption is agriculture.
And then there’s a whole other equity side of food security and climate resilience. E. coli is great, you can make a lot of cool chemicals with it — but I think if you’re not looking at plants, you’re missing a huge lever on many civilization-scale problems.
Learn more and stay in touch
Brad mentioned in the podcast that some big things were in the works. What we didn’t know at the time was that his project has spun out of X and is its own independent company — Heritable Agriculture. Keep an eye out for future developments there, and keep up with Brad and his work via LinkedIn!
Meanwhile, check out his recent paper covering how population-level gene expression can repeatedly link genes to functions in maize, and read his essay on agriculture in the age of sustainability.