Lab Meeting: George Church

“I am even more excited today than I was in my early years about science.”

In 1963 Southwest Florida, a nine-year old boy stumbled upon a pond monster.

Intensely shy, a young George Church found solace collecting specimens from the muddy pond in his front yard. He soon encountered an interesting creature: “one day I found what I thought was a pond monster…it certainly seemed like a predator. I put it in a jar on my shelf,” recounts Church. He then ran an experiment—introducing small bugs into the jar and recording what the monster would eat. After a few days he found something shocking: “it was apparently dead: there was an exoskeleton at the bottom of the of the water…I unscrewed the lid and looked on the inside, and there was a dragonfly.”

The boy took a trip to the library, which presented some difficulties: “I was dyslexic for many years…but I wanted to find out what had happened. I went to the library and started looking for books on bugs with pictures.” Soon he stumbled upon an illustration of a dragonfly larva, and the truth emerged. The “monster” was simply a precursor: “the whole idea of metamorphosis…just completely blew me away.” Perhaps more important was the transformation that occurred within the Church himself: “I realized that I could do my own research. I could figure out what was going on through books…it was very liberating.”

In his journey to becoming one of the most prolific scientists of his generation—the shy, dyslexic, narcoleptic boy from the Floridian mudflats would repeat this process countless times: observation, intense research [self-described “obsession”] and ultimately an “aha” moment. As a high school student at Philips Andover Academy, Church had free reign of the chemistry lab, photography studio and greenhouse: “From the day I arrived, it was like arriving in Oz” (Q#3). He excelled in math and science, but (outside of class) spent years on a Dartmouth computer, pursued photography and played varsity sports (Q#3). As an undergraduate at Duke studying both chemistry and zoology, Church graduated in just two years: “Part of the reason for graduating quickly was that I didn't want to wait to get to ‘real’ research… and also I was worried about making it through undergraduate if it took four years” (Q #2).  

His worries were not unfounded—as a grad student at Duke, Church spent so much time in Sung-Hou Kim’s crystallography group (working on the structure of protein-DNA complexes) that he flunked his graduate school coursework. Following a formal expulsion letter from Duke [now displayed on his web site] wishing Church “a productive career,” he re-applied to grad school and landed at Harvard in the lab of (future) Nobel laureate Wally Gilbert.

There, Church completed a PhD in molecular biology, studying mobile intronic genetic elements in yeast, and the structure of mouse immunoglobulin genes. Gilbert had a huge impact on Church: “he and I shared a genuine, broad curiosity, and multidisciplinarity. Wally was a theoretical physics professor when he switched over to doing experimental molecular biology. He  was the CEO of Biogen and later pursued venture capital. He also was expert on archaeological artifacts and has been an exhibiting photographer for many years now” (Q#6).  

In the 80s, Gilbert’s group was on the cutting-edge of gel-based DNA sequencing (for which Gilbert and Sanger shared the 1980 Chemistry Nobel)—however the methodology used was laborious and took years to sequence a few kilobases. Here Church saw into the future—envisioning that whole genomes could be sequenced rapidly and cheaply— in a process that would come to be called multiplexing: “When I first started my lab, there weren’t a lot of people who believed in my dreams…but after affordable sequencing, which was supposed to be six decades away, but arrived in eight years …people started thinking: ‘well maybe he's not going to be killing our career’” (Q#8).

After a brief post-doc at Biogen (with Gilbert) and UCSF (with Gail Martin), Church started his own lab at Harvard Medical school in 1986.  His group developed the first direct genomic sequencing method, allowing his company (GTC) to read and sell the first cellular genome – that of H. pylori. He helped initiate the Human Genome Project in 1984 and the Personal Genome Project in 2005. Technology from his group—molecular multiplexing, “barcode” nucleotide tags, complex microfluidic systems, array DNA synthesizers, homologous recombination methods and gene-editing systems (e.g. CRISPR and SSAP)—have formed the basis of dozens of companies, including: Editas, Gen9bio, Veritas Genetics, Colossal and Manifold Bio. He has participated in technology development, licensing patents and advising most of the Next-Generation Sequencing companies, including Illumina and Complete Genomics. Now 90 members strong, and embracing over 300 alumni, the Church lab tackles problems spanning biology, chemistry, computer science, engineering and even interstellar travel (Q #10). A Professor of Genetics at Harvard Medical School and the Wyss Institute and an elected member of the National Academy of Sciences, Church shows no signs of slowing down: “I would say I am probably even more excited today than I was in my early years about science. I have more of a fire hose, and I'm more able to consume the fire hose” (Q#8).

Though Church is considered a father of synthetic biology, and already credited with several breakthroughs, his greatest contributions may lie ahead. Now in his sixth decade of doing science, Church sums up his prolific career to date: “I'm a late bloomer” (Q#5).

Below is an interview with Dr. George Church, Professor of Genetics at Harvard Medical School from November 2022:

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1. Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings. What were the killer experiments? 

Nettie Stevens is my wife's hero and mine. She worked at one point in Thomas Hunt Morgan's lab. But she was unquestionably discovering on her own, the chromosomal basis of genetics… so extending Mendel formalism [for alleles], to real structures [condensed chromosomes] in the cell in 1905.

I think so much of what we do these days is dependent on the chromosome theory, rather than just the abstract theory of genetics. So, she seems like a good person for this question… and certainly very few people have heard of her. Although, one positive thing is that I did see her name on Google – you know how they feature different people on the homepage logo design. So, that is ‘arriving’ in some sense.

2. You’ve mentioned your high school math teacher (Crayton Bedford), photography teacher (John Snyder) and college professor Sung-Hou Kim as big influences. Are there any traits that they shared, which made them such great mentors?  

Three of my early mentors were people whom I met as a teenager. I met Crayton Bedford and John Snyder in ninth and 10th grade, and Sung-Hou Kim when I started as an undergraduate. What they had in common was encouraging me to do independent research. It wasn’t that they were going to hover over me or hold my hand, which is often mistaken as good mentorship. For example, Crayton Bedford handed me a book off the shelf that he used for his [math] thesis. It was pretty advanced math. He had seen that I was narcoleptic and falling asleep in his math class, and felt that would be a win-win if he could get me out of his class and working on something else... so I actually programmed a computer directly from his linear algebra textbook [as a high school student 1968-69]. And it worked.

John Snyder was my art history and photography professor. He was a tremendous photographer himself. By the way, I have kept in contact with all these people, up until very recently, though it has been 50 years since I was a teenager. So, John [Snyder] had singled me out. He had 300 photography students, and he picked my portfolio and gave me his 35-millimeter camera. Up to that point, we were using these 49 cent surplus plastic cameras with plastic lenses. He gave me this this great 35-millimeter camera - it was actually his own – to use instead.

Sung-Hou Kim was my mentor that really shepherded me into publishing peer reviewed articles. I started with him as a teenager, and he introduced me to a very multidisciplinary field which is macromolecular crystallography.

[Do you still pursue photography?]

Imaging has been a big part of my life, and also three-dimensional thinking. I do a lot of photography still. I gave one of my favorite cameras - a 1943 Speed Graphic 4x5 camera - to my daughter, which kind of inspired her. She studied photography as an undergraduate and is now a professional photographer, among other things. I have a collection of 3D cameras from back in the ‘50s, as well. So yes, I'm still a photography enthusiast.

I think that you can trace next-generation sequencing all the way back to my thesis where I was essentially working on a process of having a latent image that you then develop with chemistry, and then you go back and you get another latent image from it, and you continue through the cycles of fluidics and imaging. I used to do a lot of darkroom work that contained cycles of fluidics and imaging. These were multiple images from the same latent image, very much like NGS.

[On finishing undergraduate at Duke in 2 years]

I did two degrees – chemistry and zoology. Part of the reason for graduating in two years was that I didn't want to wait for my degree to get into the research. I also didn't want to be a burden on my parents. I think Steve Jobs had a similar attitude, although he did it in a slightly different way. I also I think there was a part of me that was worried that I would not make it through undergraduate if I did in in four years. In fact, that intuition turned out to be true because about a year later I flunked out of graduate school. If I had still been an undergraduate at that point, I would have ended up with no degrees. So, it turned out that finishing in two years was a good move.

3. What was your first taste of running a science experiment? Briefly, what about this initial experience drew you in? 

My first experiment was in my first or second year in high school. I did quite a few experiments - mostly in chemistry and biology - in high school. I had the complete run of the chemistry laboratory on nights and weekends, which is a pretty strange situation to provide for a young high school student in the 60s.

My first experiment (with controls) was with gibberellic acid on pea plants (1970 at Andover). This is my data plotted by hand. I did have access to computers at the time, but by hand was the way it was done. These were three different nodes of the pea plant and one concentration of the plant hormone, gibberellic acid. These are three different nodes going up in size, and two repeats. So here we are looking at a total of six curves as a function of time on the x axis.

[On wanting to apply this study to Venus fly traps]

I think that applying this experimental scheme to Venus fly traps was the ulterior motive behind that gibberellic acid experiment. I basically had free run not only the chemistry lab but also the of the greenhouse. I had a lot of Venus flytraps there, but they did not respond to the gibberellic acid, negatively or positively. But these bean plants really did… there was just a dramatic difference between the controls and the experiment.

[On first arriving at Philips Andover Academy]

My third father [Gaylord Church] had gone there for two years. He had not enjoyed it, but his intuition was that I would -- and indeed I did. From the day I arrived, it was like arriving in Oz in the Wizard of Oz. It was like being on a college campus in many ways – it is actually more beautiful than most college campuses. There, they forced us to participate in three sports a year, and I ended up being on two varsity sports (which I never would have done otherwise). They also provided access to tons of extracurriculars and really excellent science resources.

4. You built a computer as a high school student, where did this early interest in technology and computation come from?

I saw some robots - what I thought were robots but were actually animatronics - in 1964 World’s Fair in New York, and I thought “that's the way things should be.” When I went back to Florida, there was no science in my classroom. I didn't know anybody who was a scientist or an engineer. I was just desperate to get a computer, but I had no idea where they were aside from New York, so I asked an electrician to help me build one.

He gave me some spare parts: a galvanometer and some potentiometers. I built an analog computer first and then I built a digital mechanical computer, but neither was general purpose. They weren't very good, really. Then in ninth grade, I got access to a true modern digital computer (a G635), which was a time-sharing system that was ahead of its time. You could type in and you'd get an answer back. At that time, most people were using punch cards that required you to put them in the hopper and come back in a couple hours for this fanfold output. But for four years at Andover, I had access to the Dartmouth computer through something that seemed a lot like the ARPANET, but it was independent of it.

5. You have worked in so many different areas. What is your method for getting up to speed in a new branch of science?

I haven't really dropped anything since I started in science. I just keep adding topics. Even things I was working on in high school, I still work on. Crystallography was my first publishable work 50 years ago, and I still work on projects involving crystallography, mostly collaboratively. But yes, I have added genomics, genetics, RNA, protein, systems biology, synthetic biology, neurovirology, immunology, stem cell biology… these are among the more recent things.

I'm not sure I'm up to speed on any discipline just yet, but I'm getting there. I'm a late bloomer. The way I approach a new area is usually in some quirky way. That is to say, I’m not out to conquer the whole field, I'm just going to do one really specific thing. I usually begin with some kind of idiosyncratic obsession with one aspect of it. And because I don't know much about it, and I’m an outsider, there often aren't a lot of experts on that specific aspect of the field.

I usually just read whatever is nearby and then develop the expertise in my lab as well. It's a diverse lab already, and it's fairly easy to distract new people onto these new topics. The process is then typically learning by doing. It helps that we usually do it in a way that is unthreatening to established researchers in the new space. Unless they know that we're going to be disruptive to the field, which usually isn't obvious when an outsider comes in and doesn't know what they're doing. One typically doesn’t assume: “Oh, in a couple years, the whole field will be different.” But it's also non-threatening because typically we work on technology rather than on the biology. They know they're going to get a gift of the technology and then I'm going to shift focus to another field. So I'm not going to be a permanent annoyance.

6. How do you mentor students in selecting a good project? How does the Church lab determine what to invest time and resources in?   

The technologies we develop tend to be ‘basic, enabling technologies’ that can be applied to many things. For example, sequencing isn't limited to biomedical; you can use it for encoding information, for bio-weather map, for forensics, for history. Most of the technologies we work on are kind of naturally renaissance person type technologies. But how do we select a good project?

First, we try to pick things with a high chance of scientific discovery that are, at the basic science level, a quirky philosophical advance of some sort. These are things where we don't have to explain why we would be interested in doing this. Second, a technological component: we are aiming for many orders of magnitude, not a factor of two, because that'll be swamped out by other groups immediately. For example, this was a factor 20 million improvement in the case of sequencing and synthesis. The third component is something that's societally beneficial. Don’t just pick something that will change the world, but thoughtfully consider what is actually needed--rather than just what would be kind of cool to do.

It used to be you had to pick one of those three, or you were lucky if you got any one of those three. These days, especially if you have an active technology lab, you can do all three at once. Having all three is your signal that you have got a good project.

[Was this the model you saw in Wally Gilbert’s lab or Sung Hou Kim?]

I don't think it was fundamentally different. It was probably a little bit more like what Wally was doing. He shared with me a genuine, broad curiosity, and was very multidisciplinary himself. He was a theoretical physics professor when he switched over to doing experimental molecular biology. Plus, he did archaeology where he collected really amazing specimens. He did venture capital and was the CEO of Biogen. He made art and has been an exhibiting photographer for many years now. So yes, he was fairly similar.

Sung-Hou was fairly different. He was like the crystallographer’s crystallographer. He was a specialist, and was very good at it. He had started in Korea where he had to do his computing on an abacus or in his head, which for crystallography only allowed you to do very small molecules. But he was very good at it and he really knew it. He was just a constant inspiration, but in a different way than Wally was. And then I did my own thing from these starting points.

7. What was the first time something really “clicked” for you scientifically and you realized you wanted to be a scientist? What has been your scientific high point?

I had a beard, even as a teenager. Everybody used to joke that beards were important for crystallography back in the 1800s, because you'd get little dandruff that would seed the crystals.

I'll give you a very early example – something that clicked that made me decide that science was for me – and then I’ll give you a later example as well. I must have been eight years old or something like that and in Florida - again, a ‘science free zone.’ I loved hanging around our pond in the front yard. I found all these what I called “skeletons” of insects. I would look in the pond, and one day I found what I thought was a pond monster. It looked like a predator to me. I put it in a jar, which I put on my shelf. A couple days later I came back excited to see if it had eaten any other things, I had given it. It was apparently dead: there was an exoskeleton at the bottom of the of the water. I thought “that’s weird” - it had completely vanished in a short period of time, and all its insides were gone. I unscrewed the lid and looked on the inside, and there was a dragonfly. I thought “well, maybe the dragonfly ate my monster.”

I was dyslexic for many years - all the way into well into graduate school - but I wanted to find out what had happened. I went to the library and started looking for books on bugs. Eventually I found a photograph - I did almost all of my reading by looking at the pictures at the time - of a dragonfly coming out of a larval nymph. This metamorphosis, and the whole idea of metamorphosis - completely different organisms stuffed inside of each other like turducken - just completely blew me away. More importantly, I realized that I could do my own research. I could figure out what was going on through books. I just felt that this whole process of discovery and nature, and discovery and books, was very liberating. I guess just never really felt like I needed teachers from that point on.

The second example is in crystallography, which is perhaps what really got me interested in real science, in publishable science. I had tried a few things, and was on my third big-ish project. I had worked for a summer at the Boston City Hospital on infectious mycoplasmas. I had also worked at Duke with a computational biologist who worked on the theoretical structure of HLA. He seemed to have no idea about what proteins actually looked like; it was entirely based on abstractions from the serology of multiparous women, who would have antibodies against HLA. Antibodies aren't even the key aspect of HLA, but anyway, I would help him on the computer modeling side of that. But neither of these first two projects really grabbed me.

Then I get to crystallography, and I’d been trying to find something where I could use all my interests at once without having to jump around from day to day. This was the real McCoy: you needed math - the Fourier transforms and matrix rotations; you needed chemistry for the bond angles, lengths and energy calculations; you needed biology because tRNA is at the core of all all life; and you needed computer science to fit and to plot the structures. Part of my interest was technical, but it was also this ability to not specialize. I  wouldn’t be a dilettante in crystallography … you really needed to know all of these areas well to get through.

8. What set of research questions or projects has you most excited about coming into lab today? 

I would say I am even more excited today than I was in my early years about science. I have more of a fire hose, and I'm more able to consume the fire hose. I actually once watched an elephant drink from a fire hose - he seemed to be enjoying it. He took a few gallons into his trunk, and then delivered it into his mouth. That is how it feels, because there is almost no friction in my environment anymore. If I have a crazy idea, it's very likely that I have a way of implementing it with my own hands, with my lab, with one of my companies, or by starting a new one. There’s now a fairly small delay between crazy ideas and something that's poised to produce societal benefit, which was not the case when I was younger. When I was a kid, I couldn't even dream of that. When I first started my lab, there weren’t a lot of people who believed in my dreams - they took things that were a little more conservative than what I wanted to do. But now, after a few examples where things arrived way ahead of schedule – for example affordable sequencing, which was supposed to be six decades away and was more like six to ten years away. After a few of those, people started thinking “well maybe he's not going to be killing our career.”

9. How do you think about company formation today?

The most far-fetched things I prefer to do in academia. In academia, your job is to spend money while in companies you're supposed to be making money, which results in a little bit more of a rigid environment. In thinking about a company, you keep your eye on the ball: you want to have something that that you can finish. And in many cases, to finish these projects requires some societal enthusiasm. For example, clinical trials might cost half a billion dollars. It can be hard to raise this type of capital if the idea is too early stage—that said, I am very grateful for any money that happens to come in, especially for the earliest stage projects.

10. Which areas of science, outside of your direct field (which is admittedly quite large), are you most excited about seeing develop in the next 5-10 years? 

Interstellar travel. Whenever I try to develop a new technology, I try to pair it up with an application that is not currently feasible. Whether the technology has just improved the state of the art by orders of magnitude or is something brand new, it's nice to pair it up with the application. One of the advantages of pairing it up, is that it lets you see a completely different route [to achieving something]. The technology we are going to develop may not be as cool as the other one (from a purely technological perspective) as you're just trying to aggressively get the solution. But our application, in this case interstellar travel, is a way of pushing the agenda of having synthetic biology systems that can make just about anything—even at great distances from typical supply chains.

I teach a course called “How To Grow Almost Anything” with David Kong and Joe Jacobson at MIT. The idea is that we should be able to grow just about anything. If you do interstellar travel and want to land somewhere, you better have a small payload: if you want to arrive there before radiation gets to it, or before people on earth lose interest, it must have a small payload that is capable of expanding into a gigantic payload. You will want to build lightspeed communications, either lasers or radio.

So that was the inspiration for a talk I gave -- followed by a paper that was accepted at Astrobiology [not yet published] talking about all the ways that synthetic biology could make semiconductors, lasers, and optic materials and other things you would need for communication. We have not yet built a non-biological system that's capable of making copies of itself. In principle, a huge and complex slice of society can make copies of your cell phone. But the cell phone itself can't make a cell phone. Robots cannot make robots…yet. Even if robots could make robots, they'd make it from chips. Of course, making the chip itself is it's hard to make from sand, let's say. But that's exactly what biology does every day - they eat atoms and/or photons, and they produce amazing things.

This talk was a response to the Breakthrough Starshot project, which was proposing a fairly radical idea of scaling down from tens of kilograms to gram scale probes, so that you could accelerate them to 20% of the speed of light. But I felt like the gram was still too heavy. I mean, 20 kilograms to one gram was great, but I wanted to go to nanograms or maybe even picograms. At this scale, you could accelerate billions of probes to the speed of light without breaking the bank. This gives you a lot of shots on goal. And that's about the size of, you know, several of the large, living cells. So, you could get self-replication (and differentiation) of these machines.

11. Who are a couple up-and-coming scientists (lab < 10 yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you? 

It’s hard to stay away from my alumni and collaborators here. Because for every new area I find interesting, I offer to collaborate with many of the leaders in those fields. I also have over 300 lab alumni, many of whom keep in touch with each other, and are very nice to each other. So, I would recommend those searching for a great lab or company to start with my lab alumni page. I know this may sound very self-oriented, but it's because I know firsthand that these folks are nice people. That’s important. I think going with the ‘world's best’ if they are cutthroat is not a positive experience, and I recommend against that.

12. What is one piece of advice for those in science wishing to work start a company based on their work? Things to consider before taking the plunge into entrepreneurship? 

You definitely don't want to start too early. It's okay to be number two. It really is good to have competition, especially bad competition (meaning ineffectual), because they make you look good. They also validate the fact that there is there is some interest in this field. But don't spin out too early; you want to build up as much value as possible so you don't get diluted out immediately. You need to accept the fact you will be diluted out, and you may even lose control over the company, and maybe even voted out. However they [investors] can't take away the fact that you were founder, as that that is a permanent record. Also, make sure you do things that you are passionate about. Don't worry about intellectual property. I mean, you need a little bit of it to get investors, sometimes. But don't worry about other people's IP. I'm not encouraging you to infringe. But at some point, you'll make a deal with holders of other IP. You want to make the best technology, so if you if you avoid all existing previous technology, you're going to make an inferior product. It's much better to plan on licensing or finding workarounds later.