Project: Archive of Agricultural Genetic Engineering and Society Interviewee: Steve Evans Interviewers: Patti Mulligan, Jason Delborne Observer: Andrew Hardwick Videographer: Nic Beery Date: 2/10/2020 Location: NC State University, James B. Hunt, Jr., Library Length: 1:43:26

Patti Mulligan: [0:00] Hello, and welcome. Today is Monday, February 10th, 2020, and we are here at the James B. Hunt, Jr., Library, at North Carolina State University. This is an interview for the Archive of Agricultural Genetic Engineering and Society, conducted by myself, Patti Mulligan. I’m the Communications Director for the Genetic Engineering, or GES, Center. And I’ve got Dr. Jason Delborne. He is a GES Executive Committee member and Associate Professor of Science, Policy, and Society, in the College of Natural Resources. Our videographer is Nic Beery, of Beery Media, and we also have Andrew Hardwick, a master’s student in Public Administration, who is sitting in with us. So, we’re very excited to have you here with us today.

[0:42] Can you please introduce yourself, your name, your organization, your role?

Steve Evans: Hi. So, I’m Steve Evans, and 11 months ago, I jumped out of corporate agricultural biotechnology, into a private company, a consulting group called Re-Knowvate. But prior to that, I worked for 30 years in small- and large-company biotechnology. So, this has been an aspiration that I’ve had, to be able to take knowledge that we’ve accumulated over that period of time and then, be able to help, especially small companies or university students, think about genetic engineering but being able to have a history of the experiences that go back well into the 1980s.

Jason Delborne:Terrific. Well, that certainly aligns with our interests for this project. So, we’re really happy to have you here, today.

[01:38] Could you give us a sort of broad sketch of those 30 years of experience, working for different organizations and companies, just to kinda give us a sense of the broad outlines of your career? And we’ll get into some of the details, later on.

SE: Sure. So, I went to graduate school last century, in microbiology, and I went to a medical school, at University of Mississippi. But after that, I went, in the early ‘80s, to University of California at Berkeley, which was a hotbed for some of the early genetic engineering technology development. After that, I went to the Department of Agriculture at Peoria, again, trying to look at how to apply biotechnology to the cattle rumen arena, all tied together by microbes.

In the late 1980s, I joined a very small biotech company, called Mycogen Corporation. I was actually in a field station for that company, so, really small, about maybe 20 people,

1 total around. But Mycogen grew from a garage of 3 scientists in the mid-‘80s, up to, at one

point, 1,500 or so employees, by then, had become a seed company. So, the idea of Page

biotech had kind of – it was an important component of it, but even at that point, we were a seed company. We were acquired by DowElanco, which was its name at the time, in the late 1990s. Dow and Eli Lilly had formed this venture, called DowElanco, at the time.

Lilly moved out of ag biotech, so, Dow AgroSciences was born in 1999 or so. And then, of late, Dow AgroSciences – well, the Dow Chemical Company and DuPont merged, and out of that came the agricultural company known as Corteva. And so, I rode those transitions from a very small group to two different forms of multinational company, before deciding to jump out on my own.

JD: Okay. Thank you. That’s really helpful. Just thinking about – so, I understand that you’ve kind of jumped off of that ship, and you’re doing more independent work, right now.

[04:17] But thinking back to your last position at Corteva, what was your role there, and what did a typical day look like for you?

SE: So, it was fun. I had a very interesting role. I was, in the organization, a Research Fellow, and what that allowed me to do is, in addition to some project work at the time, like you would always do, Research Fellows had the opportunity to specialize in some arena. And I chose to work in the area of public-private partnerships, in the field of synthetic biology. And so, from about 2008 or so, I was involved in a very large National Science Foundation-funded program called SynBERC. And it was a Synthetic Biology Engineering Research Center.

What that allowed me to do was not only be able to interact with leading lights in the field of that emerging arena, but, as Chair of the Industrial Advisory Board, we got to bring input into that organization, from, at its apex, 49 companies, I believe. And so, this was a very unique environment, took – it took place over 10 years, and out of it launched some follow- on, not-for-profit, engineering biology research consortia. So, the – the overall role allowed me to do that. My background, as I indicated, early, was in microbiology, and my role there involved analytical biotechnology, or biochemistry of biotechnology.

So, we did a lot of work looking at high-resolution mass spectrometry, helped create Corteva’s Imaging and Microscopy Center, and developed some technologies in protein expression that were used in companies that were actually spun out of Mycogen. So, my technology work allowed me an opportunity to really make lots of proteins and figure out how to measure things. But the last decade was really spent trying to help both – well, to bring technology into the company, but then, influence technology development outside of the company.

JD: So, just to stay on that for a second, it’s a pretty unique role that you were the Chair of the Industrial Board.

SE: Mm-hmm.

2 JD: [07:00] So, could you talk a little bit – and you just alluded to this, what – what was in it for

Corteva? What were some of your goals, professionally? And what do you think, as an Page

NSF Engineering Research Center, what was the university or the public getting out of this particular partnership?

SE: Very good. So, this Center operated for 10 years. It received, I think, $37 million in NSF funding. But it had allied funding brought in by a number of other companies, that I think eclipsed $100 million. So, companies were pouring into this, money that was used to help develop what was an emerging field, at the time. So, the question that came into play was something that I reflect back to Jay Keasling, who was the Center Director. And he observed that every time he had an idea, it took two post-docs and two years to just execute on one part of that idea. And they were looking for ways to speed up that ability to execute. And then, it was developing the underlying science and technologies around composing DNA. Ultimately, de novo was one of the goals.

But how could you just make biology engineering – or engineering biology something that could be accomplished more easily and more predictably? What I think the nation got out of it was, we are still one of the world leaders in that technology field. It’s been recognized in recent funding opportunities from the federal government to be important to continue development. We grew probably – we’ve definitely impacted the next generation of biotechnology scientists in the area, to the nearly 300 publications that were in prestigious journals. So, the field – the technology field grew.

Now, what did companies get out of it? Interestingly, there was the early development of computer technologies that ended up in design and software packages that – some of which were incorporated into existing company technology. But some spun their own start-ups. And so, out of that investment came scientists that formed their own companies or the ability of companies to find partners to go develop things that were still very risky. And so, again, the – at the apex, there were, I think, 49 companies involved. Some of the companies even were from outside of the U.S., trying to be able to – be part of the influence of that early development.

JD: Thanks. And we may have time to come back to some more, because that’s a pretty major part of your career, too.

[10:18] But just thinking backwards, is that what you wanted to do, when you were a child [laughs], when you looked forward? What did you wanna be, when you grew up, when --

SE: [laughs] So, I was 10 years old, when the Apollo XI Mission landed on the moon. So, as with many self-respecting kids of that time, I wanted to be a rocket scientist. My socks even have planets on them, right now. And that was – so, big science, science that was impacting things, not only getting to the moon, but technologies that were developed along with that, I didn’t understand them at the time, but were pervasive and impactful in society. So, I wanted to be an aeronautical engineer. By the time I actually got old enough to do something, the – the interest in the space program had shifted and was waning.

I began to be very interested in biology and, in particular, microbes, because they just do

3 cool things. They make all kinds of things, have been doing so since well before we

understood that it was a microbe doing something. But so, how could you – based on Page

work that was really impactful from the 1970s, on, how could you take microbes and do something interesting? And so, that was the initial thread.

JD: Great. Thank you.

[11:50] When you think about that time of moving from space to biology, and then, you pursued your graduate degrees in that field as well, who are some of the people – maybe one or two, who are most influential in your career, at that early stage?

SE: Well, as I said, super early, it’s kind of odd, I would say that it was my mom, because what she did was, she acquired every kind of book that one could get. I had all kinds of reading clubs that I was in, as a child. But what that taught me how to do was to learn by reading. And so, as I got into college and then, into graduate school, this love of reading stayed with me. I had a habit, at that point in time, of, when you would go to a library, much like this, and read something in the stacks, that was a trudge. You had to go leave and get there. You couldn’t just Google something. But I always would read the article before and after the one that I went.

And that’s where this love of reading, I would say, got me to be both a lifelong learner, but interested in the areas or seeing technologies outside of my own field. My Graduate Advisor, I think, was significantly influential, Rowe Byers. And what I would say, overall, is that at every point in time where I had a significant scientific figure around me, it was kind of what I needed at the time. I was able to learn and then, over time, be able to give back. Even though I haven’t been a professor, I still have people – scientists who I’ve helped influence their career, in both the academic and corporate climate.

One of the enjoyable things about the NSF SynBERC program was that I was able to be an industrial advisor to students, both in the U.S. and in the United Kingdom, who’ve gone on to do very interesting things in their field. So, learning.

JD: Nice. So, you came of age in the field of biology, when genetic engineering was really just getting started.

[14:14] So, tell us about how you first became aware of this technology. What were your impressions? How did you think it would matter?

SE: Right. So, I think one of the keys areas – so, I was on the Berkeley campus, in 1985 to ’87 or so, which was the heyday of what was then known as the ice-minus bacterium. It was the subject of both legal machinations, it was trying to make its own through the Environmental Protection Agency, at the time, and it was a genetically engineered organism. These days, it was very tame, because what it was, was a deletion. It had no transgenes in it. But the technology that was being developed and deployed at that time was new.

So, I was involved, or I was aware of that, from proximity on the campus. Again, the arena

4 that was driving my largest area of awareness was industrial microbiology. And so, the

use of genetic engineering to impact antibiotic production and some other things that were Page

contained-use technologies, as the jargon is today, was my main area. I then joined Mycogen Corporation, in 1988, and its mission was to develop and deploy genetically modified organisms in the environment. And so, since that period of time, I’ve been actively involved in GM research.

JD: Mm-hmm. So, I know the ice-minus controversy was a pretty interesting time.

SE: Yes.

JD: It sounds like you weren’t a participant in that work and maybe not a participant in the controversy.

[16:13] What were your impressions about not just the sort of technical details of what they were trying to do, but the kind of public reaction and what the scientists ended up doing, in terms of public relations and things like that?

SE: Right. Yeah. So, correct, I was not involved in that work. Mycogen, though, which, when I joined it, was trying to field test genetically modified organisms, was a direct collateral impact, I would say, of that. And so, net – if you go all the way back, I’d say the controversy into that, in my view, being driven by the photographic images of the scientists’ spraying this organism, in full protective gear, the jumpsuit, as you would call it, which, now, there’s actually a component of that jumpsuit preserved in the Smithsonian. I think it had that big of an impact.

But what it net said was, recombinant organisms, microorganisms, were gonna have a very difficult time being deployed in the environment, regardless of the field. So, that was agriculture. The Chakrabarty patents were on recombinant organisms for bioremediation, at that point in time. The government was spending a lot of money, trying to develop microbes to remediate toxic waste sites, detect hazards in the environment, and so forth. And all of that research came to a standstill, in essence.

So, our company, Mycogen, had the idea of taking a single gene out of a bacterium that makes insecticidal proteins. We had found an organism that lived on the cabbage or lettuce leaves. So, today, we would say we were doing microbiome research. Then, we just thought it was an organism that lived on the phylloplane. That was its – the term, then. And then, we were gonna put that single gene in that organism and then, spray the live, recombinant organism on – in the agricultural crops. But you couldn’t do that, net. Well, you could try, but there was no way that you were gonna outlast that view.

So, we ended up having to pivot and make a dead recombinant organism. And so, what I would say is, the act itself – the outcome of the actions around the ice-minus bacterium did appreciably change the direction of any company that wanted, or any government agency or any university professor that wanted to take a live recombinant bacterium into the environment. Transgenic crops were not bacteria. Those began to take their life by the late – the late ‘90s [correction – late 80’s] and then, were released commercially by them,

5 in the mid-‘90s. So, I would say, that was the thing that, even though I wasn’t involved,

personally, from the start, it became personal because of the company that I was in, and Page

we used that opportunity to develop an alternative approach to genetic organisms in the environment.

JD: [19:46] Did it give you pause? I mean, I’m just thinking about this moment, where you see the potential for genetically engineered microorganisms. And then, there’s this kind of political or public reality, that that’s not gonna fly. And so, you end up entering a company that has to shift its whole strategy. How did that feel, at that time?

SE: Well, I think it was – it was a nerve-wracking component, but it was also, I’d say, something that I find to be true of entrepreneurial and technological advances. You take a problem and then, try to dissect it and find a way through or around that problem. And technology is very much the outcome of that. This is true, whether it’s an engineering issue or, in this case, a biological issue. So, what’s interesting, even in the footnotes, the caption in – of the Science article about ice-minus, there was a nice little disclaimer that people weren’t wearing the suit because the organism was believed to be hazardous. It was because of a procedural requirement, because that organism was classified as a pesticide.

And so, when you think through that, it wasn’t a question overtly. There was question. Again, it was a decade after Asilomar. Questions around safety were beginning to be addressed, and questions around, is genetic engineering inherently hazardous, had begun to be addressed. I’d say, the biggest pause that I had, that I was observing, was that, shortly after that, a lot of research that needed to take place to address the role of microbes – recombinant microbes in the environment, how competitive were they, what happened to their natural disposition, a lot of work that needed to be done and needed to be done by academics and national labs, so that it had a good public perception of credibility, a lot of that simply did not happen or got delayed a decade.

That was the thing that ultimately gave me the pause, as watching the impact of the loss of the – the loss of the ability to answer questions that were gonna be important for the more widespread deployment of microbial biotechnology in the environment. We lost -- we lost two decades. And so, now, as we look at it today, with newer techniques in genetic engineering that are very different from what was deployed at that time, we’re now having to re-ask those same questions. So, what’s the disposition of these organisms in the environment? And I’d say, that’s, to me, the biggest concern.

JD: [22:55] Was – were there any discussions that you were aware of, about, I don’t know if ‘fighting back’ is the right word, but in trying to change the public discourse? Instead of, I mean, what you’re describing is that kind of pragmatic response of saying, ‘Well, this is the kind of controversy that’s going to emerge. So, let’s do something different.’ Were there some voices that were saying, ‘No, we’ve gotta – like, let’s get out there and convince people and convince our regulators that this is safe and a good idea’?

SE: The – it’s an interesting question. I think that, as you look back at the time, the – the voices and the participants were, just as today, still relatively few that are very vocal on

6 either side. So, you had a small group of entities at the time that were very much against

almost any form of genetic engineering, whether it was moved into the environment or not. Page

You had some – another group that saw it as the panacea for everything. And in the middle, I think what you had was a lot of just silence. And so, moving between polarized extremes, whether it’s in science or politics, as we see today, I think is challenging.

And so, there were efforts that were put in place in the late ‘90s to try to find, I would call them demonstration biotech projects, that would have some different – a perceived different impact or benefit to the society at large. One of the ones that came out was the Golden Rice initiative, still in the news, just this past week. So, there were efforts to try to change the nature of the discourse, but I think it was still tough. Contained recombinant technologies simply didn’t have that same level of discourse.

And so, one of the things that I reflect on is that a person will take a recombinant protein and inject it into their body, like insulin, but yet they are worried about drinking a Coca-Cola or some other beverage derived from the sugar of a corn plant that has been genetically engineered. And so, they’re very different levels of concern, and different stories that have built up around various aspects of biotechnology. But contained use biotechnology, things inside fermenters, or things that have moved through the medical – I’m not gonna say the medical approval, because there are processes that go through the FDA that go into the environment, that have not necessarily been easily accepted. But if you have a prescription for it, I think that’s been a big difference.

JD: Mm-hmm.

[26:05] So, in your – so, when you went to Mycogen, what – what sort of responsibilities did you have? Were you a – essentially someone who was working in the lab? Were you veering towards these kind of policy discussions that I know that you eventually got into?

SE: Right.

JD: Tell us about, kind of, what your first role was, at Mycogen, and the kinda questions you were dealing with.

SE: So, early on, Mycogen was trying to have its foot firmly into arenas. One is what today is known as biologicals. So, bio-control. In the ‘70s and ‘80s, every major land grant university had huge departments of phytopathology or something like that, trying to find microbes to kill weeds or to kill insects. And so, we did that. I was involved in the development of native microorganisms, fungi, and then, later, some bacteria that we could use for controlling weeds and insects. We then had – the “Myco” part of it was a focus on fungi. The “Gen” part was the focus on genetics.

What we had hoped to be able to do, as we – and I indicated earlier, was do some recombinant DNA technology that could change the way that you would make a microbial pest-control agent. So, my job was to both do some fermentation technology, analytical technology, on the native microorganisms, and then, develop protein expression techniques. And if you think about what we needed to do, at the time, what a biopesticide

7 needed to do, at the time, the use rates were somewhere on the order of, let’s say, 25 to

50 grams of protein per acre. Page

And we had to figure out how to make a recombinant protein at that level, so that a farmer could spray 25 to 50 grams of protein onto their farmland, at a price that was cheaper than Sigma would sell a bovine serum albumin, which they got as a waste product, let’s just say. And so, developing recombinant expression technologies was extremely critical to our business, and it had spin-off applications, elsewhere. And then, so we were heavily involved in that. I’d say the policy aspect, or the regulatory aspects, were that we were the first organization to try to take a dead recombinant through the Environmental Protection Agency.

And so, we were heavily involved in developing science packages that could then go into the Agency, be reviewed and accepted, as indicating what we were trying to do, which was demonstrate complete kill and some other aspects around that. So, there was a tie, early on. When you’re in a small company, you wear a lot of hats. And so, you could be a pure scientist in one area, but we had to take the work in analytical technologies in particular and help it make sense from a regulatory perspective.

JD: [29:29] And at that time, did you feel pretty confident that this non-live recombinant DNA product would sail through, or were you – were you at all worried that it was going to --

SE: We had --

JD: -- [crosstalk] controversy?

SE: -- based, again, on the other technologies, we had no confidence that it was gonna just sail through.

JD: Okay [laughs].

SE: And that’s why we were still looking at alternate, non-recombinant approaches. Incidentally, if you go back and dig into the history, that’s what actually happened to the ice-minus bacterium. AGS merged with another company, and they basically went back and started deploying native organisms. So, there are a whole series of products called Frostban A, B, C, D, that were ultimately developed from that technology. Snow-making technology derives from that. But all of them came as a result of being non-engineered.

So, we attempted, as kind of a hedge, to have some non-engineered biopesticides that we were developing. So, by no means did we think it was gonna be a slam-dunk. And it – if you think about it, in reality, what you’re trying to do is develop technology. If you grow an organism in a fermenter, you’re trying to develop technology that you could legitimately argue killed everything in that fermenter. And so, if you think about – we had to push the bounds of science.

If you think about the normal way you would think of sterilization or something of that sort, you would have these so-called D log reductions. And six logs of reduction might be

8 interesting and appropriate for your food. But six logs reduction of an organism that’s at 10 th th to the 8 or 10 to the 9 is not sufficient. You’re releasing a lot of still-living organisms, Page

even though you would have met that level. That’s been one of the interesting technologies to watch over time, as people tried to develop the so-called kill switches or auxotrophy approaches that are still being bandied around, today. How do you kill something to this high degree of scientific certitude that’s necessary, to say you’ve done that?

JD: And we – it sounds like we haven’t completely figured that out.

SE: I’d say – well, so, we did, but we used a chemical procedure. And we were able to utilize a lot of enrichment technology and so forth, a lot of statistics, to show that that was happening, as a killed chemical approach. When you think about a genetic kill mechanism that you need to be operating at that high a level, it’s been challenging. Again, I think there’s been some work in 2015, 2016, from some very prominent labs that showed a nice advance. But I have a review paper that came out prior to that, and it showed – or it hinted, it had a nice figure that showed people were working on those kill-switch concepts literally from the early ‘90s. Those were viewed to be as important for bioremediation.

But, again, with the kind of impact that the Frostban issue had, that work began to decline. And so, you had a period of almost a decade where there was very little academic development of high-efficiency kill switches or high-efficiency auxotrophic systems, because there was simply no place for it to go. That has revived. There are new approaches to that. And, in fact, there are companies that exist now, that talk about their – that their basic technology is some sort of a genetic containment or a genetic killing technology. So, again, the idea that, over time, you take a problem, try to dissect it, and then propose solutions, it has spun out solutions, but they’re 20 to 30 years delayed from the early time.

PM: So, you said Mycogen was then, later, acquired by Dow.

SE: Mm-hmm.

PM: [34:02] Is – can you lead us – can you talk about what led up to that acquisition and how things changed at that time?

SE: Sure. So, the acquisition I think formally happened in 1997, and so, what was going on at that time was a massive acquisition of seed companies by agrichemical companies. And so, the recombinant DNA technology in crops had found a path through the regulatory system, both initially the FLAVR SAVR tomato, but then, ultimately, both Roundup Ready and Bt crops. So, the large companies at that time were trying to ascertain a way to make a channel to market, and you needed seed as a channel to market. So, a number of acquisitions were going on. As I indicated, I joined a biotechnology company, Mycogen, but by the mid-‘90s, Mycogen had been acquiring seed companies, just like anyone else.

So, as part of what was then DowElanco’s movement into technologies – and so, I wasn’t inside, at that time. So, I didn’t know their total strategy. But they had – they had begun

9 accumulating seed technologies and other recombinant technologies. So, the Monsantos

of the time, the Bayers of the time, were all trying to piece together technology packages Page

that would allow them to be able to go from beginning to end. So, we were acquired by DowElanco.

I describe acquisition. So, we went from a company – let’s say we were still 1,000-ish or so, at that time, to a much larger company. It’s – it’s very much – to go into a company at that point in time that had tremendous resources, it was very different, as you came from a scrappy, small biotech company. We had to learn new ways of interacting. And projects – what I would say, projects became a much bigger deal. When we were thinking about biopesticides, you could look at market opportunities that were much smaller and so, their development costs were smaller. But a company of that size needed to look at larger and larger opportunities for their investment.

And so, by then, it was very clear that people were gonna be doing, I would call it, traditional agricultural row crops, so, corn and soybean and cotton. And so, we were heavily involved in looking at ways to then take what was a very rich germplasm source that we had, germplasm from the companies we had acquired, but also, then, the genes from our microbial collection. So, figuring out ways to mine those genes from the microbes and put them into the development pipeline was what basically changed for us. We could mine them in very different ways than we could before, but the hurdles to their deployment were a little bit larger, also.

PM: [37:54] So, how was that for you? Was it exciting? Was it frustrating? Did you like the change from the smaller company into the huge company with resources, but you had to do things differently?

SE: So, I described it sometimes as like -- going from a small company to a big company is kinda like water slide. So, the small company’s a water slide, if you think about it. It’s got very little water in it, if you think about that as resources. But you’ve got momentum. You’re always moving. You can’t sit still on the water slide. You hit the pool, and that pool, the water would represent resources there. So, you have an exponential increase in resources. You might or might not have momentum. That depends on the strategy of the company and so forth.

The good news is, what I would say is, DowElanco at the time was – they were trying to be scrappy. They were trying to make some bold moves. And so, it wasn’t like totally going to something with no momentum, but it was different. It was a different kind of momentum. Within Mycogen, I could go talk to the VP of R&D, down the hall. The President of the company was down the hall. We had Friday afternoon get-togethers. And so, you were interacting with essentially everyone in the company, or leadership, at a point in time, weekly. It’s just different in a big company.

So, you have a different level of connectivity to decision makers. So, that, again, is just something that you either learn how to do, or you leave big companies. And I think, you

stay miserable, that wouldn’t be happy. So, you figure it out, or you go somewhere else.

10 JD: [39:56] Who are some of the key people that you worked most closely with, as mentors?

How did you learn to operate in that new environment? Who inspired you? Page

SE: I would say that, overall that one of my mentors from within Mycogen was a guy named Paul Zorner. Paul had been in a number of different biotech companies, large and small, at the time. And he’s still active in that area. What Paul taught me, or reinforced in me, was that you always needed to look around to the people you are with. The people weren’t just badges with numbers on them. They were people. And learning how to interact, find the needs of people, and meet the needs of people, and then, do what you could to address questions or concerns that people have. I think that was very impactful, and it was true, when it was Mycogen, the small company. It was very true when we became larger.

Paul – what was kind of interesting is that Paul left Mycogen but then, came back in another company that had gotten put together in this acquisition mode. And so, we kind of boomeranged back into a company, several years later. The individual who led Dow’s – or DowElanco, and then, Dow AgroSciences’ discovery approach, Bill Kleschick, and Dan Kittle, who was the VP of R&D, those individuals were significant in terms of helping me think about what was important inside a much larger company.

But, again, neither of them ever advised me to take the focus off of other people and become self-focused or, you know, every person for themselves. They were both very generous with their time, with their advice, and with helping people. So, I found that – that those three were probably the biggest in-the-company influences, in my early development.

JD: Mm-hmm. And so, it sounds like you were managing teams of people and needing to think strategically and not just as a scientist.

SE: Yeah. I think – so, one of the interesting roles that I had, when I first became a Fellow, DowElanco, as that merger between Lilly and Dow had said, ‘We need to think about what our corporate culture is going to look like. Are we just gonna be a Lilly culture? Are we just gonna be a Dow culture?’ We wanted to be different. And so, they tried to develop a different – they did develop a different way of thinking about career progressions for scientists and non-scientists, within the company. So, time had elapsed. I had become a Fellow, and I was tasked with revising that career progression.

And so, the tie-in to this is, in a moment, there was a very interesting paper that had come out of a group at MIT, Katz and Allen. And they asked this question, ‘Is the dual ladder, this idea that you would be either a scientist or a manager, is that real? Or is it’, to quote the title, ‘Is it a managerial delusion?’ And so, basically, what they concluded, and they developed the data to show, is that inside technology companies, people tend to want to move in projects. And so, the idea that you would be a project leader, as opposed to just a lab scientist or just a manager, is something that they identified early, and which we found to be true with – within the company.

So, part of being a Fellow was having a deep, technical expertise in multiple arenas. And

11 so, within companies, that – the concept of Fellows really reached a pinnacle within IBM,

within 3M, Intel, and some other places like that. But there was this understanding that Page

took place kind of after the ‘80s, that deep, technical depth needed to have a tie to something outside of the company, whether that something was a tie into product development or a tie into something like regulatory depth or something of that nature.

So, I got to spend time, I think, doing both. I maintained a tie into the science, but I did lead projects, I did lead people, for a period of time. The pure managerial track, I experimented with, but I just found that I really wanted to be influencing people, both their technology, their technical development, but their career development. And so, I got back to a – a happy medium, a blend of that. I would usually have small teams, of five to six, in a project, or either – or at some point, directly reporting to me. And so, I’d say that was the thing that I got to do. The six would change, over time, so I didn’t have a group that would follow me forever.

But I would say, that was something that, being inside a company, I had the flexibility, actually, to explore and to experiment with.

PM: One – oh, one quick detail. [46:03] Where were you based? Where were you living?

SE: So, early – so, when I joined Mycogen, I was at a field research station, don’t ask why, in Ruston, Louisiana.

PM: [laughs]

SE: I quickly, then, moved to Mycogen’s headquarters, which was in San Diego, California. So, I stayed in San Diego, till 2000. I then – that was after the acquisition by DowElanco. I moved to Dow’s headquarters in Indianapolis, and that’s where I’ve been, since then.

PM: Okay. Good. I just – I needed to place you, geographically. [laughs]

SE: Yep.

JD: So, I’m – we probably don’t have time to talk about all the projects that you worked on. [46:42] But what was your favorite project, of that time, that you got to work on or lead?

SE: So, what – I – one of the things that I am most proud of was something that we did in Mycogen. And we did a lot of really cool things, in terms of advancing genetic engineering. But we bought this company called Safer Soap. And so, again, we were trying to develop biopesticides that had a – an ecological or safety profile that was – and Safer made insecticides and fungicides out of fatty acids. And a weed scientist and I got together, and we were thinking about a technology application to try to make herbicides penetrate plants, faster. And so, my technical job was screening. I was setting up a screen. And my – one of my underlying mantras as an analytical scientist is, ‘If I can’t measure something, I can’t systematically exploit it.’

So, I needed some technology to measure herbicide penetration. And we had received

12 this – these fatty acids from our acquisition of Safer Soap, and we began to wonder – I had

developed a radioactive uptake screen. And for whatever reason, at the time, that – one of Page

the molecules actually made a herbicide penetrate, very quickly. And so, we went and started doing some small research plots, outside, in the greenhouse, and then, on our plots. And we ended up doing something that weed scientists said you shouldn’t do. ‘You shouldn’t mix this mode of action with these traditional modes of action’, because the perception was that the fatty acids worked by a general disruption mechanism. And my data simply didn’t make sense, with that general perception.

And so, we did some work. We actually got some very nice data that showed what was going on, contrary to the understanding. We filed a patent on it, got it into the Patent Office a couple of months ahead of Monsanto. And Monsanto had been screening compounds for years, to try to increase the penetration of glyphosate. And our molecule did it, wonderfully. So, in the end, we got a patent. We did some dealing with Monsanto, at the time. We were still trying to be big grow crops. We didn’t have a – say, a turf and ornamental or a homeowner market.

But if you go to the store and get fast-acting Roundup or Rainfast Roundup, it’s got the component in it that we discovered. And so, it was – it was – it had a commercial application. It was looking at something serendipity – that was a serendipity of our screen, but then, not just ignoring a result that didn’t make sense. And again, it was a – kind of an interesting pairing between myself, as an analytical biochemist, and a weed scientist. And so, this idea of innovation happening at technical discipline interfaces, I have found to be true. So, that was something that I really enjoyed. And again, I can go to the store now and see that. I’ll stop with that one.

JD: Okay. [50:28] Did – so, did you continue to interface with regulatory processes, at that phase of your career?

SE: Yes. So, as we moved – one of the things that DowElanco was exploring, at that time, was the use of plant cell cultures to make vaccines. And so, the idea – vaccines, in particular, for animal health, and so, this was an area that’s a lot of interest. Our product concept was to make something that could be administered orally, from a plant tissue culture preparation, so that you could have oral immunity to vaccine – or to diseases of interest.

And so, working with the Department of Agriculture, the USDA is the supervising entity for that. And so, again, we didn’t have – there weren’t, at that time, recombinant vaccines derived from plant tissue cultures. So, DowElanco actually received the first licensure for that. And so, being part of the process that helped do that was something that we worked with. And so, again --

JD: And just – if I can stop you.

SE: -- yeah.

JD: [51:56] What – what was that like? I mean, so, you’re dealing with a new product that this

13 Agency hasn’t approved, yet.

Page

SE: Right.

JD: What was that like, for you, as a scientist?

SE: Well – and so, again, I – what it – I think it boils down to is trying to understand, you’ve got the legal definitions that you’re working through, but then, you have practical needs that both a company would have, that a regulatory authority would have, and that some nebulous third group trying to look at an application or technology might have. And so, you’re spending time, trying to think about what are legitimate needs that need to be developed, what data do you need, to go along with this, to try to demonstrate something, or rule out something. And so, it’s – it’s a puzzle. You’re trying to put together this puzzle, maybe a patchwork of things, that all need to fit together, to make a whole.

That, to me, is the fun of blending kind of what might be a later stage of development. After you’ve found a gene that’s interesting or found something, how do you get it from something that’s a curiosity on your bench into a place where it could have an impact? And that is never as simple as flipping a switch. And so, to me, that’s – that’s the fun. So, I took learnings that we had from trying to get the dead recombinant organizations through. By then, we had a really large group of people inside Dow that had regulatory experience. So, I had a different role than early on, but it was still trying to support and provide information, data.

And then, one of the things that I think is very important is feeding that back into early- stage development, because the things that you learn that become important in a regulatory process, if you apply them early on in your discovery or development phase, can dramatically change your route through that agency.

JD: Mm-hmm. [54:15] And at this time, sort of in a 2000-2010 timeframe, what’s your sense of that kind of public discourse around genetic engineering and agriculture? And did you – were you a kind of casual observer of that? Did you – did you become a participant? What was your sense of it, at that time?

SE: Yeah. So, 2000, 2010’s, an interesting window. So, that’s sort of – the last third of that, I spent in the private – public-private partnership, at SynBERC.

JD: Okay. So, maybe – before that, then. Yeah.

SE: Yeah. So – so, what I would say is that companies at that point in time, large and the few small ones that were still around, were really trying to figure out how – how to change or impact that discourse. The U.S. versus outside the U.S. was very different discussion. One of the things that I appreciated from being within Dow, at that time, Dow AgroSciences, was that there were policy decisions that would say, when we developed a genetically engineered crop, we wouldn’t sell it in markets in which regulatory approvals

were not already developed, due to exports, right?

14 So, we might be registered with the EPA in the U.S., but if you knew the product was

gonna be exported outside the U.S., we would hold off deploying that technology, until Page

we’d secured the regulatory approvals in the countries to which it would be exported. And so, I think that was an example of something. I didn’t develop that, but it was part of the business ethos, at the time, that would – it had a marked impact, because you could sell something two to three years before you would get those approvals.

But I think that’s a thing that – that our company took and learned from something like the Starlink situation. So, if you said, ‘What might Starlink have done?’, that would’ve been a direct outcome, where regulatory fed into business decisions. So, things like that were moving. There is still, I’d say, if you start looking at technology at that point, scientists were increasingly both confused as to what the ultimate, underlying issues were, but then, also, I would say, more receptive and concerned about what the neighbors would think.

Because you would sit there, and by late 2000 or so, the neighborhood discussions, I would say, of what genetic engineering meant, I think, were much more pronounced than they were in the mid-‘80s. And so, you had kind of an interesting blend, especially as a corporate scientist. So, I found that to be interesting.

JD: [57:31] How did you deal with that, talking to your own neighbors about what you did and genetic engineering?

SE: Well, I think, one of the things that I like to do in talking and – is ask questions. I – let’s don’t just start with, ‘I’ll lay out my position. You lay out your position. And then, we just keep duking it out.’ I would try to understand what it is that was the concern behind the question. And so, we’d spend some time trying to dig that out. Sometimes it was a technical issue, but often, it wasn’t technical. And that’s one of the things that I think that scientists have difficulty, maybe generally, doing, is that – that we – it’s much easier or at least maybe comfortable to try to approach all of these questions from a technical perspective.

But that doesn’t – in – that doesn’t allow a lot of space for everything from values, religious objections, political or, you know, ‘I just don’t like companies’ owning patents on whatever’. And so, you could – that’s a different discussion. If you’re throwing safety data at someone who’s concerned about corporate intellectual property, you’re never gonna get together. And so, I would spend time trying to – to understand why. And then, be as open as I could, in explaining what or how would impact a decision inside a company.

PM: [59:10] And what do you think the attitude was, kind of within the industry and within the company, towards these kinds of concerns that people had, that weren’t safety data, that were more into like the values and the religious kind of objections or concerns?

SE: Mm-hmm. What I know that later-staged deployment around the synthetic biology question did, is bring those to the forefront, right? So, if you were in an emerging synthetic biology company, there was – there were already vehicles and framing questions. Even

the National Science Foundation said, to SynBERC, ‘You’re gonna talk about this.’ And so, that was brought to the table earlier in the emerging field of synthetic biology, which ag

15 became wrapped into, at a later point in time. You know, it’s interesting. So, one of the

Page

things that I was doing in preparing for my talk tomorrow, I pulled out a newspaper clipping from – well, it’s not a clipping. Obviously, it’s Google, right? But --

JD: [laughs]

PM: [laughs]

SE: -- using a little bit of a – I think – and it’s from 1990, “New York Times”, a huge “New York Times” article, called “Betting the Farm on Biotech”. And at that point in time, one of the quotes from Monsanto was going, ‘You know, we don’t do a really good job of talking in non-scientific terms to people.’ And there was, even at that point, concerns raised around what was going to happen, environmentally, with the deployment. So, I would say, companies were aware.

We had groups – all companies had some kind of group trying to talk, tell stories. Social media changed, over that period of time, in terms of how you would engage. What I could say that I found encouraging from within Dow was that, for a long period of time -- we had developed a group called the Science Ambassadors. And what the Science Ambassadors did was talk to teachers, talk to students, provide educational materials in and around that state, and to try to bring discussions of biotech, not just push, ‘Here, you need to learn this.’ But, ‘How do we have discussions about biotech, starting as early as elementary or high school?’

So, I think there was – there were varying degrees of engagement. Companies – Dow supported that very heavily. And I’d say, those were my experiences of it.

JD: [1:02:24] So, we wanna ask you, how do you distinguish genetic engineering from synthetic biology? So, as we’re sort of in this moment of your career, as you’re going to SynBERC, and people haven’t been using that word, ‘synthetic biology’, when did you first hear it? How did you understand that? How do you understand that difference, now?

SE: Right. So, I became involved heavily with that, in 2007, 2008. At that point in time, I was kinda new to it. I was basically dropped into this but then, did the thing that I liked to do, which was, go read, and go talk to people. And so, I began tracing the history of the term, and there’s a lot of that, a couple of review articles at that time that traced the history of the term. I like – I don’t have the exact figures. At one point, I had pulled together for a document the various definitions that began to emerge. And there was one place where the definition was, like, 40 words, but it had a asterisk and a footnote to explain it, and the footnote had, like, 150 words in it, right?

JD: [laughs]

SE: And so, it’s one of these things where, because it was somewhat of an emerging field, at

the time, synthetic biology meant what you needed it to mean, for your audience. There were some groups trying to raise venture funding at the time, and so, synthetic biology

16 meant something to them. The NSF group had accepted the definition or a concept that I’ll

simply abstract, which was – again, it was trying to make biology easier to engineer. One Page

of the challenges that I could say that we saw, some large industrial firms were coming to them and going, ‘Well, what you’re talking about doing, we had brute-force done, over a period of time, before – before SynBERC came into being.’

So, what I would say is that, if you look at the terms, now, what – or the practices, now, because we have some companies that were legitimately arguable to be born as synthetic biology companies. They were not a company that then adopted it. Those companies operate differently than a company that might’ve been formed in the ‘90s or the 2000s, around genetic engineering.

JD: [1:05:11] Do you mean from a cultural perspective or from a technical perspective?

SE: I’d say, potentially, both. And again, this idea that – that ethics was baked into part of the early discussion meant that your company – and maybe it’s hard to say, in a sense. But your – some of the more visibly active synthetic biology companies have a very different stance on the environment, have a different stance in terms of how open they are with the technology, not trying to hide it or obscure it, but – but, ‘We do genetic engineering.’ And that is something that was not true, for a period of time. And so, I’d say, that’s a little different. The idea of sharing parts, the sharing of technology, the sharing of things, early in a phase isn’t necessarily a component of companies in the ‘80s or ‘90s.

So, I’m saying, there is a little bit of a different perspective. In the end, to me, the main difference, if I – if I’m gonna say, ‘What differentiates synthetic biology from genetic engineering, to me’, it’s the ability to create things that won’t work, and learn from them. The challenge with – with the early forms of genetic engineering was that the manipulation of the nucleic acids or something was very costly, very time consuming, and so, you spent a lot of time, trying to think carefully about how you would do the constructs. And you might only make two or three or four or five, some number that was relatively small. It’s not that people aren’t thinking, today. They’re simply not having to think about how to do the manipulations.

And so, there was some very interesting work that Chris Voigt put together at one point, where he said, ‘We went and designed a bunch of constructs, a couple of hundred one way, using all of our best rules. And then, we took the design software and threw out many of the constraints, and we made a bunch more.’ And some of those other things that were made, in violation, if you will, of the rules that people thought they had deduced, actually worked very well. And so, what this allows you to do, this is, I think, the engineering part of it, whereas, before, genetic engineering – some authors conclude engineering was a metaphor.

With synthetic biology, they’re allowing engineering to be a real thing. You’re making data, you’re making things, more than you can possibly have done by hand. When coupled with technologies that allow you to analyze those, you can begin to develop data sets and

learnings that let you be more predictable, down the road, with how things are gonna work. So, that, to me, is the practical difference that I see in it, over just quote, unquote, genetic

17 engineering.

Page

JD: Yeah. That’s a – it’s pretty attractive picture that you’re painting. [1:08:37] Have you seen your optimism fulfilled?

SE: So, I’m – I’m easily optimistic. That’s my nature. I was given – you see a problem, the challenge is, how do you approach, dissect, and try to get around the problem. What I would say is that, on the academic side, there’s increasingly well-developed data sets that are coming out. One of the – so, I did a lot of protein engineering. And so, one of the things that I observed over time, something like codon optimization. Codon optimization was always an idiosyncratic art. What you would see was the result of somebody’s project that worked. We have this gene, one gene at a time, it didn’t express, we did X, Y, and Z, and now, it expressed.

And so, what happened is, codon optimization rules develop very idiosyncratically, over time. And so, you would have one rule. Another publication would come out, where this worked. And you would keep adding these rules. Through the NSF, through some large data experiments, people had begun to reanalyze, because they could make more things, what – what is underlying, driving protein expression. So, that’s one example. Synthetic biologists helped begin to demystify rules, from that perspective. What I would say is that there are also companies that have made faster progress in getting to certain milestones that are important in development processes, technology readiness levels, if you will.

The proof will always be in the ultimate pudding, getting something fully deployed, into commercial operation. Those stories are just fewer and further between, right now. There are some things that have been rebranded, if you will, as synthetic biology, over time. But I would say that, if you really count just 2010 or some number like that, 2008 to 2010, where synthetic biology took a very interesting perspective from the conventional biodiversity, things of that sort, if you just take that as the metric, it’s only been, now, a decade.

And biology for all of our interest in making things go fast, biology operates on about a decadal scale. So, we’re only at the point now where we would be seeing real products of synthetic biology, I think, hit commercial development. So, I’m still optimistic that some are actually gonna work, but, just as with in any other, especially biotech thing, we’re gonna see a lot of companies that were hot five years ago, merge, buy out, or collapse.

And the real deployments – and then, the deployments of synthetic biology, into the environment, are only just now starting to happen. There are a couple of companies that have said, ‘We’re a synthetic biology company’, but they’re just now getting to field deployment of things. So, still optimistic.

PM: So, working in a field of emerging technologies, you’ve had a lot of successes. But there must have also been some real challenges, some dark days, some moments that made you rethink what you were doing with your life.

SE: [laughs] Yeah.

18

Page

PM: [1:12:41] Can you talk about – kinda like those moments, and how they shaped what you ended up doing?

SE: So, I’ll – I’ll jump – take one of the questions that was on the sheet. ‘Did you ever think you were gonna be fired?’

PM: [laughs] Yeah.

SE: Okay. And so, the thing – working inside of a company, there’s no such thing as tenure. You’re always on this edge of, ‘What is the next merger?’ Or, ‘What is the next big field trial that didn’t work?’ Or, ‘What might, either through a regulatory or political action, change funding of large projects?’ Because companies work on large projects. So, there’s this -- there’s this tension that one has, in biotech, at least, where you’re sitting here, going, ‘Hmm, I wonder if the next employee meeting will be the pink-slip meeting.’ And so, you would have that, moving on, and waves of technology challenges would bring that up.

On the – I don’t think – I don’t recall being overly concerned, at the technical level, of having down things. In graduate school, the project that I was on, I went for almost 10 months with no positive results, right? And so, that’s one of the things where you would just [inaudible] – but, again, because I like to measure, I – my negative is really a negative. And then, one day, I walked in, and my positive was really positive. And so, the same thing can happen, when you work on hard problems, I think it’s – I think a disposition that can take negative results, if they, then, provide a framework of what to do next is still doable.

Part of – I – this is maybe a little off of the question, but I’ll say, part of my optimism in biotech, despite negative challenges, so – my wife’s a two-time breast cancer survivor. So, in the – 1995, again, when a lot of things were going on, with biotech, my wife was having an experimental chemotherapy treatment. So, personally, that was a down thing. But the only reason that this experimental treatment could happen is because Amgen had developed and had, on the market, a biological molecule, Neupogen, that was available from about 1991. So, that biotech thing is largely responsible – it was responsible for her surviving the treatments, but she’s still here, today.

So, I have this view that technology, over a long cycle, the right things can float to the top. But the challenge with that is that there are a lot of things that are maybe interesting, that just won’t make it. Or they’ll make it, in a very time-delayed fashion. And I would say that’s one of the things that maybe differentiates emerging technologies in biotech from, say, emerging technologies in electronics, right? 30 years is the length of time that it took, whether you agree, conceptually, or not, it took 30 years for the AquaBounty salmon to make it from laboratory to the environment. It took – it’s still 20-some-odd years with Golden Rice.

Again, this is not a question of – there’s legitimate discourse about their – both their

19 societal benefits, or – but 20 years to decide to get to the point, to go, maybe, ‘Can it even

work?’, I think is a challenge to the field. And so, I’d say, those really long timeframes, that Page

are, in part, when you start thinking about microbes, again – that are, in part, delayed because we just don’t have some of the data from – that could’ve been collected over the past 10 to 15 years, that’s a challenge.

On the other hand, new sequencing technologies and new analytical technologies that are coming out of academic labs, national labs, they’re changing how you can look at things in the environment. And so, that will potentially give a way to begin addressing some of the technical questions around genetically modified organisms in the environment, without overtly having to do more genetically modified organism trials. I think they should be being – I think they should be done. I think we should put together ways to get them done, but those technologies simply weren’t available in 1990. So --

JD: [1:17:51] Any roads that you did not take in your career, that were real tempting, or that you have personal regrets?

SE: [laughs] So, I – what I – in thinking about that question, I had – I took cul-de-sacs.

JD: [laughs]

SE: What I did was, I – after grad school, I looked at an academic post-doc at Berkeley, to give me a view of academics. I took a government post-doc with Peoria, and then, I went to a small biotech company. So, I kind of looked at academic, government, and at least baby corporate. I don’t have regrets. The – what I would do today, the environments in all three of those areas are very different today. So, I don’t know how I would approach the scenario, today.

But, right now, I’ve – through going with the small company, got to a big company that got me back, through the public-private partnership engagement, to some very high-quality academic labs, and then, into the discussion and discourse around societal acceptance, I don’t think I could’ve asked for anything more. And I couldn’t have planned it.

JD: [laughs] That’s definitely the case. [1:19:19] Are there – are there controversies that you find yourself in, that sort of went across the science, the regulatory, the public, sort of post- 2008 and later, the last 10, 12 years?

SE: So, I – when I – things that I would say, I’ve been involved with, as a spin-out of SynBERC, both with the Wilson Center, Todd Kuiken, who is here, was at the Wilson Center, at the time. We were involved in a number of approaches to try to anticipate needs, should synthetic biology reach the lab threshold and want to be deployed broadly, in the environment. And so, if you can remember back to 2010 or so, the political environment here was heavily skewed towards biofuels and algal systems were the big thing.

So, through the Wilson Center, through an NSF grant, we were able to pull together

groups that – of diverse interests to begin to examine the way you would re-approach that question, today. You can’t ever just erase the board and start over, but, hopefully, what

20 have we learned? So, I developed some very good friendships with some – some

individuals, at that time. Ended up on a Delphi study with Jennifer, here, all through that. Page

And so, what I would say is, the questions – the topics were different, right? So, gene drives were one of the things that popped out. But just, ‘How would you think about a recombinant – or a synthetic biology derived blue-green algal system, if one of these were to miraculously show up, somewhere?’

But, so, to be able to talk about the technology developers, we had EPA scientists, we had insurers, we had ecologists, we had several different groups that expressed concerns. I got introduced to Chatham House Rule concepts, right? So, I can’t even talk about some of the things or some of the interactions, but I would say that they were good. And so, it doesn’t mean that any of these topics have been solved, but so, I’d say those are new and different from then.

JD: So, I don’t know if I’m skipping ahead too much. But you’ve now left the – you’ve left Corteva, and you’re out on your own. [1:22:28] Tell us a little bit about why that transition. That’s a big move. You’re trying to do something different than you have been, in a sense.

SE: Yes. It is. And I would say – so, the – the name of the – of my little company is Re- Knowvate, Re-, Know-, -Vate. And my idea, there, is to go and take historic knowledge that has been out there, repurpose it. So, that’s the repurpose of knowledge, to change how we innovate today. And so, the aspect that I think I have a way to contribute is to take some of these learnings. Again, I’ve been in or around environmental biotechnology since the mid-1980s, and my role did bridge some degree of science, some degree of interaction with U.S. regulatory agencies, and then, later, through the SynBERC activities, to start to think about some of the societal or other implications.

So, I think I have an ability to sit down, say, especially with the start-up or a smallish company, and help them think through things that I would say are just not always top of mind to an academician. Things about elements of constructs that you just don’t think about, from the lab, but that can have a make-or-break perspective, in how something would be looked at, inside a regulatory agency. And then, to be able to just recapitulate some of the knowledge that’s – that’s hard to find.

I – I love iGEM, the International Genetically Engineered Machines competition, and so, I was spending a lot of time looking back at Frostban and some of the technologies around that. And there was a group from Paris, from France, that in 2017 decided they wanted to rethink both frost and heat protection. But what was really nice about this iGEM team is, they really spent some time digging into the history of this. And so, their report on the history of how the ice-minus bacterium got developed was very good reading. But there was a quote that I thought to be really interesting. And one of the students said, ‘One of the writers of this report was not alive, at the time this happened’, right?

And so, if you think about that, if you’re – if you were a 35-year-old-ish scientist at the time of Asilomar, you’re 80. If you – a post-doc today, the average age of an early post-doc,

they might not have been born at the time that the ice-minus bacterium was being sprayed. And so, what you have, on the one hand, is the chance for a lot of loss of knowledge,

21 right? You’ve got individuals who simply weren’t born or are dying off. The good news is,

is that you have an opportunity to rethink, without being a product of those times. But Page

merging those two together, I think, is something that I could, hopefully, uniquely do, at this period of time. So, try to accelerate people’s rethinking about how – and whether to deploy a synthetic biology solution, for instance, to an environmental problem.

JD: Mm-hmm. So, I think we just have a few kind of big, broad-picture questions for you, and you can answer at these, however you want to. [1:26:39] What do you think has been the most significant moment in the history of genetic engineering in agriculture?

SE: Boom!

JD: [laughs]

SE: I think that there are lots of ways to look at it, but I – I – we’ve mentioned a lot about Frostban. I will go back to Frostban. It was the first genetically engineered entity. By standards these days, it is boring. It was a deletion. But the image of spraying that organism inside a full, protective suit with a respirator, and that not only going from a science community, that image, into the public, has something that I think has been very difficult to overcome. That was unquestionably an agricultural component. People might tend to think of agriculture, now, as recombinant crops. But this died. This killed, at a point, the development of a lot of environmental applications of microbes.

So, what I would say is, it became a watershed moment, such that microbial deployment, in essence, ceased. And the thing that happened after that, the only model that we see, after that, was the deployment of recombinant or transgenic crops. So, that has made the crop a focal point. All of the good and the bad of how that would work moved through crops and, for lots of economic reasons, it only moved through big, large-acreage crops. So, I would say, the cost of that is that we lost a lot of conceptual time about what the microbes might look like.

People are beginning to re-ask those questions, with regard to genetically modified insects or other things. So, going from a giant corn plant, down to an insect, we haven’t gotten all the way back to microbes, yet. But I would say, that’s the thing that really set off a direction that’s taken 30 to 40 years to play out.

PM: [1:29:04] So, considering that you have folks workin’ on their Ph.D.’s, they’re post-docs, right now, who were not born when ice-minus and Frostban and all those things were happening, what would you – what resources would you tell them to go look at, to read, to re-know that event?

SE: So, interestingly, if you – if you – if you will Google hard --

PM: [laughs]

SE: -- I’m gonna tell you to Google hard, you’re at a point where there are a number of the people who were active at that point, are now writing, I would call ‘em – they’re synopses

22 of the history. I just read one that was in a scientific publication, again, looking at the

history of Agrobacterium. How did it develop? How did it move through academics? How Page

did it move in the corporation? And so, understanding that things aren’t simply – things aren’t simply beautiful stories, right? So, going and reading from as many people as you can find, first-person stories of that point in time, I think is important.

And that’s one of the things that I commended – or I commend this little iGEM team for doing. They went back and said, ‘We weren’t alive’, and the next part of that sentence was, ‘So, we went and called Steve Lindow and had a talk with Steve.’ So, I think that’s the other thing, is that, through whatever tools you have, try to engage with individuals at that time. I think the second thing to do, though, is, engage more broadly, because it’s not just the scientists who were impactful at that time. So, figure out how to talk to people outside of your discipline, and engage with them.

So, I think one of the nice things that’s happening now, because of a higher interest in societal impact is that we’re getting stories of those developments through departments of political science or through schools of ethics. Go read something from a religious scholar about genetic engineering, or – so forth. So, I think there are lots of different ways to engage. The important thing is to engage. Just because you have a really cool idea for some little genetic circuit doesn’t mean that it will actually solve the problem that you think it will.

I’d say, that’s one of the interesting stories about Golden Rice, is that there – while there are other solutions to that, there just get to be operational challenges with how rice is grown. Okay? And so, you can have something that might do a really nice job, but if it’s in a genetic background that nobody will use, you don’t have something, yet. And so, just thinking about things that are not part of your discipline, that impact how something’s deployed, means you need friends outside of your peers. So --

JD: [1:32:28] What are your – another broad question. What are your greatest concerns for the future of this technology, and what are your most hopeful future scenarios? So, think about genetic engineering or synthetic biology, if that makes sense.

SE: Mm-hmm. Well, and – so, I – one of the things that I would say about the concern, it’s a little bit of a riff off of the story about my wife and the Neupogen, right? So, the beauty of that story is, at the time something was needed, there was a regulatory scheme in place that had had that material approved, by 1991. So, we went from insulin, in the early ‘80s, to a variety of biomedical products. So, things were in place to get products through a system, in under 10 years, at that point in time.

One of the things that I – that I observe is that a lot of the rules and regulations that we have around genetic engineering were framed around vocabulary, from the ‘70s, out of Asilomar, Coordinated Framework initiation. And they were framed around technologies and words. You know, we talk about cell fusion in the Regulation. Nobody even knows what that means, anymore, right? And there’s a lot of things about splicing, and we don’t –

and so, our regulations, both the real regulations and the application of those regulations, are a little bit anachronistic, in one sense. The actual words are anachronistic. The

23 concepts are probably okay.

Page

But so, one of the things is, is if the rules say, ‘You can’t do some – or if you do something by X, Y, and Z, we’re gonna regulate you.’ As technologies begin to advance, you can go do something, now, that doesn’t use X, Y, and Z. So, my concern is, is that we now can get into a new discourse that says, ‘Well, now, if you don’t do X, Y, and Z, you’re trying to evade oversight.’ So, this concept of evasion, I think, can be a legitimate point. If somebody’s clearly trying to evade, that should be called out. But simply because you don’t have to do something the way that it was envisioned at a point in time doesn’t necessarily mean you’re evading anymore.

So, how can we make sure that we don’t just use easy targets on new technologies? How can we make sure we don’t have the equivalent of the Tyvek suit, today, in words? That – so, that’s my concern, that we will continue to – that we will figure out a new way to take new technologies and paint them, that way.

JD: [1:35:27] And what about your most hopeful scenarios?

SE: [laughs] Well, I am hopeful. I think the idea that I had kicked around, in one sense – so, I’ve got a lot of people who weren’t born at the time. I view something like agriculture, if you think about the – agriculture, the minute you put a seed in the ground, nature’s conspiring to kill that seed. Right? And so, you’d have to be crazy, to want to do that, for a living.

JD: [laughs]

SE: But what that means is that – that farmers need to be, I think -- part of a disposition is this idea that they are very adaptable and malleable. And if you look at, at least domestic, U.S. agriculture, you could say that’s true. They went in and then took whatever they needed, at whatever time of technology, from automation and mechanization to chemicals to not chemicals to whatever you need. So, ag has done a very good job of integrating what it needs. It’s made some mistakes along the way. You figure out how to fix those. So, I think that view of optimism over time will continue to play out, in domestic agriculture, because the need to feed is still gonna be there.

And to flip it around and think that everybody’s gonna turn into a backyard gardener to feed, it’s an interesting thing, but I just don’t know that people are gonna do that. Have your garden. It’s fun. But agriculture, per se, for the U.S., has allowed a very interesting standard of living, from that perspective, to change. The USDA numbers are very intriguing, over – the productivity changes, but the workforce decreases, is probably still gonna happen.

JD: Are you ready for the last two questions, or --

PM: Yeah. Perfect.

JD: -- okay. [1:37:30] We just always ask if there is anyone else that you think that we should

24 interview for this project on genetic engineering in society. Who comes to mind?

Page

SE: So, I would say, there might be three people. There are a lot of people. I don’t know how these three would stack up. One is an individual who is having a retirement party this month. His name is Leonard Katz. Leonard was, in fact, the industrial liaison, kind of as a fifth career, for SynBERC. But Leonard was involved in biotechnology within a pharmaceutical company, a long time ago. So, the development of antibiotics, over time, the movement into recombinant technology and then, the movement into engineering biology, he’s been involved in a lot of that. So – and he’s just retiring, again, this year. And so, if you haven’t talked, he would be an interesting person.

I would be surprised if Jay Keasling isn’t already on the list. If he’s not, he’s interesting, because of his role, both as the principal individual on SynBERC, but his role within pushing genetic technologies. I like individuals like Reshma Shetty or Jason, at Ginkgo, Jason Kelly, at Ginkgo. They’re examples of the individuals who have in essence created a billion-dollar entity, after graduating in, what, 2007, 2008. So, they’re a new generation of scientist entrepreneur. That could be interesting in thinking about this. Pam Silver, at Harvard. Pam’s very thoughtful in the deployment of technologies, and --

JD: You mentioned Reshma Shetty. [1:40:01] Could you say where that person is?

SE: -- she’s at Ginkgo, also.

JD: Oh, she’s at Ginkgo, okay.

SE: And it’s kinda – there’s the trifecta, Tom Knight, who is one of the --

JD: Okay.

SE: -- they – he was their PI. But Tom was an engineer at Sun Microsystems and other places like that and decided to jump into genetic technologies, as a third or so career, while he was at MIT. And he’s considered by many to be one of the foundational thinkers for synthetic biology, at least, which has then moved into genetic engineering. So, in fact, some places have redubbed the decreasing cost of synthesis or the increasing productivity as Knight’s Law, rather than --

JD: [laughs] I heard that.

SE: -- Moore’s Law. So, he’s a very interesting individual. So – and then, Pam, Pam’s involved in not only biomedical work but trying to look at environmental applications. She’s got a very interesting hybrid system for developing energy from a synthetic biology- enabled entity. And so, I think you’ve got just a tremendous number of individuals there, that have had some either academic or industrial impact in an emerging field.

They’re – people like Reshma and Jason are gonna be – they’re the people who are

gonna be around, if you think about it, at a 20-year lifecycle, right? 2040 is when you would start seeing a commercial product, if things stayed kinda the same, for technology

25 that you had right today. And so, thinking about those individuals would be interesting.

Page

PM: [1:41:55] And so, our final question, as always, is there any question you expected us to ask that we didn’t? Any question we should’ve asked you?

SE: [laughs] No, I read through the questions. I thought that they – I thought that they would allow kind of a general framework and then, again, we can pick out something that – a thread to run on. I – I chose to kind of run on Frostban, which might be a little bit of an interesting or a different riff. But that was the thing that I chose to run on. So, I had the opportunity to do that. I think I got to say just about everything -- that I think that I wanted to say.

JD: Great.

PM: Wonderful.

JD: Well, we’re really grateful for you takin’ the time and putting the energy to think about this ahead of time and to talk with us. It’s a real privilege for us to talk to people who’ve been through a history of a technology. I – I came to this field, basically, at around 2000, a little bit before, and already, much had happened. And so, it’s really valuable for you to share your experience and your perspectives, not only with us, but for future people who look at these videos. So, thank you for taking the time.

SE: Okay. Right.

PM: We appreciate it. [1:43:26]

26

Page