Max Hodack gene synthesis Transcripts, Inc.

We're developing virtualization platforms for life sciences. Instead of a wet lab bench, you could develop it in a virtualized facility and get data back. It's mostly just synthesis, and other methods are outsourced. We'll be doing custom assays, and you can do the full life sciences basic research. Right now this is by hand by research orgs and contracts.

We don't have diybio customers, but we have to speculate on how we would handle it. From our perspective biosafety is much bigger in diybio, it's a matter of extreme discipline to prevent accidental release. On the other hand, engineering of organisms is still very complicated, and you guys lack the infrastructure, so we don't see that as a likely risk factor in the next 5 or 10 years, and if people want to set out to cause damage, there are many ways to do that. So we filter all of our orders throug hthe harmonized screening protocol from IGSC. The contractors screen us again.

It's pretty good for screening for basic things, so if someone will order the spanish flu, well, it's easy to break it down by ordering oligos into parts and PCRing that together. It's an improvement from the state in 2007 or 2008 when all the harmonized screen protocols got these ad-hoc databases together.

From the perspective of gene synthesis, this is a relatively new technique. We've been doing molecular cloning since the 1980s. Do you really need gene synthesis to cause something damaging? If you just refuse to ship genes to anyone but professional labs, you're not really controlling the risk surface area. You can order this backbone from AdGene for $50, and you can clone or insert it. There are these agents in nature that you could synthesize that are probably going to be easy to get access to, then what they get from de novo synthesis.

It's almost- almost every method in biology has a "dual use" characteristic. Gene delivery and viral vectors is a very basic method. Most of the capsid coating sequences are not checked for by the harmonized screening protocol. As long as you go domestic, the domestic use it doesn't apply. There's this question of gene regulation. Do you not send viruses to an amateur user? If you don't, then you're excluding this huge range of really basic methods from amateur biologists, and if you don't, then you could do a lot of damage without a designated toxin. There's pressure in how you handle it, but I don't know hwo to handle it yet.

So, our model is centralized virtualization. The idea is that the lab isn't with the customer, and they're controlling it as a direct extension of their hands. It's different from a contracting or outsourcing model where Genscript does it for 6 months, you write them a million dollar check and they give you a drug in a few months. This is for exactly carrying out the protocol at a remote facility. This fits naturally.. enable people to create. But you want to control the distribution of the results.

Now, the costs are still beyond the range of amateur biology. They are expected to fall.

Working with your hands is a core value of DIYbio.. why would you ever send this out? You get an intuitive feel, you build synthetic bacteria.. you can do a lot of that, you can build your growing yogurt, if you want to do amateur professional work, if you are thinking of the transition of the PC revolution, then you want a pathway to ramp up to productive output, and that's what our platform can be used to. It addresses biosecurity to the extent that our customers are screened, but it's unlikely that a nefarious actor would choose to use us anyway.

Biosecurity is a hard problem, but in practice home and amateur labs are going to result in environmental release of ecoli all the time, and I don't know what you can do about this. We need DIYbio, probably more likely, 40k PhDs in life sciences a year, you're more likely to have disgruntled grad students with access, rather than DIYbio... DIYbio has restricted capabilities, that's not profitable, it's not a profitable vector.

Anyone can write protocols to the platform, but we only ship out to professional labs, say you want to do this synthesis or virus, we can deliver the data back in digital form, but we only ship back that data, and not material.

I just want to re-affirm a couple of things. The bad guys, it's a heck of a lot easier than synthesize smallpox. The bad guys aren't going to do this as their first line of attack. The biosafety risks is that- congress reacts especially often to stupid events. One bad safety breach could result in regulating DIYbio immediately.

What's a difference between a startup doing biotech, versus working in biocurious, or me working in a garage lab, and now I'm a professional lab if I file some paperwork? It seems some arbitrary decisions, like if I have been in business for 5 years or something, which then cuts out startups. It is certainly arbitrary right now, down the road, it's going to blur. There's a common sense boundary.. people who have had passed through professional labs on their way to garage labs. Is Biocurious a professional lab? No, only an academic lab or major institution or Gentech or something. Imagine if we found a boom in biotech like we did in the PC revolution, where the order between amateurs/professional gets blurred, then yes it's blurry, it's even beginning now, but it's .. I think today, we can define it as did you pass through a mentorship of a professor. Yes, in the mean time it's a little bit of a limitation.

I want to defend you guys a little bit. I'm wondering if this is a risk/reward question. Are there not enough financial customers from the DIY sector that you're not willing to sell to them at this point, or are you worried about it? The HHS guidelines specifically state that amateurs should be able to order this from the companies. I know they are voluntary, and I know that if you sell something to the wrong person, it's your responsibility, yes.. but the guidelines don't say that. Is this a risk/reward about how much moeny you are going to make on a customer, and whether it's worth taking the risk?

Simon: We make the gene designer software available on the site for free. The HHS guidelines will limit one's restriction on selling to the bad actors on the lists. So for us it's much more about what is the sequence that you are requesting? And are you on an exclusionary list, and not whether you are a professional/amateur because it's very hard, and as the questions have indicated, it's a hard line to draw. It's a commonsense issue, though. If you are asking for 60% of the smallpox genome, no, I'm not going to do that under any circumstance no matter who you are. And if you are on the exclusion list, we're not going to sell you what you asked for. The grey area is evolving, but we don't have, we don't have a wholesale restriction on a class of customer. Now, we do .. they are not-cancelable. So we aren't going to take financial risk in that regard because we can't, as you know, this business becomes decreasingly profitable at the boundaries because it's become commoditized.

These guidelines apply more to the larger ocmpanies than the amateur community. It gives follow-up screening, that a principle user affiliated with a firm or laboratory, then they contact the supervisor or lab director, biosafety officer, and verify legitimacy, also conduct a literature review, ask the customer if they are affiliated to provide references that could start to identify and verify the legitimacy of the order. Even looking at the something statue, .. the justification of use for research or peaceful purposes, so uh, this is guidance. And it's being provided to those gene providers, and I can see how certain companies want to interpret this in a certain way, and it depends on the feelings.

Simon: for those who aren't familiar.. it's a two-tier analysis. First we look at the person and the sequence, and if there are issues of concern and listed, then you are obligated to do a higher level of investigation into the recipient, things like the biosafety officer and looking into the publication, etc.

Ellen: This discussion about the sequences. Is there anyone in this room that has intention of working with a controlled sequence? That's like a given, we're not here for that. That's in 10 years maybe? So I also think that, it's interesting, and I said this to Nathan, the FBI and DIYbio have a common problem which is that people over-estimate our capabilities and under-estimate our ethics constantly. It's funny that in one graph you can see, there's going to be this accident that happens at some point that is harmful, it's not that easy to build something harmful. I did my first genetic engineering experiment in the 1970s in Charlie Hamper's labs, and I've been around cloning and it's not easy, certainly not by piecing it together the old fashion ways. If we're not going to be able to order it from you, it's not that accessible. It's not that hard to teach cloning. I would stack up Sung, who came to our lab 3 years ago, who has been mentored by someone from Harvard, I would put him up against anyone in this country with his ability to do genetic engineering. This sort of arbitrary line with who is a professional and who is an amateur and who is qualified to work with you guys.

Simon: I am in complete agreement with you. Those of you in the DIY community are not ordering dangerous sequences, but the only thing that I do worry about is the potential not for a genetically dangerous substance, but your basic volatile. Some lab accident. You know? Where someone gets hurt through something, the kind of things that do happen in labs. And a bad accident, even a bad kind, nobody can be fully protected against it - we have our protocols in place, and it's not going to protect that from happening. The regulators are looking for an excuse to pounce. That's the impression I'm getting. I'm advocating that you should have a high level of care, and I know nobody wants that.

Nathan: It sounds like representatives from this synthesis community feel comfortable engaging wtih the proactive amateur biology community. This is federal guidance and to help drive the process, but it's not fully clear about how this interface can operate. It makes it more clear with institutions, but how this interaction might work.

Avery: So you guys control 80% of the synthesis market. And you guys also confirm to these guidelines? What about the other 20%? A lot of that work is being done in China.. we're so happy to see at least one of the Chinese foundries present at the meeting in Heidenberg. There are some europeans that are not under this, the 20% is covered by another organization out of Europe, but there are a number of Chinese companies outside of that. The head of BGI came to one of our meetings last year, and they are driving the IC elect or process. I am hoping personally, I am hoping the next step to internationalize that to find personalize that do that, and the US federal guidance, but the principles that underpin it and find a common international agreement, countries in which there are other companies, so that there is a common agreement on the principles.

Carlo: Will the virtualization platform be open source? Well, when you specify the protocol, it's actually performed in the lab. There's a limit to how open source there is. I was talking with Mac Cowell about this. We have a high-level scripting environment for the machinery. We might open source that. One of the interesting things is that you could compile to English or you could write backends for other devices, if you have a liquid handler in a garage or some other little smaller robots, you could have that control that. It's not mature enough yet to release, but when we do, we'll seriously think about open sourcing. On the other end, a lot of it is just logistics and operations. There's, we have these vendors, there's when you send out for oligo synthesis, we have coordination from chippers, and it's not just software. To the extent that we can open source the front-end software.

Max: Do you see the cost of synthesis going down significantly in the last few years, are they spending money in that? Yes, the cost is going down.

Genoblast guy: How come we don't have the biological repositories people represented here? Shouldn't they be involved here? Second thing, is an anecdote, not, I guess a story with the AGCC. I was working with some BSL 2 organisms and to get them from the ATCC, they weren't so much interested in my qualifications, but they wanted to know about my procedures and equipment in place to make sure there wasn't accidental approach. Instead of looking at the qualifications, but the process that is used to ensure the safety. Maybe they can use that?

Simon: I don't think we've ever sold anything that requires a BL 2. Maybe I am wrong.

Nathan: I don't know what we're accomplishing with this talk. It looks like we have some checks in place, and everyone needs to go through those checks regardless of professional or amateur affiliation. And just to, just to bring us back to reality, the definition of profession is a paid occupation, with training and so on. So if I start paying anyone in here, some for instance, maybe doesn't have a degree in GMO, but sounds like it has three years of training, and I give him $5/hour and now he's a professional. This just looks like smoke in the path of progress. Anyone nefarious or otherwise can buy a business for dummies book and figure out how to setup a non-profit in California, to become a registered association, pay the $10 and do some bylaws. I guess I'm not really sure we're accomplishing anything, unless we're talking about what the future of regulation or self-regulation is, just not sure why we'er atlking about this.

Max: When I was asked to speak here, right now DIYbio is sorta small. Nobody thinks you guys are nefarious. What happens if it really explodes and it becomes something different? How do the security implicatinos change? Right now you all know each other, and it's relatively reliable to check each other. But in 10 or 15 years, if you have teenagers growing up with this tech reliably available for low cost, what are the implications of that?

Simon: It was to let you know that if there is a perceived antithapy between the boundarues of the DIYbio community, then yeah, it's just not. There are issues that we all have to look at, we all have to look at, though we have a higher level of scrutiny, and we voluntarily signed on to those protocols and we are a visible player to government regulators and we can be sued. There is no hostile or activity here. If you heard that, then you missed something.

Nathan: Looking forward, what is there? Simon: it's exactly as Max said, you guys are a small community, you're not realy on anyone's radar, you're ... some formal or informal voluntary self-regulation that is visible that you could show people that you've done, that's what we did with the IGS protocol.

Piers: I am an international player to this, as far as I understand it, everything you just said works in this country. I'm not sure it's the same approach that, for example, the only other country that brings to mind is Germany, but we're having a discussion about this. They have a different regulatory approach to what it means to be a scientist. These discussions about professional or amateur, well, professionals are licensed individuals. For a German synthesis company, selling to a German scientist, it's a simple question of whether you have a license or not. If you don't have a license, you're out of luck.

International Association of ...

iasc-something.. there are two Chinese foundries on that. The Chinese foundries that are operating outside of the screening protocols I don't knwo of. Importing materials from places might fall into other regulations should you find it.

If you pull up the HHS guidelines, and you will get the formal names of the exclusion lists.

How do the other labs address training and biosecurity for labs that are open to everyone? It seemed that BioCurious biosafety manual, I think they specify they are BSL1, no human experiments, no human primary cultures or human tissues or things like this. Are there other kinds of guidelines that other things put together.

GMO work in a European work is quite difficult. I have no idea how many labs do this work because of all the other licenses. You have to put all these things into place, so it's about containment, usage, and all those safety procedures are quite serious. I think maybe in the European context you already do take it much more serious, it's much more regulated than in the US.

It's the same in Germany, if you want to establish a safety lab level 1, then you need to have a permit that is reliable, and actually doing teaching for new staff memebrs. Everyone gets there, they take seminar to be able to do any genetic engineering work. I think this is a good idea for community labs too, to not really force them, but they can start working, but within 2 months they need to take a seminar or a day to get teached by the safety person. THere needs to be one person that is reliable for all safety questions, and he/she needs to do this seminar to teach them these things in the lab.

I also know that BIoCurious for example is more stringent about the BSL 1 stuff than in other academic labs for instance. I do see academic labs in my professional life, working with environmental isolates in BSL1, and I see classes being taught to undergrads even working with human microbe data, there's a long list of the human microbiome data list, who would like to be sequenced, and they are isolating human gut organisms in an undergrad class in a BSL1 class, and they destroyed the .. after they extracted the DNA, and at one point you do have an isolate. We're not doing that at biocurious because we're sorta under the radar, we're trying to stik to some of the regulations closer than we necessarily have to.

At Genspace, we have a lot of guidelines. We have liability waivers, we have a safety officer, we give a formal safety course to incoming members, we have a series of lectures that go into that. We also give a tour of the lab and point out all the safety equipment and proper usage of the equipment. This is all very similar to the training that people would get entering a lab in a university. We are a BSL1 lab, there's no formal agency that goes around diong checkmarks, unless you are getting federal funding. It's a type of lab, with types of experiments, which is teh type of experiments you do in the high school environment, so there are NIH guidelines, and there are people that need to be aware, you need to tutor incoming members, you have certain recommended guidelines like having a sink and proper procedures. We adhere to all of that, so those are good steps to put into place for everyone else.

Ellen: I wnat to return to what you said. That really kills me. We had a woman who was at ah igh level of the biosecurity place at the NIH. She taught a human microbe class at Penn State where she had people swabbing mouths and putting it on a petri dish. So it's really confusing for us for what the safety guidelines actually are. If someone is only working with their own cheek cells, and the samples will be destroyed soon, and we have a professional service take away the biowaste. But we don't do that with the solid cultures, we put them into one of the orange bags, and someone takes it away and incinerates it in a regulated way. We had a professor from a community college who wanted to do phage hunting, they would dig up soil and culture some bacteriophages from the soil. This is called FiRE, so there are lots of high school experiments that you're not doing at BioCurious, so that seems like a really odd disconnect. I don't know what to do with that. We do a few of those things at Genspace that might be considered on the line. But the K-12 biological kits from Carolina are no gloves no eyewear, I don't know what to do about this. Use your best judgement. The other thing to reassure people is the two biggest things: first what do you do with your waste, and two what do you do about knowing which projects? If you have a science advisory board, then with your qualifications you would very rarely need to go tot he board, the fact that you have one gives people the warm fuzzy feeling that you are operating safer. That's the best advice that I can give. Just encourage people to not work alone in the lab, that's a given. We're lucky, because we're on a floor with a lot of people, either Genspace people are there or not.

Do Genspace or Biocurious have general liability insurance? Uh.. we've been struggilng with that at Genspace. We're trying to get that insurance. The minute yuo mention students and laboratories they run screaming in the other direction. Eventually we will get it. I will let Joe answer that for Biocurious. Yeah, I had a bunch of calls about this. Eventually we found someone and wrote a policy. We went through 30 questions that we had to do, but it was pretty standard, like, just in case the place burns down, that type of insurance policy. There are a few things. There's also a directors/officers insurance in California, or anywhere, because you are personally liable in California. You can kinda finesse it. We didn't know the amounts of chemicals that we can have on campus, so we just answered some numbers. They will eventually write the policy. Don't freak them out talking about biohacking, pitch it about - finesse the way we present that.

Can you list those Chinese companies?