TRANSCRIPT: Meeting 2, Session 7

Amy Gutmann:

So we are going to take a deep dive now into biosecurity and biosafety. And we have three terrific experts to join us for these purposes. We’ll begin with David Relman. David is an Associate Professor of Medicine as well as Microbiology and Immunology at Stanford University. He’s a member of the National Science Advisory Board for Biosecurity. And he was co-chair of the National Academy of Sciences’ 2006 Committee on Advances in Technology and the Prevention of their Application to the Next Generation Biowarfare Agents--I said that in one breath. Dr. Relman also is a member of the Institute of Medicine’s Forum on Microbial Threats, and he advises several US government agencies on matters related to the nature of present and future biological threats. Welcome, Dr. Relman.

 

David Relman:

Thank you. It’s a pleasure and an honor to join you. I have to say that my high-school biology days began here on the Penn campus only blocks from here when I did my senior biology research project. It was hardly do?it?yourself but similarly inspired.

 

Amy Gutmann:

But it launched you.

 

David Relman:

It launched me.

 

Amy Gutmann:

That’s great.

 

David Relman:

I’m going to focus on comments largely on biosecurity issues, but I have to say that I do so somewhat reluctantly in part because I’m a clinician and I would like to think that most people wish to do the right thing and often do so, and yet I think I’m also realistic enough to know that that doesn’t always happen and that in some ways mindful attentiveness to the possibilities of what could happen are as important as anything else. So the outline of my comments is the following: A few very brief comments about the life sciences landscape, although I now know that you have heard and thought about this to a great degree. I’m going to make a few comments about what is synthetic biology, and I want to offer perhaps a broader definition than might have been discussed here and I think that may be important, and then concentrate most of my comments on the basis of the experiences that I have had as a member of the NSABB where, as you mentioned, I chair the Synthetic Biology Working Group and I’ll review for you some of the efforts that we have made to date for addressing and minimizing risks. Sorry if I keep looking off to the side of you at these screens.

 

Amy Gutmann:

No, that’s okay.

 

David Relman:

So the landscape I think is now somewhat apparent to all of you, and I just want to make a few simple observations about it. I think the only thing that we can be confident about today is that we should not be confident about what this landscape will look like in a year’s time or certainly five years’ time. This is yet another example of how biology and the inspiration that comes from the life sciences permeates our society.

 

Many of our high-school and pre?high-school students are thinking about processes and goals in the life sciences in a way that none of us did just maybe a few years ago in some cases and more in other cases.

 

I will note ?? and I don’t think this pointer is going to show well ?? but this particular kit does suggest itself to be ideal for the budding forensic scientist or secret agent, so just as a note.

 

[AUDIENCE LAUGHTER]

 

I don’t mean to be flip about this, and there are many ways of viewing a slide like this or the point. One is the packaging of biology and its accessibility, but just again the diversity of places and people and quests and goals and motivations for getting involved.

 

You also alluded to this study, and I just want to highlight a few of the findings. This is now four years ago, but I think these findings are appropriate today. We found after enjoying many, many months of thinking and talking about where the life sciences are headed and the great opportunities that there are for benefit, we also, of course, realize that there are opportunities for misuse and the potential for deliberate harm. We recognize that the science and technology is widely dispersed. It’s literally global in many ways although in different forms and shapes. And, again, we can anticipate some of the developments but not others.

 

One of the important conclusions that I will come to on my last slide is the importance of returning to all of the questions that we will talk about and you have talked about here yesterday and today on a recurring basis, there is no way that one can answer these issues at a setting at a given point in time with any kind of likelihood of explaining the future.

 

There is one other aspect of the life sciences that I suggested in my opening comment, which is that synthetic biology is really one piece of a landscape of technology and capability that is in many ways complementary and synergistic. But one should not think that synthetic biology as some might describe it is the only story here or the only place in which one needs to think about where benefits and risks may lie. We on this committee four years ago realized that there are many technologies dedicated to the acquisition or generation of novel diversity.

 

DNA shuffling -- and I will show you a few slides quickly about what that’s about.

 

Directed design of which synthetic biology may be one example but only one. There are other ways of designing biologic systems. Third, efforts to understand biologic systems. Now these may be in many ways very simple and rudimentary at the present time but they, too, feed into and play off of each of these others efforts and technology areas. And then finally production, packaging, and delivery.

 

So when you begin to think about synthetic biology, we need to realize that there is a history into which it fits and a number of other kinds of science and technology that must be viewed as a part of the same landscape. This is a paper from now 15 years ago illustrating what has now become a quite simple procedure for expressing live virus from DNA. In this case it was not synthetic DNA, but you understand the connection.

 

I mentioned DNA shuffling or directed molecular evolution. Again, this is one of these pieces of the landscape today that emerged maybe a decade or more ago. It’s a way of generating an amazing amount of genetic diversity in the laboratory starting from a family of somewhat related sequences. In many ways, this is also synergistic with efforts in synthetic biology. This was a paper from one of the originators of this technology, Pim Stemmer, who showed that one could evolve interleukin-12, an important human immune system regulatory factor, in a way that hadn’t been previously even guessed. And it’s perhaps an unfortunate term here, but he called it evolved IL?12 (EVIL-12), something that might have been a flag.

 

Today this technology moves on. Again, it’s merged with other kinds of genetic engineering techniques. From this campus and others, one sees viruses with new tropisms, viruses with new features that have many important beneficial properties associated with them. But you begin to understand we are tinkering in many different kinds of ways with life organisms that could potentially yield some problems and potential threats. So Gregory Benford has called this the biological century -- unimaginable capabilities, untold benefits, unforeseen issues, and unavoidable risks.

 

And so the rest of my comments will be dedicated to a few of these strategies for mitigating the risks, in particular, raising awareness, education, norms, guidelines.

 

A few very brief words about synthetic biology, and this is now based on the comments that I have just made. Some in practical terms would refer to synthetic biology as the process of what is really resynthesizing a life form whose blueprint is known to us. And, of course, this is relevant to the recent paper by Craig Venter.

 

Some would include this genetic engineering feature that I’ve been alluding to in these last few slides. So plus or minus means we’re modifying a life form. Others -- and this is in particular embraced by those that you heard earlier this morning -- would take the bottom?up approach in describing their science and talked about novel design based on modules that are brought together from sort of first principles. All of these are relevant and no one of these is "the" definition alone.

 

So where are the risks? Well, one would have to say it’s a time?dependent question.

 

Today, in my estimation, I think we would all probably agree that most of the risks from work in this broad area are from the resynthesis of known organisms with known properties plus modification, which again we know how to do quite well and which can lead to properties, phenotypes, that we have some means of predicting.

 

Where might the risks be at a later point in time? That is where I think the novel design and the kind of science you heard about this morning may begin to pose questions and potential risks.

 

So some words about the National Science Advisory Board for Biosecurity. Amy Patterson was here in July or you were with her in July. I know that she described this, so I’ll just highlight a few features here on this one slide. The purpose of this board is to advise on strategies for mitigating the potential for misuse or dual-use biological research. It operates on the basis of an understanding with what are now I think about 15 US government departments and agencies that have a role, a vested interest, in the life sciences. I think you know some about the structure of this board, and so I will leave it at that. I’m happy to discuss it more.

 

We early on grappled with the challenge of trying to describe what it is we are concerned about because, of course, one could argue that almost everything in the life sciences is of dual use. So we came up with this definition, and it’s somewhat convoluted and hard to say in one breath. It took us about a year to write this, I will have to say, and I will just point out a couple of words in that middle line there.

 

We talk about research that can be directly misapplied by others. We realize that to think about what might pose a risk a year from now or five years from now is so difficult or what might pose a risk when misused by someone who then has spoken to the first person to have contact with work; in other words, an indirect misapplication. Those are scenarios that are almost impossible to think about in real terms. And so we attempted to refine and confine what it is that we would talk about and be concerned about words like those, but we realized that it’s in some ways arbitrary and vague and may be missing the boat on other aspects of this problem.

 

We have formed multiple working groups. The one that I’ll tell you about is the synthetic genomics or synthetic biology working groups. We have gone by both of those two names, so pardon me if I use them both. We had two phases to the charge given to us.

 

Phase 1 was to examine the potential biosecurity concerns raised by the synthesis of select agents. This was meant to be a very concrete specific charge, to address what was viewed as the possible problem with the adequacy of our current regulatory scheme, the select agent regulations. This was our first phase of work. It concluded with a report that was released in December of 2006. I think you have it or certainly have access to it, and I will take you through the recommendations from that.

 

Phase 2 concluded just earlier this year. It was last fall really. And that was a broader charge which was to look at the potential dual?use concerns that may arise from work in the much larger field of synthetic biology, and we had a number of workshops for each of these phases of our efforts. In the case of Phase 2, workshops that were dedicated to exploring the definitions of what the science might be, the viewpoints of those who practiced various aspects of this science, and then an exploration of how well one can really predict the kinds of outcomes from work in this area, and I will return to those points.

 

Here are the working group members. I won’t dwell on this. We have a Penn faculty member here, Harvey Rubin.

 

This is the first report, December 2006. Recommendation 1, very simple. We thought that we would start with the easiest kind of suggestion, and that would be to essentially harmonize the guidance that we saw in the extant regulatory world as of 2006 which at that time had some very discrepant and almost contradictory kinds of terms and suggestive language. So this was the first recommendation. It was embraced by the two major governmental entities that orchestrate the select agent program: the CDC and APHIS or HHS and USDA. And I think it’s fair to say that these have been addressed in a very productive manner.

 

Recommendation 2 was a standards and practices-oriented recommendation, but it focused on the importance of trying to understand what are the sequences that are being made by our major providers, realizing that we can’t hope to address all of the local more highly distributed efforts in synthetic oligo production.

 

So for the sake of trying to address the problem of the select agents, we simply said basically, providers should be aware if they are synthesizing a large portion ?? certainly the entirety -- of what is a select agent, especially if that nucleic acid is easily expressed as the live agent. It only makes sense that they should at least know that, and the providers should be aware of what they are asking for if they are not already, and everyone should have some sense and awareness of this kind of activity.

 

This was the recommendation that led to the federal guidance proposal that you’ve read in the Federal Register. There was also a proposal to think about whether this should be a requirement or a guideline and suggestion. And we ended up deciding as a group that it might make sense to require at least federal grantees and contractors to order from providers that follow what might then be the government’s guidance about how to do this the best possible way. There are other takes on this, of course.

 

We also recognized that this industry is a global enterprise, as you know, and it would only make sense to do this in an international dialogue kind of setting. But we, of course, then realized very quickly that when you’re talking about suggesting to people that they recognize that they are making Organism A or its genome, you begin to have a problem with a definition.

 

What is it that when mean when we speak about variola virus, smallpox virus, or any of the other select agents? Traditionally we have relied upon a taxonomy, a name, a nomenclature. But, in fact, the whole idea behind synthesis and engineering is to explore diversity, diversity to a degree that may now stray beyond what you might think to be the bounds of defining something as A. And we realize, of course, there is a big challenge here. We don’t yet know exactly how a specific sequence can be translated into an organism of a known property. So we suggested that this might be an area that is in need of further explanation and study, and you will hear in a moment about that.

 

There is already a problem though with trying to use a poorly?thought?out definition of an organism. This is existing US code which has a definition for the smallpox virus which includes any virus with more than 85 percent sequence similarity to smallpox. It turns out there are a lot of much more benign poxviruses out there that would fit this definition, so we have a little recommendation about this as well. But this is just an example.

 

You have seen this Register item. I will just offer a few observations about it. I think we -- and I, in particular -- view this as a useful starting point, but it is certainly not the last word as you know. There are a number of technical issues with the particular terms and definitions that have been used. 200 base pairs is in some ways very arbitrary and almost subsumed by where technology is today for assembling smaller pieces in one’s own laboratory. If not today, then sometime soon.

 

How one defines what is a match is again a very important issue. Some view it as a minor detail, and it was in some ways swept to the side in will-be-figured-out-later mode. But it’s exceedingly important because of the potential harm that one can do to the beneficial scientific enterprise if one starts to have a lot of false positive hits.

 

There is also, I think, an unwarranted sense that we understand what our pathogenic sequence is. We don’t really. There are some, of course, that encode toxins that are sufficient on their own to cause disease, but they are quite rare. Most sequences can’t be easily defined. And it’s really the context in which they’re expressed that’s the important point.

 

I won’t take you through this except to simply suggest that there are a number of papers now in the literature where, one, scientists thought they knew what we were going to get when they put a gene into a new context. This is a fungal toxin gene into a benign fungus. They thought they knew what the result would be. The result was a fungus that was lethal for tomato and tobacco, and that was not the stated purpose of the project.

 

Again, a knock?out experiment in Mycobacterium tuberculosis. They expected that it would be an attenuated strain. Instead, even based on the best available science, it turned out unexpectedly that the resulting mutants were hyper virulent. That’s because the gene sequences turn out to be attenuating sequences in Mycobacterium tuberculosis.

 

Okay. The last few recommendations, and I will end. Three was to essentially deal with some extant law and regulation, and these have been addressed although I have to say number one received partial attention and is now the subject of revision or at least better instruction.

 

Biosafety has been addressed now by the NIH now through the RAC, and I think Amy Patterson told you about those efforts. I don’t want to spend time on that.

 

The last recommendation was to explore how well today and how well in the future we might be able to predict the properties of an organism if all we have are its sequence or the properties associated with a bit of DNA if we have a sequence. And this was then the subject of a National Academy study whose report was released this summer in prepublication form and the findings were these.

 

A sequence-based prediction of, in this case, select agent properties is not currently feasible nor will it be in their view in the foreseeable future. However, one could classify on the basis of sequence features and perhaps this could be useful. But this committee was not sure it should be developed for fear that the effort might harm the science that we need dedicated to these and other biologic agents. So it’s somewhat of a nebulous ending to that study.

 

And my final bit here is the last part of our charge which was this report on synthetic biology that came out this spring. Here are the four recommendations. You may not be able to read them, but the simple point is that we felt that synthetic biology at least currently is adequately covered by the oversight system that we, the National Science Advisory Board, have suggested to the US government as a means of promoting oversight and awareness of all emerging and potentially threatening science ?? well, science isn’t threatening, but the information has the potential.

 

We did see, though, the need for further outreach and embracing of communities some of which you have heard about this morning, others of which cannot be at this table because we haven’t adequately defined who they are, where they are, and what their motivations and purposes might be. But outreach and organization is the main point of this report. And, finally, the importance of ongoing tech-watch. And I just want to end this last slide.

 

Amy Gutmann:

You’ve got to stop. Okay?

 

David Relman:

okay.

 

Amy Gutmann:

We can ask you about looking forward, but we just won’t have time for questions and comments otherwise. Thank you very much.

 

Damon Terrill is Senior Vice President and General Counsel for International Legal and Regulatory Affairs at Integrated DNA Technologies, one of the leading US-based gene synthesis companies. He is here today also representing the International Gene Synthesis Consortium, the primary mission of which is to promote safety and security in the field of synthetic biology. Mr. Terrill, we are happy to have you with us. We would love to hear what you have to say.

 

Damon Terrill:

Thank you. Good morning, Chairperson Gutmann and Vice Chair Wagner and to all assembled. My name is Damon Terrill, and I’m with Integrated DNA Technologies or IDT. I’m IDT’s General Counsel for International Affairs and also coordinate its work on biosecurity matters relating to gene synthesis.

 

Joining me is my colleague, Dr. Ralf Wagner, the CEO and Chief Scientific Officer of GENEART. GENEART works with IDT and other member companies of the International Gene Synthesis Consortium or IGC -- much easier to say. On this collective behalf, we both appear here today. I speak for all of them when I thank the commission for affording us the opportunity to introduce you to the work our companies are doing to promote biosafety and biosecurity in commercial gene synthesis.

 

I’ll begin with what I hope will be a useful summary of how and why our companies -- competitors when in pursuit of our commercial missions -- came to cooperate and collaborate in pursuit of a common public interest; namely, protecting safety and national security while promoting the beneficial application of gene synthesis, a technology fundamental to synthetic biology.

 

In September 2009, five of the world’s leading gene synthesis companies came together to form the IGSC. I’m missing a slide, but that’s okay. As the use of synthetic genes in bioresearch grew dramatically in the first decade of the new century, Blue Heron Biotechnology, DNA2.0, GENEART, GenScript, and Integrated DNA Technologies had each developed our own systems to prevent the potential misuse of genes and each contributed actively to the public discussion of how best to promote biosecurity.

 

The IGSC member companies had then and share now two primary goals. First, we knew that a common protocol to screen both the sequences of synthetic gene orders and the customers who placed them would help us all to ensure that people who obtained genes from us with related to potentially dangerous organisms are both engaged in beneficial research and have a legitimate need to use them.

 

Our commitment has been to establish and put in place that protocol and over time to improve it as the technology evolves. Second, the IGSC member companies committed to devote their common resources to working with governments and others concerned to promote the beneficial application of gene synthesis technology and to safeguard biosecurity.

 

We shared the belief that the broadest possible understanding and adoption of biosecurity practices among synthetic gene providers would most directly advance those objectives. And it’s this second charge that brings us here today.

 

Some additional background will help the commission to understand how exactly we have acted to advance the biosecurity agenda in the past and what the IGSC member companies are doing now to ensure the safe exploration of all that synthetic biology has to offer.

 

There is the slide we were missing. Those are the five companies involved.

 

Even before the 2006 publication by the NSABB of its report, Addressing Biosecurity Concerns Related to the Synthesis of Select Agents, the IGSC member companies then engaged in gene synthesis were using sequence and customer screening methods to identify potentially hazardous genes and to limit their sales to customers able to safely work with them and legitimately.

 

As the NSABB report suggested, however, and as the use of synthetic genes and biomedical and other research expanded, it had by then become clear to the academic, regulatory, law enforcement, and gene synthesis communities that the risks associated with the potential misuse of synthetic genes, however latent or theoretical, required systematic evaluation and eventually a framework for practices by both producers and users of synthetic genes that would limit those risks.

 

From then to the present day, the IGSC member companies have played a leading role in that evaluative process working closely with our colleagues in government, private industry, and academia.

 

In general terms, the IGSC member companies’ contributions took three concrete forms.

 

First, our members participated actively in the discussion of the available policy changes most likely to achieve real gains in biosecurity. That policy discussion took place over more than four years in a variety of fora including, for example, in panel meetings hosted by AAAS, by the US federal government, and perhaps most notably by the group that produced the options for governance report including MIT, CSIS, and the Venter Institute.

 

That policy conversation involved the broadest possible collection of stakeholders of whom commercial gene providers were only one producing a rich literature on which lawmakers and regulators have been and will be able to draw as they consider the most promising policy choices. We’ve been pleased to contribute to that body of knowledge as we could, and we look forward to helping it keep up with changes to the industry and in technology over time.

 

Second, the IGSC member companies have collaborated to engage together with the US government agencies, in particular the Department of Health and Human Services responsible for drafting the screen and framework guidance for synthetic double-stranded DNA providers. As it happened, our collective engagement in that process contributed significantly to bringing the member companies together within the IGSC to welcome the publication of the draft guidance and continue to support its final adoption. Each of us has committed to incorporating that final guidance spilling into our sequence and screening practices including insofar as it may suggest changes or improvements to our current practices as they are reflected in the IGSC’s harmonized protocol, which I will describe in a moment.

 

Finally, the IGSC member companies have worked closely with federal law enforcement, most especially with the Federal Bureau of Investigation, as it developed its pilot program for reporting by gene synthesis companies of problematic orders. Two of our companies, Blue Heron and my own IDT, hosted agents from the FBI for visits to our facilities and meetings with our managerial and scientific staff. Those visits were extraordinarily useful to us as we learned how law enforcement approached the subject. We’ve been told they also helped the FBI better to understand the technology and reality of how synthetic genes are ordered, produced, and distributed around the country and throughout the world.

 

The concrete result is that each of us knows exactly whom to contact and how within the FBI should our customer and sequence screening ever produce significant concern about a particular order or prospective customer. We have confidence, too, that the agents with whom we would speak in that event are well informed of the issues surrounding biosecurity and synthetic genes and could respond appropriately.

 

I am pleased to report that so far our companies have had occasion to take advantage of the FBI’s readiness in that regard in only a very few instances. And Dr. Wagner may describe similar notification procedures in place in Europe. The FBI deserves credit in another respect. While Blue Heron, DNA2.0, and GENEART, GenScript and IDT were all participating in the FBI’s conference in San Francisco in the fall of 2009, it became clear that we should combine our theretofore individual efforts at effective sequence and customer screening.

 

We agreed then what seems almost obvious in retrospect that by taking advantage of the IT resources we each deploy, by sharing our experience with customer screening, and by collaborating to refine how we identify potential matches of ordered gene sequences against the various databases of pathogens sequences, we could simultaneously benefit from the economies of shared work while improving the end result for safety and security in the industry.

 

Together the five IGSC member companies account for roughly 80 percent of the commercial gene synthesis capacity globally. We complete vigorously against one and the rest of the industry for the opportunity to provide the genes to the scientists who need them. We absolutely do not compete for the business of customers who would misuse synthetic genes and we all have an especially acute interest in common with law enforcement, our governments, and with the public at large to do all we can to prevent the misuse of this vitally important technology.

 

The first result of that shared interest and of the work among us that has followed is the Harmonized Screening Protocol or more precisely the harmonized sequence and customer screening practices that the protocol describes.

 

The IGSC announced that the member companies had adopted and were applying the protocol almost exactly a year ago on November 19, 2009. In it, the IGSC member companies describe for all to see how we each apply the protocols’ five core components to promote the safe synthesis and sale of synthetic genes.

 

First, the screening of the complete DNA sequence of every synthesis gene of every order against a regulated pathogen database developed by the IGSC and one or more of the internationally coordinated sequenced reference data banks and for orders originate in the United States against the US select agent’s list.

 

Second, the screening of each potential gene synthesis customer to establish identity and clearance for delivery of genes in accordance with national guidelines.

 

Third, all of the IGSC member companies keep all screening, customer, and order records for at least eight years.

 

Fourth, the IGSC member companies reserve the right to refuse to fill any order and to notify authorities -- mostly notably in the US, the FBI -- upon identifying potentially problematic orders.

 

And, finally, the IGSC member companies, of course, comply with all applicable laws and regulations involving synthesis, possession, sale, transport, export and import of gene synthesis and other products.

 

So what’s next? As we made clear when we announced the harmonized protocol, its launch was not an end but rather a beginning. It marked the first step of a process of collaboration amongst our member companies that will continue with others in the industry, with our customers in the academic, government, and private sectors, and with the regulatory and law enforcement communities whose job it is to ensure the safety and security of the public.

 

For ourselves, we are at work now to improve our own sequence screening methods and to adapt them to growing order volumes and increasing complexity. In particular, we face the challenge of developing we hope with the support of others within and outside government sequence databases designed specifically for sequence screening and the software needed to perform that screening more effectively.

 

In addition to whatever recommendations the commission may make, our first opportunity to engage with the regulatory community an eye to the future will likely come as we implement the US government’s final screening guidance and to incorporate its detail into our own Harmonized Screening Protocol.

 

Specifically we believe that the US and other governments ought to consider seriously supporting a centrally curated database of problematic gene sequences for use by gene providers who must screen their orders. Such a database would need to be designed for use in sequence screening and maintained to incorporate new sequences as they become known.

 

The US and other governments might also choose to require verification of best sequence and customer screening practices as a condition of the use of public funds for research purposes of synthetic genes.

 

Finally, governments should evaluate whether public funding of independently developed gene sequence screening software could encourage its ready availability for companies and others who could put it to legitimate use.

 

For more discussions on those issues in an international context and to describe in greater deal the vitally important uses and applications of synthetic genes, I give the floor to my colleague, Dr. Ralf Wagner of GENEART. Thank you very much.

 

Amy Gutmann:

Well, Damon, you’ve done your job and my job at the same time. Ralf Wagner, welcome. You’ve been introduced.

 

Ralf Wagner:

Okay. I assume why we’re here, to have a balanced discussion to take advantage of the opportunities and at the same time to minimize the risk.

 

The gene synthesis industry as you’ve heard is just a subfraction of the syn-bio industry. Nevertheless, it is a big part of the syn-bio industry where we really have solid numbers where we can measure developments based on figures, and I would like starting to give you a few of those figures.

 

How many companies, gene synthesis companies, do we --

 

Amy Gutmann:

Pull the microphone a little closer, the microphone.

 

Ralf Wagner:

Is that okay?

 

Amy Gutmann:

Yeah.

 

Ralf Wagner:

Okay?

 

Amy Gutmann:

Yeah.

 

Ralf Wagner:

Okay. In numbers, how many gene synthesis companies do we have worldwide? I think the five biggest gene synthesis companies worldwide are organized in the International Gene Synthesis Consortium. But there is a few, many two hands full, maybe more, smaller companies worldwide. Most of these companies have been founded during the last ten years.

 

Our estimate, IGSC estimate, is that around about 700 or 800 colleagues are working in the gene synthesis industry which is a highly interdisciplinary exercise, if you do that on a large scale. "Large scale" means synthesizing several hundred or thousands of genes per month.

 

These companies are located, primarily the big five at least, in the United States and the European Union, but there are others in China and Australia and it is obviously an international business.

 

The gene synthesis companies taken together today have a capacity to synthesize about 7, 8, up to 10 million base pairs per month, and this volume is more or less covering around 80 percent according to our estimate by the IGSC member companies.

 

The size of the current market has a volume of estimated 75 to 100 million US dollars annual sales with a dramatically strong growth over the last couple of years.

 

And as we’ve heard also during this meeting, gene synthesis as part of synthetic biology has the potential to revolutionize genetic engineering as a first step and the platform technology or is considered the platform technology for syn bio applications.

 

Who are the customers today? Today, the customers are pharmaceutical companies, chemical companies for GENEART and represent about 36 percent of the revenues being generated; the biotech industry, about 33 percent of the revenues; and universities and public institutions around about 30 percent of the revenues.

 

But with the customers with the genes provided by the gene synthesis companies, synthetic genes are mandatory today, I have to say, for vaccine development, for the development and production of antibody-based drugs, cytokines, chemokines, hormones, detergent additives, fine chemicals, genetically engineered material to produce biofuels, environmental remediation, and small molecule drugs, and so on and so forth.

 

The customer benefits are many?fold. There is a relatively quick access to a certified source of a gene, immediate access to physical clone, free design, accelerated research and development, reduced production costs and at the same time providing capabilities to improve product properties.

 

A few projects just to name them quickly which might be of public interest that have been done by the gene synthesis companies in the last couple of years. The Mammalian Gene Collection has been completed for the NIH and for the NCI. All human genes are available, optimized for expression in bacteria and in mammalian cells; genes involved in hereditary and infectious diseases for research purposes and development purposes have been made available. The complete human mutanome, kinasome, and secretome has been synthesized, quality controlled, and provided to big pharma companies. Antibody display libraries have been leveraged to a high level which allowed the development of antibody diagnostics and vaccines. Bacterial genomes, as we’ve discussed, have been synthesized. The flu genes for vaccine development have been developed on very, very short notice in record time in just three days to pharmaceutical companies to boost and accelerate the research. And there is certainly a whole bunch of more very, very important projects that have been done.

 

So this is speaking for the potential of the gene synthesis industry. Of course, there are risks and it’s in our key interest to minimize the risks and to be cooperative here as good as we can.

 

We have established several layers of screening. First of all, to distinguish, biosafety and biosecurity are two different topics.

 

Regarding biosecurity, customers are being checked. There is a country check, and we do a sequence check and we do that, as I said, on several thousand genes that are being synthesized per month. This requires certainly a degree of automation. Nevertheless, there is in our company, for example, nine Ph.D.’s working on the screening process and on the development of software tools we have.

 

In Europe and also in the United States, there are customs regulations. There is export control. We have to document whatever we do. I can from Germany we have surprise visits were offices without prior announcements knock on the door, require an office, require a computer, and they stay in the company for as long as three weeks and check every e?mail, if necessary, So, in reality, I can tell you that happens.

 

The next slide shows it in more detail, and I don’t want to guide you through the scheme but just to show you there is highly sophisticated software tools already available amongst the gene synthesis companies where sequences on a protein level, on a sequence level are very, very carefully screened, and we receive hits. The hits are compared to black lists, to white lists, and it’s not just an expert software. It also has a user?friendly interface service with very clear?cut results so that you’re pretty sure that, based on the standards we have set, that we are able to appropriately judge the sequences that we get.

 

Nevertheless, also we at the gene synthesis companies, we have a couple of questions, and we would like to have some guidance and we would very much like to share the expertise also that we have.

 

Advice from some bio experts. We definitely need a uniform screening practice and uniform screening agenda. We do not like to work in gray zones, so we would like to have very, very clearcut criteria for screening. The Australian Group list, for example, names only organisms and not sequences. The definition as we’ve just discussed in the prior talk, the definition of genes associated with pathogenicity leaves in many cases room for interpretation. And a definition of "match" is central, of course, to the sequence evaluation.

 

We need a screening base that is continually updated. I think that’s one of the major achievements within International Gene Synthesis Consortium. We have all provided our white list sequences and black list sequences and have unified them in a common and joint database which we are using. I believe this database is maintained by the US government, by European institutions jointly. And, of course, the database should be complete, should be updated, and should be classified on a regular basis.

 

And last, but not least, to us and to me a very important point is an internationally harmonized list of suspicious persons and organizations is mandatory. And I think this is a topic that needs maybe more deeper discussion.

 

A few things that show clearly that there is a need for regulation is, for example, in the European Union we can deliver botulinus toxin genes without any problem to customers. But we are not able to send the Dengue Envelope gene to Novartis in Switzerland or to my friend, Gary Nabel at the NIH. So that’s not possible, not on short notice and even not in an emergency, in an emergency case.

 

What’s the consequence of a hit for a shipment within Europe? So there is a hit. What should we do with it?

 

How can export limitations to institutions such as delivering genes to the European Union or NIH be overcome, for example, in the case of an epidemic? And, again, this brings us back to the central role of customers and the customer screen.

 

The last slide, this is not the most important one, but nevertheless I would like to mention there are several ways to bypass the US or European Union based gene synthesis companies if synthetic genes are needed. You can order oligonucleotides at oligo firms both outside the European Union and the United States; synthesize oligonucleotides on new or purchased synthesizers or on a synthesizer that was built according to construction plans which are easily available via the Internet. Oligos can be assembled via published technology so that’s not sophisticated, highly sophisticated. Synthetic genes can be ordered from outside the European Union and the United States. You could use conventional, more or less, genetic engineering. You could isolate harmful species from natural habitats. And last, but not least, once more, customer screening and identification seems to be very, very important to me as a part of a screening process. That’s it.

 

Amy Gutmann:

Thank you very much, and thank you all. And I know there are questions from the commission, and we’ll begin with Nita.

 

Nita Farahany:

So thank you for these presentations. Even though, unlike Alex, I’m not paid to be paranoid, I am nevertheless. And so I’m grateful for all that you all do to increase the security and to decrease the potential dangers from the dual use of this technology.

 

I wanted to start actually, Dr. Wagner, with the last slide that you presented because that’s one of my major concerns, which is a lot of the types of approaches that you all just discussed seem to turn on the ability to identify particular harmful sequences that are being purchased by customers. And it seems if I was clever in trying to circumvent these different types of regulations, what I would do is I would order the oligonucleotides and sequence, whatever pathogens that I wanted to develop, which would then, it seems, circumvent most of the different regulations which are designed to ensure biosecurity.

 

So one question is, what types of security measures are there to ensure that if somebody is sequencing a pathogen, even one that is a known pathogen, would you be able to prevent them in doing so. And, second, what about the development of new or novel pathogens? So it also seems that a lot of this is premised on the notion that people are going to be developing existing pathogens or existing dangerous organisms as opposed to trying to develop novel ones. And it seems like one of the promises and also potential dangers of synthetic biology is the development of something that didn’t previously exist. And so how are any of these mechanisms going to actually detect the novel pathogens or novel organisms that people might try to develop instead?

 

So this is open to all of you, I think, but I’m picking up on the last slide from Dr. Wagner.

 

Ralf Wagner:

So maybe you can assist me. I think there is -- we have a certain gray zone and I think there will be, there will stay, a certain gray zone for those genes which are not precisely described regarding their pathogenic potential. So there are loads of pathogenic material out there. And really to make a clear statement for each individual gene, this gene is associated with pathogenicity. If it’s not in a new given context, in a given new context, I believe this is extremely, extremely demanding and difficult. And, today, I do not have a clear answer. Maybe you can help me out there, but I think it’s --

 

Nita Farahany:

Is it right that if it was a dangerous gene sequence that you could simply buy the DNA synthesizer and sequence it in your own laboratory rather than purchasing the sequence from one of these companies?

 

Ralf Wagner:

If you have the expertise as a molecular biologist or as a chemist, you could buy a used oligonucleotide synthesizer and have some basic molecular biology know-how, of course, you could do that. Yes.

 

Damon Terrill:

But if I may complete -- I will respond to the first part of the question perhaps by calling attention to the fact that synthesizing ones own genes from oligonucleotides would be a much more complicated exercise, a more burdensome and more expensive exercise, than choosing to buy the gene from one of the 20 percent that has not harmonized its customer and sequence screening protocol that may or may or may not follow the US guidelines or other applicable analogous guidelines in whatever jurisdiction they happen to be operating.

 

That would be the much more direct way of going about it, and I think that calls attention to the need to which we referred -- and I know the NSABB is very aware of -- to internationalize the scope of this sort of guidance. Whether other countries adopt word-for-word whatever final guidance emerges out of that process or not, the basic components of effective customer screening and sequence screening with all of the questions that are left over within each of those two activities, nonetheless, will go long way to eliminating or at least reducing the possibility that someone with nefarious intent would simply purchase the gene from a noncompliant, if I can use that phrase, provider.

 

So that is just one part.

 

Amy Gutmann:

David?

 

David Relman:

I think your concerns are well founded. I think there are a number of reasons for worrying that a sequence?based screening approach can only be at best a very small piece of the mitigation strategy. As I tried to suggest, first of all, we have a hard time recognizing a sequence that in the right context might prove harmful. The context is all?important. And I think it’s going to be years before we fully understand a tenth of what we need to understand. So, therefore, I think it’s much more appropriate to focus our attention on the user, on the sociologic and motivational context in which these sequences are being used and manipulated, and that’s where the board has spent a large amount of effort in the outreach and education awareness building, responsibility building part of this story which is where I think the big payoff lies.

 

Amy Gutmann:

Dan?

 

Daniel Sulmasy:

Several of you have made allusion to this. But obviously biology is globalized and terrorism is globalized. So are any efforts ongoing right now to do what you’ve suggested of having an international conversation about harmonizing these sorts of regulations. And, if not, what venues would you suggest would be good ones for pursuing that?

 

David Relman:

I’ll just mention there are a number of on?going US government?sponsored efforts to engage international partners, defined very broadly. The NSABB has it’s own through what we call the International Working Group. It’s a very active organization or portion of our board. There have been a number of web?based seminars and symposia held in many regions of the world. Dave Franz and Stuart Levy are the leads on that. And there is still a lot more that needs to be done, but it’s an area of great interest, especially from the Department of State, etcetera.

 

Amy Gutmann:

Just a quick follow?up. You all seem to agree that we need to internationalize the scope of guidance, as you put it. Do you have recommendations, practical recommendations, of how to do that, how to capture the 20 percent that are not now captured, for example? Is there a practical way of doing that?

 

Damon Terrill:

Well, I should say -- if I may, I should say that the 20 percent may be within or outside of the United States.

 

Amy Gutmann:

Do we know where they are?

 

Damon Terrill:

We have a sense, but just to be clear --

 

Amy Gutmann:

That’s not knowing.

 

Damon Terrill:

We represent -- we believe that the members of our consortium represent about 80 percent of the --

 

Amy Gutmann:

Yeah, you have said that. Now I’ve asked you the question ??

 

Damon Terrill:

It could be other, in other places including in the US. I believe -- it’s my view -- that the US government has gone much further than any other government in describing in the context of the draft guidelines how customer screening ought to be done and how sequence screening ought to be done. To the extent that that becomes final, I think that that would be an excellent launching pad for the formal process of internationalizing that kind of guidance.

 

I believe that the State Department -- I know that State Department has participated actively in the process of producing that guidance, and I like to believe that they are standing ready to at least participate actively if not lead the process and persuading others that it’s a good place to start, but that is for my government to do and not for us.

 

Amy Gutmann:

So persuasion is what you’re suggesting?

 

Damon Terrill:

I’m sure the State Department has available to it many means to persuade other governments to follow the US government’s lead if that’s what they believe is the right thing to do, and I suspect that they’re proud of their guidelines and will suggest to other governments that they serve as a useful starting point.

 

Ralf Wagner:

And the International Gene Synthesis Consortium -- this is not a closed shop. So this is an open consortium and we would be happy to include more companies -- very, very important. Of course, there are certain obligations, for example, to follow the regulations as set by the International Gene Synthesis Consortium. But this is an open platform, and we would be happy to have more members to shrink that 20 percent remaining.

 

Amy Gutmann:

Yeah.

 

David Relman:

The true percentage of what we really care about which are those that are not parts of these discussions and haven’t begun thinking about these issues is, I think, truly unknown. We’re talking about a very small segment of a technology area which all might be defined as synthetic or engineering based recombinant biology. I think a large amount of the practical measures that need to be taken are going to have to be grassroots measures from the bottom up as much as from the top down. And the board, National Science Advisory Board, and others have begun to think about who are the right partners for this overseas. Is it professional organizations? Is it local scientific or nonscientific agencies that capture the respect and following of those that we really care about out there?

 

Amy Gutmann:

Just so I understand what you all who have studied this longer than we have -- we’ve gotten an intense -- now we all feel like we all know an awful lot but it’s all secondhand. Am I right to say that the 20 percent is an estimate?

 

David Relman:

Yes.

 

Amy Gutmann:

That is an estimate?

 

David Relman:

Yes.

 

Amy Gutmann:

That you don’t really know who constitutes that.

 

David Relman:

Correct.

 

Amy Gutmann:

And that you’re recommending and that the guidelines in effect and the will of the US government is correct and basically we need to do more outreach in trying to capture ?? to capture the hearts and minds, if you will, of grassroots organizations?

 

Damon Terrill:

I think that is fair.

 

Amy Gutmann:

And I’m just trying to get what you’re saying.

 

Damon Terrill:

Absolutely. I would add that the 20 percent is commercial gene synthesis.

 

David Relman:

Yes.

 

Damon Terrill:

So that doesn’t even capture the noncommercial gene synthesis activity that might be going on.

 

Amy Gutmann:

Okay. 20 percent estimate of commercial, but that doesn’t include what would be a small from what we’ve gathered of the DIY and others ?? small, maybe large numbers but a small amount of activity.

 

David Relman:

Yeah, presumably.

 

Damon Terrill:

The other thing I would say is that we just mentioned a few because we only had a short time. But there are certain sticks in addition to carrots that might be used and one was mentioned by Dr. Relman, and that is simply requiring that in order to use public funds that one purchases from a provider that screens. Now that is going to broaden the practical coverage of the guidelines, but that’s not going to capture those who simply aren’t interest.

 

Amy Gutmann:

Right, because that’s using public funds.

 

Damon Terrill:

Absolutely.

 

Amy Gutmann:

Okay. Nelson?

 

Nelson Michael:

You have touched on a number of the vulnerabilities that started from the questions that Nita asked because, if you’re going to attack someone, you don’t attack them where they have strength. You go to the 20 percent where they don’t have regulation. You figure out ways to go around it by buying your own synthesizer, etcetera.

 

What would you recommend in a realm where you can control things -- and, David, you have spoken now multiple times about something that I touched on a earlier this morning about do-it-yourselfers and the iGEM process in terms of engaging the community. What else can we do, either from a technological standpoint or from an engagement standpoint to ensure the public you continue to strengthen the process, continue to strengthen robustness of the process that you’re developing. You said yourself that the science is evolving. And if there is going to be an iteration of looking at the strength of this system to identify either customers or orders that are not appropriate or questionable, how often do you war-game that? How often do you ensure that the system is strong enough?

 

David Relman:

Yeah. Again, I think you have to start with the user, with the individual who wishes to do science. And one place to put, I think, a great deal more emphasis is norms and codes. We should expect that anyone who does life science or engages in its technologies embrace and explicitly agree that they first will do no harm, willful harm.

 

We don’t ask that of our graduate students or technicians or any of those who are out there operating in the space, and I think that is a place we have to begin. And I think it would show an awareness and a sensitivity to the rest of the stakeholders, the public, the policymakers that we, the broad community, understand that there is an issue here and we have some awareness. That’s a start.

 

Ralf Wagner:

Yeah. I think that’s the key, and I mentioned it several times. I mean, we, of course, will do the sequence screening as good as we can and we invested a lot and will invest a lot into doing the sequence screening. But I think an important key to regulation is the customer. To have a certified customer, to have some kind of identification, would be extremely helpful for the gene synthesis companies.

 

But, generally, it’s my impression at least in Europe people are extremely well trained regarding biosafety. People are untrained to a large extent regarding biosecurity issues. So there is a significant education task involved in that.

 

Amy Gutmann:

Thank you. John?

 

John Arras:

As an educator, I’m the last person to question the efficacy or the importance of education. But I’m sort of worried about that nub of bad actors out there. So we start with the 20 percent, then we engage in grassroots education. We’ve got all those good citizens and they’re waiting out there, waiting to be converted to the side of the angels through public outreach and so on. But, of course, the people that we’re really worried about aren’t the people who suddenly are going to have their head turned by public outreach and community-building. They are the people who want to tear down various communities.

 

So I’m not even sure how to formulate this as a question. Okay? But what about that residue of bad actors who are within that 20 percent who are not going to be turned by healthy salutary outreach measures? I mean, what is left? Do we have any clue how many, how big a threat that really is?

 

David Relman:

I would say it’s a very important issue that wakes a number of people up on a regular basis.

 

John Arras:

They should be paid to do that waking up.

 

David Relman:

In the middle of the night, too. He’s right there, right there, and others, and it’s not just the professionals who are paid to worry about it as you and others have suggested.

 

First of all, there probably at the end of the day is no way of ensuring that there can’t and won’t be a bio-Unabomber operating in a distant city who is not on our list by him or herself or maybe with one other person that decides to do something harmful and execute something. I just don’t think that’s going to be possible.

 

The idea would be that, while no one measure will suffice, that if you have a network or networks and they’re overlapping and independent somewhat that you will catch much of hopefully nearly all of what goes on out there. And the idea behind the sensitization campaign and awareness-raising campaign is that you are now creating a network of censors who may be close to that person who wishes deliberate harm and they will recognize something and report it. That’s the idea.

 

Amy Gutmann:

Yeah, yeah.

 

Damon Terrill:

What we had hoped to do is ensure, of course, that we ourselves don’t supply synthetic genes and certainly not those associated with the pathogenicity of an organism to someone who doesn’t have a legitimate need for that material. And what we’d like to do is broaden the number of commercial providers that similarly act to prevent that misuse. Perhaps by doing so we can play a significant role in identifying the reminder that really remains and will forever remain the focus of law enforcement and intelligence that is not our business, but we’ve tried to begin the process of isolating that probably very small group of people that, nonetheless, could do very significant harm through our work.

 

Amy Gutmann:

Thank you.

 

John Arras:

Just a factual follow?up. How many people, how many bad actors, have your screening mechanisms turned up to far?

 

Ralf Wagner:

Actually, we have occasionally journalists asking for black?listed sequences and we found them all so far. So they have either a private address or they make some mistake during the order process and usually you identify them.

 

Damon Terrill:

I can answer this way. None of the IGSC member companies yet since we’ve implemented our own mass protocol and since we’ve been doing our screening, I can confirm none of the IGSC member companies has ever, in fact, received an order for a bad gene from an in-fact bad person. So the answer to your question is zero.

 

Amy Gutmann:

Yes, and if there is anybody else in the audience who has a question, please just stand up.

 

Tim Trevan:

Tim Trevan, International Council for Life Sciences. I’d like to address the international side a bit more. It was a little disappointing that neither of the IGSC members actually mentioned IASB which does cover some of the remaining 20 percent. It has German companies and two Chinese companies signed up for their screening guidelines.

 

And it worries me either that you don’t know about them or that you’re not cooperating with them. I think it is very important that the IGSC and the IASB actually do talk to each other and make sure that there is some ongoing dialogue to make sure their guidelines don’t drift apart.

 

Ralf Wagner:

Definitely, I would like to ask you --

 

Amy Gutmann:

Why don’t we take that as a question, okay, to our panelists?

 

Tim Trevan:

I would also just like to address the other issue of, what is the 20 percent?

 

Amy Gutmann:

Could we just that -- because you did made it as a claim which I see that Ralf wants to answer, so let’s let him answer it and then you can go on to the second.

 

Ralf Wagner:

Actually, I’m grateful for the question.

 

Amy Gutmann:

Use the microphone.

 

Ralf Wagner:

This is a good comment. I can say that we are in a permanent dialogue with IASB. I can say that my company is part of the IASB and in particular to network the two different organizations. And there are additional organizations out there. But in the long run, it may become an issue whether or not it makes sense to have two or three parallel organizations, whether these are being harmonized or unified. So this is on our agenda. And there is neither a competition nor a mutual exclusion. I can say for my company we are members of both of these networks to bring those networks together.

 

Amy Gutmann:

Okay. That’s helpful, yes.

 

Tim Trevan:

That’s very good to hear. I think Bob Micheletti at the State Department in addressing this issue did do some research as to where the capabilities are in the world, and as best as they came up with, it was western Europe, North America, and China with not really significant production capabilities elsewhere, although with significant clients elsewhere in the world.

 

And just before I come to the last issue of the clients, I would like to come to this issue of, what is the significance of the 20 percent or the percentage of the 20 percent that doesn’t come in? This isn’t a new problem particularly in relation to arms control treaties. It’s a long?standing problem. And the basic premise is by having, as was indicated, these overlapping networks of obligations and notifications that you both make it more difficult to cheat and you raise the costs and the profile of cheating so that you can never expect to get rid of all of the risk, but at least you make it much easier to identify the bad players. And I think that is the best we can do in an international context.

 

And I fully accept that you have to put a lot of emphasis on the clients. But this gets rather difficult to have unified lists when you go international because who is a dodgy player for the Americans may be very different from the Chinese. So agreeing who the bad players are is not a purely simple nontrivial question.

 

So my question comes to the clients. Are there any plans in the IGCS or the IASB to go beyond the producers and to develop a relationship with the clients so that you have not just horizontal but also vertical approaches to this issue of screening?

 

Amy Gutmann:

Thank you for that. Anyone wish to take that question up? Is there a movement internal to your organizations to take up the clients?

 

Damon Terrill:

I will confess that I am not sure I entirely understand the question, so I will interpret it and answer the one that I interpret.

 

Amy Gutmann:

Okay.

 

Damon Terrill:

There is a need in the context of industry group like ours to be sensitive both to the perception and the reality that we focus our efforts on this collaboration and not share certain information that is of a commercial nature. So there is that limitation when it comes to sharing information about customers. On the other hand, if we were to receive ?? and we’ve discussed this primarily in theory so far. But if we were to receive an order from a customer who we identified, not by virtue of that customer’s membership on a US government-administered list of persons who should not purchase anything, much less a synthetic gene from a US company subject to an export ban, for example, but rather was identified by our own investigation as having been suspect in some way -- we weren’t sure about them -- we would inform each other of that to prevent that customer from simply moving over to GENEART or to DNA2.0 from IDT, for example, or the other way around.

 

But that hasn’t happened yet except in the case of the journalists that Ralf mentioned who were trying to see they could fool us, and we red?flagged one another. But I think that is a good example of how that operates.

 

In general, it’s governments who decide who bad people are. And I think it is a worthwhile observation that China and the US could have very different ideas about who they are. In the time being, however, we have not had any trouble administering an approach that treats from the US perspective a bad person as being the same as a bad person that the Germans might identify or others might identify. But it’s certainly a potential inconsistency.

 

Amy Gutmann:

Would you please identify yourself?

 

Neelima Yeddanapudi:

My name is Neelima Yeddanapudi. I work for Gryphon Scientific, and I have a question that goes towards the effectiveness of your screening processes. And so I’m not quite sure if this was answered exactly before. But I was curious as to what fraction of the orders that you’ve gotten have you rejected and then have you also seen a decrease? You said that you’ve incorporated the screening practices for the past year. That’s what I understood. I could be wrong about that. But have you seen a difference in your clients? Have they changed? Have they decreased?

 

And the reason I ask that is there are plenty of legitimate clients who may have economic reasons for going through easier channels than going through the screening processes that you have. So I’m wondering, has there been a change in the people who are ordering from you?

 

Ralf Wagner:

The ratio of orders that we do not take remains the same. So there is no dynamics in the sense that there are more orders that we are not able to fulfill.

 

There are embargo companies where we do not accept any order, of course, by legal requirements. There are other countries which are not embargo countries but which for good reasons order like dengue virus envelope genes which feed into a very tedious administrative process on our side where we occasionally say, "Well, it’s not worth it."

 

But we do not see an increasing fraction of dual?use genes currently. But occasionally it happens that we do not fulfill an order.

 

Amy Gutmann:

I think I’m going have to leave it there because our time is up and we have another panel which will commence immediately. So thank you very much, all three panelists. Thank you.

 

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