Building Life

An interview with Prof. Dr. Ralf Wagner

An interview with Dr. Ralf Wagner, professor of Molecular Microbiology and Gene Therapy at the University of Regensburg and CEO of the biotech company GeneArt (“The Gene of Your Choice”) about the opportunities and limits of synthetic biology.

Dr. Oliver Müller / Josef Mackert: Professor Wagner, the goal of synthetic biology is often defined as the production of tailor-made biological components which can carry out certain tasks. What does that mean?  

Dr. Ralf Wagner: I like using the definition offered by the bioengineer Sven Panke, namely synthetic biology follows an engineering agenda and represents new methods of biosynthesis on the basis of standardized bio-components in a form that does not occur naturally. Research in biology has long been hypothesis-driven. However, in this age of genomics and post-genomics, we have access to new analytical tools. Not only can we form hypotheses with more precision, but also construct what we know about cellular processes. We find ourselves at the threshold of a new age. Ideally we should be using – and this is what engineering agenda refers to – standardized bio-components. This is comparable to electro-technology which uses resisters, capacitors, electrical circuits, etc., and depending on how I assemble these components, I can build a radio, television, hair dryer or vacuum cleaner. The same goes for standardized bio-components, which, depending on their combination, can be used to produce organisms with wide-ranging capabilities.


Müller / Mackert: How is this different from conventional biotechnology?

Wagner: The degree of modification. In the past we used to insert a new gene into a bacterium, usually E. coli, or we modified one or two components of a metabolic pathway, which altered a secondary metabolism, causing it to produce, for example, large amounts of vitamin A. These were minimal alterations. A significant modification would be to take an organism’s entire metabolic pathway and implant it into another organism. That’s extremely complex and has an entirely different quality than what we’ve done in the past. And finally, I would classify something as substantially modified if it’s absolutely new, for example, enzyme functions which never occur naturally in combination. In other words, when a bioengineer produces biological components that are yet unknown to nature.


Müller / Mackert: What components, for instance, are unknown to nature?

Wagner: We have 20 amino acids, the building blocks of life. Maybe 21 which occur in nature. Nowadays we have the ability to produce artificial amino acids – a 22nd, a 25th amino acid – up to 80 artificial components, possibly more. I no longer use the cell’s chemistry, but the ‘machinery’, the ‘apparatus’ inside the cell to generate entirely new protein components. I build a kind of parallel universe within the cell. That’s what I would designate as ‘artificial’. The bioengineer Petra Schwille claims that she builds life from scratch. She constructs artificial membranes which she could place in a transcription machine. In combination with a translation machine, she could then produce more than basic proteins. This may lead us to wonder why evolution occurred as it did. It could have run a completely different course. For example, why do proteins have a polypeptide backbone? And why do they have peptide bonds at all? Other covalent bonds would work just as well, why, they could be completely different molecules. In my view, this has a completely new quality.


Müller / Mackert: What consequences will this have in terms of our concept of life?

Wagner: Eckart Wimmer from Stony Brooks University recently created an artificial polyvirus in the lab. Are such artificial viruses that are capable of penetrating cells truly alive? I try to look at it from a technical point of view, that is, life is everything that can reproduce, full stop...


Müller / Mackert: There are attempts to ‘denucleate’ cells, construct a ‘chassis’, on the basis of which new organisms could be produced – like what the bioengineer J. Craig Venter is doing. Are these the living machines, which researchers in synthetic biology are talking about?

Wagner: All that Craig Venter did was to synthesize a genome that looked a little different than the genome that was originally inside the cell. He simply inserted the genome – the programme of life, if you will – into the cell. Then the cell starting running the new programme, because the integrated selection markers helped to override the old programme. And following several cell generations, the new software (or new DNA) made corresponding changes to the hardware. So what is life? If a scientist looked at the chassis and DNA which Venter and his colleagues combined, he might call the DNA a physical component. Nobody would say that the DNA was ‘life’. It’s more like a programme for life, comparable to a software tool. And when you insert it into a cell – to summarize the paper published by Venter’s institute – the cell reboots. And this is where the analogy to computer science ends, because in biotechnology, the software determines the hardware. After a few cell generations, new hardware is created. I find it difficult to draw a line – to say, that’s artificial life, a living machine, and that’s not artificial life.... But when Venter says, regarding his most recent experiment, “I simply take the genome and insert it into a cell, and that reprograms the cell” – that I think is probably the most ‘artificial’ aspect, but a living machine, I don’t know...


Müller / Mackert: Throughout our cultural and scientific history, life was regarded as something inexplicable and mysterious that couldn’t be completely controlled. Are such elementary concepts and metaphors for life suddenly a matter of debate when synthetic biology makes life a product that can be manufactured and controlled?

Wagner: Hmm, I think I’d approach the issue from a scientist’s perspective. How is what we’re doing any different than what we’ve done in the past? Of course, I accept that a definition of life can have both a technical and ethical or religious aspect. If I wanted to be provocative, I could ask, what difference does it make if I change one gene, or five or six or more? It’s just old wine in new bottles...


Müller / Mackert: But according to your original definition, if a characteristic of synthetic biology is that it produces organisms which don’t occur in nature, then this is, programmatically speaking, different compared to what was being done ten or twenty years ago, right?

Wagner: Yes and no. We’ve always created things which go beyond what exists in nature. For example, nature could have never produced the rye or wheat plants that we have today. Evolution would have never gone in that direction by itself – and yet research in breeding has produced these things. We are now doing the same with biotechnology – just more specifically. An oil-eating bacterium, I could build one right now, but there are surely other ways I can help evolution along...


Müller / Mackert: Is that what you mean by a parallel universe?

Wagner: Apart from the fact that we can produce therapeutic medicine and new medication more efficiently in such intracellular parallel universes, I find the idea especially fascinating because it encourages us to reflect on why our life looks the way it does. As I’ve mentioned, there are very specific amino acids and peptide bonds, and that’s the way they are. But could evolution have taken a different path? Why didn’t evolution head in different directions?


Müller / Mackert: With the goal of maybe heading in these different directions someday?

Wagner: In the very distant future, perhaps yes.


Müller / Mackert: There are biologists who predict that someday it will be possible to insert an entire artificial chromosome into an embryo....

Wagner: Just because some things are possible doesn’t mean we ought to do them... Sure, it’s possible to construct and synthesize a chromosome, it’s probably not even very difficult. Technically speaking, I don’t find the goal especially visionary. Let’s take E. coli, for example, that’s a simple bacterium. E.coli has 4x106 base pairs, which we at GeneArt are able to synthesize in four to six weeks. Not a big deal. If you take a look at how the synthesizing capacity at GeneArt has developed in recent years – eight years ago we were able to synthesize 10,000 base pairs per month, and today we can synthesize 5x106 base pairs per month. Maybe I’m going out on a limb here, but I might tell you next year – no problem, we can do 107 base pairs in four weeks. All you need is a few small technological advances here or there and before you know it, you’ll be able to synthesize a chromosome. And now the question is – How far do we go? Where is the limit? When should we stop?


Müller / Mackert: In view of how science is organized and the breathless pace of advances in recent years, is it even conceivable that the scientific community can form a consensus on setting limits?

Wagner: At least at my company, we’ve been discussing possible self-imposed limitations. We’ve set up a database at the IGSC (International Gene Synthesis Consortium) with information about gene sequences and external requests for them, along with explanations as to why we opposed certain requests. This applies particularly to dual-use cases, that is, organisms which bioterrorists could use. We don’t provide all our customers access to everything. Generally I would supply material to colleagues, whose project I’m familiar with and can review, while I wouldn’t support researchers who I don’t know or who don’t work at a university. But, you’re right, it’s difficult to impose voluntary limits worldwide.


Müller / Mackert: The difficulty with self-imposed limitations might have something to do with the fact that they would limit work in areas that are generally known for being limitless and unrestricted, namely art and religion. Creativity and the perfection of creation seem to characterize synthetic biology – even the name of your company is GeneArt....

Wagner: Yes, our name – Gene and Art – there’s no such thing as a completely artificial gene. We were actually thinking of art in a technical sense. Constructing a gene is an enormously complex process, it’s an art to construct a gene in a specific way, and it is a fine art to optimize a gene to carry out a certain application. What also played a role was the idea that nature is a Gesamtkunstwerk, an unattainable design option that we as humans can only begin to fathom, much too complex, much too...well, divine. We do not say we are superior to nature or God in any area. For us and personally for me, playing God has never been the issue, contrary to what I’ve heard Venter occasionally mention...


Müller / Mackert: There seems to be a trend in synthetic biology to offer life as a designer product – which inevitably puts one in competition with nature, doesn’t it?

Wagner: Better than God, or as good as God. This question always comes up when we’re asked what makes our work so special. When we say, we do it differently than nature, we do it better than nature, then by all appearances we’re one step away from making the claim: We’re better than God. Let me explain it another way. The pancreas produces insulin on the basis of physiological parameters, and nature has developed the perfect method for regulating insulin production. It’s a stroke of genius – nobody could have come up with a better method. Now when we say we’re better than nature because we produce more, we’re referring, for example, to the production environment. I’ve got a fermenter, a bioreactor and the right laboratory conditions, then I take a cell with which I will use to produce insulin. I ask myself, how can I alter the gene and apply the optimal aeration and stirring rate so that the cell produces the most insulin possible? Based on this analysis, I modify my gene. Compared to the compendium of rules that nature has produced, this is a completely banal process, using the most basic of tools. Sometimes I stop and ask myself what exactly I mean – better than nature? And then I try to clarify in what sense it’s better than nature.


Müller / Mackert: What kind of bio-building blocks does your company offer? How do you do business with these titbits of life?

Wagner: When I was working on the development of HIV vaccines, I was looking for someone who could make an artificial gene for me. Of course, I googled a few companies, but most of them turned me down – high prices, long delays in delivery, technical problems. So then we tried it on our own. It was hard work, took a long time and was very expensive, but in the end, we got exactly what we wanted – the capability to produce the HIV gene in large quantities. Then we realized that if somebody could produce such artificial genes fast and at a high throughput, it would completely revolutionize genetic engineering – it all comes down to money and time. If it were cheap enough, then everyone could order tailor-made genes for their experimental needs. Our business concept was basically to lower operating costs and reduce the price. To do that, we required an elegant process, ideally arranged in modules, so that we could automate individual modules and miniaturize them further in the future. And that’s what we’ve been doing, step by step...


Müller / Mackert: So you offer base pairs that customers can order from you?

Wagner: Exactly. The customer says, GeneArt, I’d like to order an optimized HIV envelope protein gene and the protein sequence should look like this, please make me a gene that fits that description. Or I’d like to produce a Chinese hamster ovarian cell protein. Please construct a gene for me, encoded to produce exactly this protein! So then we sit down and figure out what the gene has to look like to produce the highest possible output in this production system. This initially involves design work, after which we synthesize the gene, place it inside a gene shuttle, put it through quality control and then deliver it to the customer.


Müller / Mackert: Gene sequences can be patented. But patenting living material seems strange...

Wagner: Our patents are essentially process patents which protect the methods we use to manufacture genes. The technical uniqueness of the process is important. By this I mean that we use a technology that specifically alters the gene – be it a protein or functional gene – and combine it with a genetic optimizer in order to improve output in production. We have an entire series of patents for this type of procedure.


Müller / Mackert: Which means that you wouldn’t be able to patent entire microorganisms?

Wagner: Yes, you could! You could patent a bacterium, for example, into which you’ve inserted a new metabolic pathway.  Entire genes have also been patented. You wouldn’t be allowed to patent a gene which looks just like a natural gene. But you could patent artificial genes which have been ‘improved’ in terms of their production, or if they’ve been encoded by a protein whose function has been modified. In addition to these genes that are optimized for certain applications, the scientific community is now discussing whether there should be patents on switches that control the genes. These biological pathways, also called BioBricks, are collected in databases, and now the question is whether researchers will have to pay for them in the future, or whether there will be an open-access policy.  At present we find ourselves in a grey zone because many BioBricks are offered for free. But many switches, genes and reagents are already patented. But I’m sure that if any of these find a commercial use, there’ll be somebody out there who will make use of his patent...  

Müller / Mackert: The American computer scientist Ray Kurzweil claims, with the application of information technology and biotechnology, we will be able to build the first bridge to immortality in fifteen years. Kurzweil believes that it will eventually be possible to reprogram our biology so that – according to his calculations – we’ll be able to add another year to our life with each passing year. Do you think it’s possible?

Wagner: I find that rather improbable...Look, twenty years ago, when I began my career, we had hypothesis-driven research. Ten years ago the instruments were finally available to start decoding the genome. And at the time, around the year 2000 when Venter published his findings, everyone was saying, wow, we’ve got it! Now we understand life. In hindsight, what we knew back then was like alphabet soup. We have to write words, we have to write entire books, rather volumes and volumes of books to tell that one story of life. We’ll definitely succeed in achieving new levels of complexity, from constructing a cell to organs to groups of organs. But achieving the goal of immortality? I don’t know.

The interview was conducted by Dr. Oliver Müller, researcher at the Institut für Ethik und Geschichte der Medizin at the University of Freiburg and Josef Mackert, deputy general director in artistic matters and head dramaturge at the Theater Freiburg.

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