Mirror Life: Changing the Pharma Landscape with Synthetic Biology- An Interview with Professor George Church

George M. Church
Contributor: George M. Church
Posted: 09/15/2013

Gerald Clarke:           I’m Gerald Clarke, Editor at Pharma IQ.  Today I’m joined by Professor George Church, Professor of Genetics at Harvard University, Professor of Health Sciences and Technology at Harvard and MIT and founding faculty member at the Wyss Institute at Harvard University.  Professor Church, it’s a pleasure to have you here.

George Church:         It’s great to be here.

Clarke:          Professor Church, could you introduce yourself and give us a little background as to how you became involved with synthetic biology?

Church:           GMC   So I’m Professor of Genetics at Harvard Medical School and have been fascinated with technology for reading and writing DNA and the rest of biological components that one can make from DNA.  That is, at a fundamental level, how we can screw with technology to reduce costs, improve the accuracy, typically by miniaturisation and multiplexing.

Clarke:          So what are the top three challenges that you face now in synthetic biology and how can these challenges be addressed?

Church:           Well, I would say that one of the top ones is getting high quality genome scale DNA, whether it’s for large libraries or for particular genome scale projects like recoding, changing that to another code.  The second one would be selection.  That is to say, once we can build large numbers of genomes, which we can, how do we get what we want, in terms of functionality.  You can easily build a genome which is lethal, nonviable or one that is viable but doesn’t accomplish anything new.  So that’s kind of a second challenge.  Wrapped up in both of those is a third challenge which is computationally integrating large amounts of data from both the design analysis and synthesis.

Clarke:          You mentioned it there but the media’s justifiably excited about the promise held by next gen sequencing but, when I interviewed Professor James Collins and Professor Paul Freemont, they both cited, as did you, faster synthesis of longer DNA sequences as a key hurdle that we have to pass before we can advance synthetic biology further.  What do you see as the next generation of DNA synthesis?

Church:           Well, although it’s a reduced cost, and the code accuracy that synthesis on chips has been moving forward since around 2004, when we published Nature paper...  Another thing is genome editing is a way of obtaining high fidelity at low cost, especially if coupled with genome sequencing as a way of making sure that there is either nothing off target or what you see off target is not alarming.

Clarke:          So, aside from next generation DNA synthesis, what technologies do you see as changing this field the most in the future?

Church:           Certainly the ability of going from synthesis to selection at the cellular level to design and selection at a multi cellular level, whether it’s synthetic ecosystems or human tissues and organs.  I think that’s a really interesting direction that the field of synthetic biology has had its origins in electrical and microbial biology but I think now we’re adding to that more sophistication on human biology.

Clarke:          What are some of the projects in the field that you think show the most promise?

Church:           Well, certainly, historically, there’s been promise in optimising metabolic production, whether it’s done with chemicals or pharmaceuticals.  I think, in the near future, we’re seeing engineering of human systems which is resulting in the kind of next generation of gene therapy, which is much more precise, and similar agricultural benefit and possibly even organ transplant progress.

Clarke:          You mentioned a couple of projects there, including gene therapy.  What are the major aspects of the pharmaceutical industry that you think synthetic biology can change?

Church:           Certainly the ability to manufacture drugs has been demonstrated in the case of artemisinin, the ability to screen drugs in a highly prescriptive manner is always up for grabs, there is a stock of new drugs that are very complex and are hard to manufacture chemically.  Then, of course, the more complicated the system, whether it’s going up from small molecules to proteins to engineered bio system cells to tissues, each layer of higher levels or organisation gives us much more programming flexibility, in the same sense of going from a 1k computer to a terabyte computer gives a lot more power and options.

Clarke:          There have been some fairly high profile cases where bio processing plants have been closed down due to viral infection.  In your book, Regenesis, you describe something that you called Mirror Life.  Could you describe Mirror Life and how that would render the sort of production bacteria or yeasts resistant or immune to viruses?

Church:           There are at least two ways of getting blood in the multi or total virus resistance in microbial systems and potentially in other agricultural species.  Mirror is probably the harder of the two.  The slightly easier of the two (still hard) is engineering the genetic code so that it’s foreign to the virus, the virus expects a fairly standard set of genetic codes and you can go outside that range and make it so the virus can’t even mutate enough to be functional.  The mirror isn’t necessary for viruses but it becomes more valuable if you want to be resistant not just to viruses and enzymes and degradation and predators and so forth.  There, the baby steps that the field is taking is in making ribosomes, the protein synthetic machinery, that are capable of handling their mirror image amino acids, incorporating those into long polymers.  As soon as we get that, then we can take the next step towards getting a self replicating ribosomal based system.

Clarke:          You’ve been involved in the founding of many biotech companies.  What’s your key to translating primary research into commercial success?

Church:           I think, at the start, it seems like just sharing information and articles would be enough.  There was a fair amount of do-it-yourself behaviour in biology in the 70s but it certainly progressed to kits and then to instruments and services.  So the fact this is developing accurate, low cost and turnkey systems to making sure that they get into some sort of commercial setting, where they can be self sustaining and improve further support, but you can’t just drop it on their laps or throw it over a wall.  There are transitions you have to work with, whoever is going to be in charge of making it commercially available to the world.  So that’s for a few years. 

Clarke:          Looking slightly broader than just synthetic biology to the broader industries of pharma and biotech, what do you think are the trends that are going to define it for the next, say 18 months, through 2014?

Church:           That’s a very short period of time.  I’m not sure we’re going to see a whole lot of surprises in that period of time.  I think, in some fields, that might be a reasonable period of time but in pharma we have these long wait times due to regulatory consequences.  I think we’re beginning to see more tests in things like work on chips, where you can see where the drugs are patented with a particular individual, not just predicting it based on a genome but actually seeing how it flows out in surrogate tissue, better personalised, but also start to see the beginnings of the thousands of gene therapies which are probably in the pipeline.  Move a little bit further down the pipeline with it, closer to making a big impact on society and changing the pharma industry forever.


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George M. Church
Contributor: George M. Church
Posted: 09/15/2013


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