Innovating research, policy and education in synthetic and systems biology

Mammalian synthetic biology comes of age

Mammalian synthetic biology will make a huge impact on medicine and healthcare if just a fraction of the many exciting projects discussed at the 5th Annual Mammalian Synthetic Biology Workshop in Boston (May 5 and 6) come to fruition.

The opening keynote speaker, Prof Crystal Mackall of Stanford University, set the scene with a review of the success of CAR Technology, the ‘poster child’ for mammalian synthetic biology. Last August, the US FDA approved Novartis’ Kymriah for treating certain paediatric and young people with a form of acute lymphoblastic leukaemia (ALL). Kymriah is a personalised T-cell therapy and offers a route, in some patients, for prolonged control of ALL, arguably a full ‘cure’. However, CART is not without its challenges including ‘exhaustion’ of the T-cells over time and/or excessive toxicity: Mackall provided an overview of her elegant studies to explore ways of using synthetic biology to address these problems. Clever use of drug-controlled CART systems, which can turn the therapy on and off as necessary, could be one way to prevent T-cell exhaustion. Generating bi-specific CARs may be a viable route for avoiding off-target toxicity. Other speakers in the ‘synthetic immunology’ session explored alternative strategies for fine tuning routes to address these challenges including Crispr engineering of defective T-cells and creating synthetic T-cell receptors using notch receptors. The next challenge will be to use a synthetic immune system to attack and eliminate solid tumours. 

Another highlight of the meeting was the ‘viral vectors and gene therapy’ session. Adenoviral vector (AAV) is the most widely adopted viral vector for human gene therapy. AAV offers a handy way of shuttling large pieces of synthetic DNA into cells and comes in at least 68 different ‘flavours’ (serotypes), making it suitable for personalised therapy. However, Nature did not design AAV to be an illicit gene ‘trafficker’ and so it is not particularly effective at infecting many cells types with sufficient capacity to be of any use in gene therapy. Here synthetic biology can really make a difference. O’Shea’s lab have found ways create to make a cut and paste modular system of the different serotypes, producing a useful viral toolbox. Dr David Schaffer of the University of California, Berkeley is using directed evolution to modify the viral capsid, the component that directs viral infection. He has now developed AAV that can target retinal cells and will be suited to treating blindness caused by retinal degeneration.

The microbiome continues to attract the attention of the big names of the synthetic biology world, Profs Jim Collins (MIT) and Pam Silver (Harvard Medical School). They are engineering bacteria to explore the mode of action of antibiotics or even to work as antibiotics themselves. Silver is harnessing E. coli to prevent Salmonella infection – engineering detection and killer functions into common gut bacteria. Ingenious.

Others sessions included topics such as genes and circuits, the funding and investment landscape (apparently microbiome companies are the ‘Marmite’ of VC investments - they either love ‘em or hate ‘em) multicellular systems. There were excellent presentations on modelling of complex systems, which will continue to be vital if we are to be able to engineer cells with any reproducibility.

George Church (Harvard University) closed the meeting with a review on his very many projects and a brief update on progress with the Human Genome Project Write, which had been the topic of a meeting earlier in the week in Boston.

While still relatively small in number, the mammalian synthetic biology research community is big on ambition and creativity. The challenges ahead are still substantial but with the success of CART in the clinic, the prize does not seem quite so unachievable any more.

To date, the Mammalian Synthetic Biology Workshop has only been held in Boston, but the organisers have seen the need to broaden its horizons. Next year, the event will be in Chicago, and we hope to welcome it to Edinburgh in 2020.