Using cell circuits to program cellular outcomes

Author: David Kent, 10/29/14

One of my favourite things about the Till and McCulloch Meetings (#TMM2014) is the careful thought that goes into session organization. The balance of basic science, ethics, engineering, and industrial and clinical applications has always been a nice feature of the meeting. Having just listened to the speakers in the Systems, Synthetic & Applied Stem Cell Biology session, I am again pleased that the organizers have taken care to invite a broad range of speakers that give a nice overview of stem cell related advances in Canada and abroad.

The standout talk for me was from MIT professor Ron Weiss who spoke about creating biological circuits to sense, process, and action various outcomes inside of cells. Dr. Weiss introduced the concept of synthetic biology as the application of a systems-level bioengineering approach to bring together multiple biological parts that have not been brought together before. Ideally, biological “parts” could be incorporated into rules and protocols in order to facilitate the design and re-design of circuits that can be optimized to numerous applications. For example, if a protein has an established role as an activator of a gene that makes a protein that in turn always represses a different gene, these rules for parts can be built into a circuit with defined outcomes. Sense a molecule, process its levels, and actuate a response – can this be encoded?

Weiss described his approach and explained that smaller circuits aren’t actually so bad, but when things get bigger and variables more diverse, the circuits cannot be designed by intuition alone. They therefore developed a toll to help with the complexity – it is called BioCompiler and it tries to make sense of a large set of genetic tools and their potential interactions with each other. The idea, Weiss explained, was to know what tools were available in the freezer, know exactly what each tool did, and then have liquid handling robot take instructions to assemble the genetic circuit. Weiss wants to make a microfluidic device in order to miniaturize the process and make it cheaper so that graduate students could have a mini-robot on their bench for $3,000-5,000 where they could assess hundreds of different circuit variants in a single day.

After Dr. Weiss’ joking admission that the rules of biology don’t always play nice, he proceeded to show some pretty neat examples of the technology in action. In one proof-of-principle, he set up a circuit that could detect the expression of a particular microRNA which, if found at high enough levels, would result in the expression of a fluorescent molecule. He then showed that cells expressing high levels of the microRNA could be distinguished from those that did not in a cell culture dish because they were now glowing with the fluorescent molecule.

Imagine if, instead of glowing, the circuit released a toxin that would specifically kill cells. Weiss wants to create smart viruses that can go inside a cell, inspect biomarkers (e.g., gene X is expressed), compute “cancer” or “not cancer” and kill the cell (or not) – a real time assessment followed by a real time decision. This is pure fancy for biologists studying diseases with known biomarkers – sounds incredible right? I can’t deny salivating a little at the potential applications.

This breath of fresh air is very welcome – new ideas for how we might specifically target cells that we don’t want in our bodies – but there is certainly an enormous amount of work to be done before these tools can come close to the clinic. For example, if you load up these therapeutic packages with something that is toxic to cells, how do you ensure it never gets released or produced in normal cells?

I’m sure that groups like Dr. Weiss will continue the quest and I wholeheartedly endorse efforts to explore novel approaches that push the technological boundaries of what we think might be possible. I hope granting agencies and policymakers think the same way and lend a hand in identifying and supporting novel ideas with as yet undiscovered applications.

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David Kent

David Kent

Principal Investigator at University of Cambridge
Dr. David Kent is a Principal Investigator at the University of Cambridge in the Cambridge Stem Cell Institute ( His laboratory's research focuses on fate choice in single blood stem cells and how changes in their regulation lead to cancers. David is currently the Stem Cell Institute’s Public Engagement Champion and has a long history of public engagement and outreach including the creation of The Black Hole in 2009. He has been writing for Signals since 2010.
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