Considered the “father of synthetic biology” George Church is most known for his contributions to genome sequencing, genome engineering, and a project to comprehensively map the neural connections of the brain.

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You downplay the emphasis on CRISPR in the media and point out that there are actually nine main gene editors in use at present. In layman’s terms, can you explain the fundamental pros and cons of these various methods? Also, what would be the use in combining editors as I’ve seen published, with CRISPR and Lambda Red?

The first methods for gene therapy and still the most prevalent in clinical trials are for gene “addition”. The second wave of methods (like ZFNs, TALENS and CRISPR) are focused on gene "subtraction” (aka knock-outs). A third class are "gene regulators” more fine-tuned than complete addition or subtraction.

All three are easy to use and efficient, but aren’t what you normally mean by “general and precise editing” in which you can make virtually any small change in a genome. That is done by homologous recombination or HR (2007 Nobel for work done in the 1980s). The first two CRISPR papers in 2013 also showed HR in human cells, but this has not been the main use (in say the 3 CRISPR companies in Cambridge MA). Lambda Red is very efficient at precise editing but has until recently been restricted in species. Other recombinases (like Cre) work in many species but are so far challenging to customize for your favorite gene.


What is the development process of building a therapy? Are you pulling from your protective alleles list and/or from HAGR’s list of significant genes?

Yes. Pulling from the 307 genes in GenAge (part of HAGR, initiated in 2009 as one of the 11 publications that Joao Pedro de Magalhaes and I co-authored) focusing for now on genes that can impact.


With Nebula Genomics gaining traction, what deep insights might we uncover from whole genome sequencing, both on the clinical side and for basic science?

The biggest and fastest payoff is likely to be reduction in $1M costs (and harm) per child of the 5% of children exhibiting severe Mendelian diseases.  Another percent or so preventable adult-onset diseases like 68 genes on the ACMG list. Also, an important open-ended set related to de-risking old and new drugs based on precision medicine and related research.


What is the status of the BRAIN Initiative’s “functional connectome” mapping? I imagine the long-term results would have a profound impact on cognitive science and neurotechnology.

Are dynamic phenomena such as neuron spiking also studied in correlating function, or is the project primarily focused on spatial connectivity?

The IARPA MICrONS project is integrating calcium spike imaging with synapse level connectome.  In addition, my lab is trying to not only measure these complex activity maps but find the rules for synthesizing such brain structures. 


A personal question; what jumpstarted your love for science and technology?

It’s funny what we recall.  When I was 8 years old,  I melted a toy metal fork by sticking it in an AC socket. Then I figured out (on my own I think) what happened to a nymph in my jar of pond water (it turned into a dragon fly). But probably the biggest impact was the 1964 World’s fair in Queens. 


Lastly, I would like to end with a few thought-provoking and profound statements from your work “Regenesis”:

With so many options ahead of us conferred by advanced technologies, we cannot be content simply to ask, What can we do? … we must go one step further and ask, What should we do?

We are already using parts from hundreds of previously separate species/kingdoms in human-induced pluripotent stem cells, DNA enzymes from fungi that promote genetic recombination, transcription factors from Xanthomonas, green fluorescent protein (GFP) from jellyfish, enzyme genes from plants to make essential fatty acids, and so on.

Maybe instead of the genus name Homo, we should adopt the genus name of our chimpanzee cousins, Pan (… for “all inclusive”).

Thanks George!

07/2018

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