Mar 242017
 

About a month ago I attended Hanson-Wade’s “Crispr Congress” in Boston. This was their third such event, and I’ve attended all three of them. Below, a very quick report on what I saw and learned there.

CRISPR of course, is the shorthand name for the revolutionary new family of genetic editing techniques, derived from a recently elucidated chemical process used by bacteria to defend against infection by viruses, that allow scientists to programmatically alter genomes (DNA) however they like. This post assumes you have a basic familiarity with how crispr works; if not, the Internet is your friend. There’s no shortage of explanatory material out there.

Over the last three years the field has matured astonishingly. There is already a whole ecosystem of companies, both startups and established biotech vendors, that provide the tools, services and products necessary to do work using crispr techniques. The greater crispr community includes researchers in academia, in industry, in medical settings, and elsewhere. There were representatives from all these domains at this conference.

This crispr ecosystem is starting to sort itself out. Three years ago many of the presentations at the Crispr Congress were about basic discoveries of how the crispr mechanisms evolved by bacteria could be understood, measured, and adapted. People were hinting at ways these new gene editing techniques might be used therapeutically — that is, to cure diseases in humans. There were more presentations on areas of investigation than on breakthrough results, a lot of speculation, a lot of open-ended questions. The situation three years ago seemed to me somewhat akin to when Howard Carter first opened the door to King Tut’s tomb and discovered room after room filled with nearly unimaginable riches and wonders, much of it in a jumbled mess.

Now, it seems to me, there is more order. The wonders and riches are still there, many of them untouched, but we now have a map of the rooms. People are figuring out what they want to study, whether it be the golden burial mask or the glorious and inscrutable wall decorations or the bewildering funerary text on the sarcophagi. (OK, I think I’ve milked that analogy enough.)

I noticed two distinct themes at the Congress this year: (a) cataloging tools and techniques and (b) using the tools to do new kinds of genetic editing.

Cataloging Tools and Techniques

Several of the presentations this year seemed like filling out a periodic table of the elements of crispr. For each endonuclease (e.g. Cas9, Cpf1, . . .), for each assay used to measure a result (circle-seq, BLISS, . . .), for each delivery mechanism to get enzymes and RNA and “donor” DNA into a cell or nucleus (various viruses, lipids, nano shells. . .), for each method of DNA repair (homologous, non-homologous), etc, what are the parameters we can measure? What results do we get? For any given experimental situation, what are the best techniques for measuring off-target activity? What are the best ways to control off target activity? etc. This makes for a pretty comprehensive n-dimensional matrix.

It turns out that the answers to these questions vary a great deal from one situation to the next. Depending on the precise DNA sequence you’re trying to edit, and exactly what edits you’re trying to make to it, the techniques you use may vary greatly. The difference of a single base pair in a target gene may dictate a different approach.

Presentations along these lines came from, among others, Megan van Overbeek, Caribou Biosciences, who talked about DNA Repair Outcomes Following Cas9 Double-Strand Breaks. Her talk was basically slide after slide about how DNA puts itself back together depending on how and where you cut it. Her report summarized the results of literally hundreds of experiments.  In a way, listening to her presentation was about as thrilling as listening to a reading of the atomic weights and valences of all the elements. But yet it actually was kind of exciting to see this data getting out into the world. It means that every Crispr experiment will have fewer false starts, a lot less guessing, a lot less trial and error. It’s easier to fix something when you know which tool to use.

Over the 2 days of the convention there were about a dozen talks that I would put into the general category of “technical mastery of crispr technology as it’s now understood”. Not all of this is glamorous work, but it is pure and necessary science, and it’s fascinating to see the picture taking shape.

Putting the Tools to Use 

There were also some presentations of not just how Crispr works, but of what you can do with it. The most dramatic result that I saw was presented by Daniel Anderson, a chemist at MIT, who explained how he and his lab had used a sphere of lipids to encase a Cas9/RNA/DNA package in living mice, which was then differentially taken up by the liver — since one of the functions of the liver is to process lipids “it’s like feeding them a butterball”. In their study of mice, they found that they could correct the mutated gene that causes a rare liver disorder, in 6 percent of liver cells — enough to cure the mice of the disease, known as tyrosinemia. So this looks like a promising approach for actually curing certain kinds of genetic diseases in humans. Of course this lipid delivery mechanism would not work to direct a crispr genetic repair package to, for example, the heart, or to the spinal chord. Organisms are complex. Cells vary a lot in form and function. Several other speakers talked about the challenges of getting Crispr systems exactly where you want them, to edit precisely the cells you want to edit, and no others.

Ru Gunawardane and her lab at the new Allen Institute for Cell Science (where she is Director of Stem Cells & Gene Editing) are doing some fascinating work that will help with this problem. They used Crispr to introduce flouresent tags into stem cells, which allows us to watch, under the microscope, processes that we have until now only been able to view in a kind of animation, by stopping cells and staining them as they performed various life functions. Their new approach promises all kinds of new ways to understand how cells work (and how they malfunction). Check out the videos on the Allen Institute web site for a peek at what they’re doing and where they’re going.

Another nifty talk came from Harvard post-doc James Gagnon. His “Whole Organism Lineage Tracing with Genome Editing” showed how he could edit embryonic stem cells in zebrafish and then follow them through the organism’s development. The implications for developmental biology are enormous.

In his closing remarks, Bill Lundberg, CSO of CRISPR Therapeutics, touched on the bioethical questions that we’re all going to be dealing with sooner or later.

And, as expected, George Church gave a (low key) rock-star talk, full of compelling visions of a world without disease, where everybody is immune to all viruses, where age is reversible, where nobody goes hungry. He was provocative, as always (example: “non homologous end-joining isn’t genome editing, it’s genome vandalism”).  His talk moved at lightning speed from one fantastical, science-fictiony scenario to another. But Church wasn’t just spinning scenarios from science fiction; every far out vision he offered was based on (straightforward) extrapolation of science that’s happening right now, much of it in his own Harvard laboratory.

As a non-specialist I’m sure I misunderstood or failed to grasp the implications an awful lot of of what was discussed at Crispr Congress 2017. But I still took in nearly more than my little brain could handle. I look forward to Crispr-Congress 4, in 2018. I can’t even imagine what we’ll be discussing by then.

 

 

 

 

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