Murray Blackmore

This talk is called The Hunt Continues: Novel Therapeutic Gene Targets for Spinal Cord Injury.

This is the conference I look forward to the most all year. The fact that this exists and that you’re all here means everything. And yet the goal is to kill it. Get rid of it. Let’s never have this conference again because we did it. (applause)

I’m at the other end of the spectrum from Wise. I’m doing basic science, and I’m not done until we have voluntary movement.

Reviews the problem: your axons grow out of the neurons in your brain, and so messages can’t get through. What can you do about? You can maximize function of cpinal circuits and any spared fibers below the injury site. You can improve the growth environment and get some connections made, which is what Jerry Silver was talking about. There are certain types of neurons in the brain, though, that just don’t respond to those kinds of strategies.

So my work is focused on those. There are 2 hurdles to clear to get this done. The cell has a giant metabolic task to get that long, long axon to grow. And it has to be madly organized.

But it can be done. We know this because fish can do it. The peripheral nerve system can do it. Embryonic state humans can do it.

DNA is the blueprint for protein production. Some regions of DNA are active, others silent. It’s hard to rebuild the axon protein by protein by protein . . . so we take a different tack. We focus on transcription factors, because they’re fundamental coordinating units that manage lots of proteins. This is what we focus on in our lab.

Transcription factors regulate DNA which produces proteins, which manage axon growth, which then find targets, which lead to functional recovery.

Down at the level of transcription factors there are genes that act like kill switches. They shut off the whole thing. So what if you find one? You put it into a virus and inject that virus into the brain of a rat and then you get axons growing. They have two genes identified: KLF7 and Sox11.

Does it benefit the animal? Does it get function? KLF7 does, a little. But with Sox11, we get worse outcomes than before we started.

We were very discouraged by that . . . but points at a key need in this field.

How do we monitor the functional output of regenerated fibers? it should be simple. You evoke activity in the fibers (and only those fibers) and then record responses in target cells. But how do you specifically evoke activity in a subset of axons? You use something called optogenetics, which involves putting a protein from algae into a neuron, and that makes the neuron light up when it fires.

So we did that. We can tell exactly which neurons are active and responding. If you have cells in the brain firing, you should see activity in the cord. And we do, in the healthy animals. When we looked at the Sox11 animal, what we saw is that there were synapses, but there were strange differences in the type and location of them. So now that we can measure it, we can improve it. So next we’re going to add some training and some chABC to see if we can get better results.

Okay, so what else are we doing? We’re trying to figure out how to get more axons to grow. And where do you find people studying lots of growth? In cancer research.

So he went and found all the transcription factors from cancer research. And there are 1400 of them, and it turns out that there are 12 factors that need to be studied.

This takes expensive equipment to pull off . . . and we have it thanks to Geoff Kent and his Spinal Cord Injury Sucks group, who rolled up one day with the money to pay for the microscope we needed.

One cool outcome from this is that we have been able to do high content screening to find new transcription factors, and some of them work. We’re looking at genes that nobody has ever studied, especially one called HHEX.

The support from private foundations (u2fp and scis) has allowed exploratory directions not otherwise possible. We would not be doing this work without you. No way.

Question: what are you going to do with HHEX? We think it’s an important inhibitor of axon growth, and we’re going straight into mice with it.

Question: why aren’t we focused in one location? Why are there people all over the place doing this work instead of being in one place, sharing their information instead of hiding from it? It’s a good question and speaks to the importance of collaboration . . . I obviously can’t answer the “why” . . . but there is some benefit to having things spread out. I’m at Marquette, and I do talk with people at sci centers, but I’ve also had benefit from people who aren’t working on sci . . .

Question: How can you measure living axon growth? Well, it’s an active area of research but right now we don’t have a good way.

Question about collaboration between people in chairs and scientists. Murray says that there should be a bottom-line collaboration requirement to funders. We should force the field in the direction of collaboration with the most powerful lever we have, which is the dollar.

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