A couple of harsh realities.
Only 1 in 10 clinical trials is successful. Hardly any rat model therapies translate well into humans.
Sensory Input in the Injured Spinal Cord: Plasticity, Pain and Automonic Function, and Use in Neuromodulation of Motor Function
How many people in this room are in pain right now? Lots of hands go up.
Okay. After injury you have altered descending input and normal sensory input. You have changed integration inside the cord, which results in new motor or autonomic output.
Hmmm. In rats if you pinch the back of a rat, you get this weird skin shrinking thing. Showing this on a video of an anesthesized rat. Tweezers. Skin shrinks up all around the pinch.
It’s called the CTM intersegmental pain reflex. He’s going into technical detail about how this works, using a wiring diagram . . . eventually he’s going to circle back to how it relates to sci pain. Cross section of a cord showing big fat axons with lots of myelin and thinner ones with a lot less, and then abundant axons with no myelin at all.
Okay. Has anybody had to get medical care because they burned their thighs with a hot laptop? Half a dozen hands go up. So, pain is good, sometimes. But neuropathic pain is backwards, because lighter touch makes it happen instead of harder touch.
Why do we have pain above the injury level? Why do we have pain at all? Oh, people, this is a fail. He’s talking very fast, using a lot of jargon, and showing busy slide after busy slide, each one covered in data that I’m sure would be super helpful and informative if I could slow him down by about a factor of six. And he just said, oh, I need to speed up or I’ll run out of time.
He’s showing data that (I assume) explains why electrical stimulation works. It has to do with finding the right level of stimulation and the right sensory input. There are ways to use stimulation to decrease spasticity in motor incomplete type of injuries without taking away any voluntary motor control that the patient might have.
The work he’s discussing is about using sophisticated methods and measurements to home in on the exact quality of stimulation that benefits each individual patient. There could be a device that a person would get in, be assessed, and get a custom-designed stimulation program.
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.
Rachelle Friedman Chapman
I was paralyzed 4.5 years ago at my bachelorette party. A friend playfully pushed me into the pool. I fell weird and hit my head. c6 quad.
Talking about how much she loved the movie, Murder Ball. In college she helped people with adaptive sports as a volunteer . . .
Sometimes looks around and goes, this is crazy. The news media got hold of my story when I was about 6 months post. Yeah, my best friend. Yeah, my wedding only 4 weeks away.
One interviewer asked me how much of it is attitude . . . and I said all of it. But that became a thing because people take it to mean that if you only try hard enough you can do it. That’s not true, as everybody knows. People don’t want to hear about the bad stuff, right? I don’t think I’ve had a good morning in 4.5 years. I have very severe neuropathic pain, sometimes so bad that I wake up in tears.
Everything takes forever. Getting dressed, going to the bathroom. I need my mom to help with my bowel program. I have to have people help me get the bag out of my pants. When I go on tv, every single time I talk about science, about the need for a cure, and every single time they cut it. Every time.
I started writing a blog because of that. More than equality, we want a cure. We want equality, sure. But more than that we want to get well. People actually ask me if I’d change this if I could.
Yes. And you know what else? I don’t think everything happens for a reason. I don’t want to be an inspiration. I want people to see that I’m a person, sure, and I want people to understand that they could be me, and that this can happen to everybody.
I used to teach line dancing at senior centers, and now I have more in common with 80 year old people than I do with people my age.
Once I did a panel with people who were against stem cell research, and this guy who was against it admitted that he’d be in favor if it was his own daughter were injured.
We need to be louder than the people who say this is okay.
I’m going to do something I have not done before. In the last few weeks I gave several talks, and I realize that some of the videos I showed were distracting the audience . . . they weren’t listening to what I was saying. So I’m going to talk for 20 minutes before I get to any slides.
I’m also doing something I haven’t done before. I’ve actually written up what I’m going to say, because I want to cover all the territory.
(Okay, I’m going to recap this as he goes, but I’ll get you the text itself if he’s wiling to share it.)
Most of history, no hope for repairing damaged cords.
Discussing some papers and history that are the background for his work in the China Clinical Trials . . lithium, lithium, lithium. Umbilical cord blood cells. They’ve done six trials.
1. 20 complete sci people given lithium
2. 40 subjects double-blinded to lithium or placebo . . . significantly reduced neuropathic pain in 5 out of 6 people treated. Unexpected result.
3. 60 subjects with severe neuropathic pain ( more than 5 out of 10) . . . have randomized 42 subjects from this trial. Half of them report significantly less pain, even 6 months after the trial has stopped. 18 more patients left to randomize and 6 months to evaluate them.
4. Transplanted 1.6 or 3.2 million HLA-matched umbilical cord blood cells, having spent 4 years developing a procedure to store and ship. They’ve seen no adverse effects. At one year, 2 of the patients had nerve fibers crossing the injury site. We don’t know if these are axon fiber bundles, but it’s hard to imagine what they are. Very disappointingly, none of the people who had these fibers growing had any motor return, though some did get sensory return.
5. At the end of 2011, beginning of 2012, we did 20 patients with chronic complete injuries – except one who was a c3 ASIA C. They got 1.6 or 3.2 or 6.4 million cells. Then we did a fourth group who got 6.4 million cells and a bolus of mp. And finally there was a fifth group that got all of that plus lithium.
6. 6.4 million cells into 13 subacute patients + lithium
Now talking about Kun Ming trial, which I think is #5 above. No study before this had ever shown recovery of walking . . . 3 of the subjects quit training partway into the study; they had fractures in their legs which were apparently there before the study. At 3-6 months, 75% of the patients were walking in rolling walkers with someone behind them with a rope to keep their knees from buckling. One patient was walking without help. When they went home, those who kept walking kept getting better.
Okay, I can’t keep up with all the data he’s reading . . . the gist is that there were people in these studies who regained walking. 10% of them could walk more than 100 meters without help. By one year 55% of the patients were no longer using catheters.
We don’t know what this is all about; we’ll have them back for a 2 year follow up.
The data seems to be all over the map . . . 17 subjects who got intensive motor training, and 15 of them recovered some walking.
Based on these results, we’ve proposed new trials around the world. They plan to sort people into groups that get one of five possible treatment menus. All will get locomotor training, no matter what else they get. The 5 menus are surgery only, surgery + lithium, surgery + lithium + cells, surgery + lithium + cells + MP, and um . . dang it.
But wait . . . we have people walking who seem not to have any voluntary motor scores. What? If you don’t have voluntary motor scores, how are you walking?
Why was the first study controversial? Because the idea that taking a couple of lithium pills could have an impact on the volume of cells was just weird. You’re not getting more cells, you’re getting cells with more dendritic trees.
What was the dose? The same dose that’s used to treat manic depression. It’s correlated with blood volume.
Has anybody ever gotten worse neuropathic pain from these studies? In the double-blind randomized study of 40 people, 2 of the placebo people got worse pain, and 2 of the lithium people got increased pain, but it was less than the 5-10 score.
Still HLA-matching? Yes, (goes into some technical detail about how this works)
Do the people who don’t cath have control? We estimate that half are using the crudet procedure, which is scrunching down and pressing on their bladders. I wondered if it had to do with the cost of catheters — nurses say no, it’s not that.
Describe walking with assistance. There’s someone behind using a rope to keep the person’s knees from buckling. They use a rolling walker for support.
Reggie says that they need to talk. I’d say.
Reminds us that the twitter tag is #w2wseattle.
Points to the event survey on each table . . . because this is a community-based event, it matters that people fill out the form and get it back to them. (This reminds me that you readers out in the world might have feedback for the organizers; if so, put it in the comments, or email me).
They’re also looking for donations, no surprise. Got a few bucks? There’s a donate button on their page. u2fp is a very, very low overhead organization, but they do have a few expenses.
And Barry Long rolls up to emcee the morning events.
First speaker this morning will be Wise Young.
A dozen people in the room . . .
What’s your road map to get to clinics . . .need FDA approval. To get there you need your devices to be safe. Probably they won’t approve the implants together at this point; the brain one is now being tested through a company called Cyberkinetics, but the investors rolled back. Now it’s being done out of Brown University, Ohio State. They’re using the blackrock system . . . c4 ASIA A spinal cord injury is the injury model. Have done 5 patients now.
Would do brain stem stroke patients as well, because symptoms are the same and there are about as many of those as there are sci patients. The whole package is extremely expensive.
What will the collaboration between stem cells and stimulating wires look like? They’ve been working on this but haven’t seen good results yet . . . also haven’t seen negative ones. They put 100,000 iPS cells in, sacrifice the animals after a month, then count how many cells survive. This is how they know that the cells survive.
Differences in inflammation with or without wires? . . . haven’t done that. All their animals get wires, but only some get stimulation through those wires.
Results of epidural stim stuff . . .is that informing your work? It has us very excited in thinking about an early human trial. We have a new neurosurgeon who is doing about 2 surgeries a month on people who have been losing sensory or motor loss to relieve bone compression on the cord that happens in people with longterm issues. They’re talking about adding the epistim device to the patients who are getting this surgery.
Seems very low risk and a case of “why not” since they’ll already be in there. We’re seeing this as the most exciting thing we’ve seen in the last five years.
The epistim model mechanism hasn’t been explained . . . lots of people are prepared to jump in.
Was there improvement from your stimulation in any area? We didn’t see improved pain sensation. We don’t have good animal measures for sensation improvement or proprioception. Anecdotally, we saw evidence that there may have been some improvement in both. There was also a marked reduction in flexor tone, like you see in FES cycling.
What’s the end game for the core research tracts?
I’m a basic scientist. We’re looking for partners, though, in the commercial medical device world.
How realistic is the wireless thing? I think that will happen very soon. We don’t have to develop our own technology because consumer electronics are doing it for us. The challenge is whether or not we can make it stable biologically.
But your electrodes look very small . . .
We have a grid that will cover a larger area of cortex . . . most likely a thin wire that works like the epilpsy stimulator. The issue is breaking the skin, which is how infections happen, but once you’re inside you can run wires safely all over the place.
What about the creepy factor? When you’re looking at somebody who’s chronic and complete you’re more likely to say yes, no matter how creepy it seems. It will be worth it to some people. This isn’t going to be something anybody wants to do during the first six months because they might be getting return during that time.
Question about proprioception. The answer is technical and has to do with setting up electrical fields instead of doing stimulation. He says that stimulation works better.
Another techy question that is going by me, sorry. It looks like a lot of the people in this room are AB folks who work in the field rather than people in chairs/caregivers.
With the pace of technology, it seems like the time lengths are getting really compressed . . . but how much time are we talking between today and when this gets to patients in the field.
What we know is that getting all the way through a clinical trial takes 5 years. From starting today. But we aren’t starting today. So, much longer. That’s where the 5-10 years comes from. BUT there are a lot of smart people working on the device/body interface, and there could be a breakthrough that changes that whole calculus.
What would you tell a patient to be doing to be a candidate? Our intervention is stimulation to restore movement. So patients will need muscles. That means FES. Maintain good health generally. Keep doing rehab. Don’t believe people who tell you that 6 months is a physical plateau . . . it may be a psychological plateau, a place where adjustments have been made, but there are people in this room for whom 6 months was not even close to being a physical plateau. Someone adds that range of motion is also important.
What about a brain/exoskeleton interface? it may not be technically that hard, but I don’t know anybody who has moved down that path.
Anything you didn’t get to? Okay, bladder and bowel. There are some opportunities from Big Pharma . . . they think they’ve tapped out pharmaceuticals, and they want to get involved in devices. In large populations, which isn’t us. For example, if we could develop something for mass consumers who have bladder issues — an implant in the peripheral system that could tell when the bladder is filling . . . you would wave a magnet over it and it would assist with voiding. It would be a small surgery, not terribly invasive. Would you be interested in that? Someone says that it’s more complicated than that . . . the muscles that control the bladder are not simple. So, if GSK wanted to spend millions on this, would people be interested?
Man says, my daughter would jump. She’s 21. She’s going to live another 50-60-70 years, and she would choose b and b over learning to walk in a second. Her network of young women with sci — all of them would say that. She was most interested in the return of b and b and sex from the epistim study.
Man says, he had a friend who lived sitting in pee for 10 years until she got a pacemaker thing. A spasming bladder has a mind of its own.
Well, GSK has set a very high bar. They want to put a cuff around the bladder that can sense the fullness, can stimulate the system JUST to void, and then can block activity if you need to. There’s currently a $1 million prize for figuring this out, along with a few others. Like blood pressure control, hypoxia, and bronchial constriction. You need to solve two of these. They’re giving out $200k to people who can demonstrate that they have a good idea. The $1 million would be for whoever solves it in the end.
So, taking a quick break here while the first breakouts happen. Sorry if you were dying for a report from one of them. While I’m down, I’ll share the text that I planned to say to the room when Marilyn and Peter Wilderotter introduced the new book.
So, here’s what happened. Last year at the end of working 2 walk in Boston, Jennifer Longdon and I were hanging out in the hotel bar.
What a shock, I know!
And we were noodling about what else could be done . . . we’re both writers by trade, and so of course we started thinking BOOK! (If you’re a hammer, everything looks like a nail. If you’re me or Jen, everything looks like a book idea. 🙂 )
Seriously. There’s no book that gathers up all the stuff an advocate ought to be fluent in. There are a zillion websites, and a dozen or so that are really good . . . but the internet is like a maze. There comes a moment when you say, “I know I read that somewhere . . . “ and it all starts to run together.
So, Book Idea: a sort of Spinal Cord Injury Research for Dummies! Those books work because they focus on the salient things. They have illustrations right where you need them. They make use of the space on the page to help highlight things that matter. If they’re thoughtfully done, they can save a ton of time for the person who just wants to understand one thing.
So that was the idea. And Jen helped me pitch it to the kind people at the Reeve Foundation, and those kind people said, “You know what, the community does need one of those.”
I spent most of the last 3 months doing interviews, writing, revising, and preparing to do more and more of all that. The result is the Sneak Preview you have in your hands — the first section of what will be a whole book sometime early next year. The first section is, as you’ll see, about the cord itself. What are its component parts called, how does each one work, how do they work together — that sort of thing.
Still to come will be similar sections that take apart the money scene: where exactly does funding come from? Who decides how to dole it out, and on what grounds? What limits the amounts granted? There will be sections on how regulation works, and what role investors play, and what it’s like to run a research center or a lab, or to be a post doc student trying to get a permanent job.
This is the question I ask everybody I interview: WHAT DO YOU WISH ADVOCATES KNEW?
The value of the book is in collecting all those answers and seeing where they lead us in terms of strategies.
Winston Churchill said that 80% of success is showing up.
I don’t know about you, but I AM DEAD SICK OF 80%. I WANT THE NEXT 20.
It’s obvious to everybody who has been following the science for the last 10 years that things have changed. Not fast enough. I don’t want to be standing here 10 years from now, saying, “Gosh, if only we’d figured out how to get organized!”
Let’s get organized. It won’t be a miracle. Don’t call it a miracle when determined people educate themselves and make something happen! That’s not a miracle, that’s how it’s supposed to work. Miracles are magic — they’re effortless. We are not going to find the cure without effort. A lot of it. It pisses me off when people suggest that the recovery my husband got was a miracle. Please! Do they have any idea how much work, how much pain and frustration, how much money was involved? Or that it was only possible in the first place because he had a sufficient number of surviving pathways? Don’t call it a miracle. We have work to do, and lots of it.