Q and A with Dr Silver, Dr Lee, and Dr Lin

Q: What are all those axons growing on in the lesion?

A: They’re growing straight thru the scar. In the scar there are OPCs that usually trap the axons, but they get turned into a highway

Q: Did you really say that the rats lived without anybody remembering they were there for 18 months?

A: Jerry: Yes. People don’t know this, but their bladders work just well enough — though chaotically — after the first couple of weeks. And the people who do the animal care just kept feeding them. It was a huge stroke of luck.

Q: What’s the CRP doing in those first days?

A: Jerry: We all know that there’s a slow circuit remodeling that goes for as long as you live; the cord is always trying to fix itself. Some of that is good and some of it is not. When we introduce our peptides, we’re uncovering synapses that are there but made silent by the net of CSPGs. That net is smothering not just the sprouts but the connections that could be working. This is my theory …

Q: In chronic SCI, the neurons are missing blood supply … they’re weak and skinny. It sounds like your intermittent hypoxia treatment is giving them an oxygen boost.

A: I hadn’t even thought about that, but you’re right.

Q: In chronics, you saw fibers growing across the lesion, right? (Right.) But those are really different from motor or sensory neurons .. what’s the plan for those?

A: Right, rats don’t have a corticospinal tract like humans do. We can do tracing studies. It’s likely there are other fibers growing through, but these are the ones we stained for.

Q: What does your BBB scale represent for humans?

A: BBB 9 means the animal can stand. 12 means it has coordination to take steps. It’s inexact, which is one of the reasons we went to other kinds of measures.

Q: I’m asking, at what point is it time to go to the clinic for humans?

A: This peptide has no toxicity (“Ok, so let’s move on!”) and there is a man in Canada who has a paralyzed daughter who wants to get the investments made to move quickly to get these peptides to the clinic. He’s hoping to get this done before 2 years pass.

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Yu-Shang Lee, PhD and Ching-Yi Lin, PhD, Cleveland Clinic

A Translatable Peptide to Overcome Glia Scarring After Spinal Cord Injury

Subcutaneous Application of Small Peptide Removes Glial Scar and Facilitates Outgrowth on Dorsal Root Ganglia

This is unpublished material, meaning the paper they’ll write with these results is not through the review process yet.

Ching-Yi:

She has a slide up that shows the bad old news, which is that after injury you get a glial scar surrounding the lesion. It’s made of those proteoglycans (CSPGs), and it prevents axon growth, like Jerry just told us. By the time a few weeks have passed, these molecules are there for good.

Unless something interferes with that scenario.

People have been trying to do that in various ways for a long time … but the best approach has been what’s called ChABC, which is a bacterial enzyme. Unfortunately, it has a short lifespan, it’s invasive, and you have to keep applying it over and over. That means we really need something better.

Enter the peptide, which they’ve called CRP, for CSPG Reduction Peptide. It solves some existing problems with ChABC — it can be applied by subcutaneous injection, it has a very selective and specific binding behavior, and it has fewer side effects than ChABC. It’s easy to control the amount applied, and to time the application. It’s also affordable.

She’s describing a “lysosome targeting motif” that I’m not familiar with and don’t really understand, sorry …

So, they took a rat, gave it a T8 contusion, waited a day and then gave it a dose of CRP … the rat got a dose every day for two weeks … what happened, if I’m understanding the images right, is that CRP interfered with the filling of the cavity with the sticky protein-sugar molecules.

Okay, now she’s talking about some astrocytes that appear to be involved in the creation of CSPGs in the first place, and making the point that their new peptide appears to decrease the production those bad guys in the first place. (At least that’s what I think she’s saying; it’s hard to understand, at least for me.)

If injected 1 day after injury:

  • CRP can efficiently enter the cord
  • Efficiently decrease sci-induced CSPGs

And when applied in vitro to Neu7 astrocytes, CRP can:

  • Be targeted to lysosome for degradation
  • Decrease astrocytes
  • Discourage production of CSPGs

Yu-Shang:

Working on moving this to humans, i.e. taking advantage of what CRP can do.

In their latest animal studies, the plan was to do the contusion, wait a day, give a daily subcutaneous injection every day for the next 3 months, then evaluate the animals. They’ve done this and seen sustained motor recovery for 3 months. What happens if they put the poor rats on a treadmill for some nice gait training?  Actually the treadmill just lets them measure accurately what has happened to the gait pattern. He’s showing measurements that show how similar the gait is after 3 months of the CRP regimen.

Also, peeing. Yay! The animals that got CRP have bladder activity that looks almost exactly like that of animals with intact cords. The intervals between voiding are smaller … the data here is kind of crazy. They know exactly how much pressure is on the bladder at every point, so they can see the relationship between that and voiding. The rats pee when they need to, is the bottom line.

Obviously this CRP stuff works in the way that they hoped — it’s preventing CSPGs from filling up the cavity and allowing sprouts to move across the half-damaged cord.

The challenge of the chronic cord is familiar — so what happened when they tried their CRP on animals with older injuries? (In a rat, 2 months is a long time; it’s chronic.)

When they waited 2 months and started giving their peptides to the animals, they saw better results than in the rats that got it right away. (Hey, something that works in chronics!) Again, they did all the testing they know how to do with rats in bladder and motor function and these animals got better.

When they opened up the cords after sacrificing them, they saw just what you’d expect — much less “filling” of the cavity, much more sprouting across the injury, which is what would account for the return these animals got.

Going forward, this looks very possible for people. The peptides are cheap, safe, and —at least in small animals — effective. They’ll be moving ahead to get them tested in larger animals and in us, eventually in combination with other strategies.

Ching-Yi_Lin

photo credit ResearchGate

Yu-Shang-Lee-People-Behind-the-Science

photo credit People Behind the Science Podcast

Jerry Silver, PhD, Case Western Reserve

Overcoming Proteoglycan Barriers to Axon Regeneration and Sprouting in the Chronically Paralyzed Respiratory System

This is my favorite organization; all of you motivate me. I want to share a story that involved the respiratory system we talked about earlier … I don’t think the respiratory system is special. The plan is that I”ll talk, and then I’ll introduce you to a couple of people.

Here’s the respiratory system. It starts down here … he’s pointing to a complicated image and saying that the pattern generator for breathing is in the brain, not in the cord like the central pattern generator is

They use a hemisection model with their rats. We’ve known for more than a hundred years that nature has a way of preventing broken axons from growing again; there’s like a net made of molecules called proteoglycans (CSPG). The net is so thick that it can block synapses from finding one another. You can watch axons trying to grow into CSPGs and getting stuck like they’re on flypaper — I’m watching it right now, in this film Jerry is showing. The question they had was about how to break the net — how to get the nerve fiber to become unstuck from the CSPGs.

The tool to do that was this stuff called chondroitinase … it’s an enzyme that breaks down the sticky part of the CSPGs. What they see in rats is recovery of 10% of breathing after 7 days. So, not great. They wondered if they might be able to give the rats some kind of rehab, like getting to breathe really hard. This worked pretty well, until it didn’t. And then it did again …

There were also — as in all cases post sci — sprouting axons trying to cross from the healthy side to the injured side.

What they saw was that after 12 weeks of chronic SCI, they saw results that were too good to be true, so they did their experiment again. Here’s the protocol, with a whole new group of animals. They gave the enzyme to all the animals and varied the amount of breath work. With intermittent breath work, they saw normal breathing , like — both sides were exactly the same although one side was paralyzed.

Wtf? Showing us a video of a rat’s diaphragm. First is the control, and you can see a red blob with a pulsing right side and a still left side. Then the movie of a rat’s diaphragm treated with the enzyme and the intermittent breath work. That blob is pulsing on both sides equally. And another film, showing a diaphragm behaving chaotically, meaning it’s just in terrible spasms. The culprit turned out to be serotonin. To test this, they gave healthy animals serotonin, which — sure enough — made their diaphragms behave like little madmen. Too much serotonin is bad, that’s the takeaway.

Here’s the mistake …. my research assistant came and told me that he had 12 animals in the basement who’d been kept alive for more than a year — a year and a half — because we just kept taking care of them. Well, that’s a big waste of money! What should we do with them? Let’s give them some chondroitinase and see what happens.

They had five animals to work with, because some of them had died of old age by this time.

So, full recovery. That’s what happened. Full recovery.

Ah, here’s the Cajal quotation about how there can be no recovery.

Okay, before he introduces the next speakers, who are from his lab, he tells us about the peptides — which are molecules that help get rid of the sticky CSPGs.

jerrysilver_1

photo credit Diaro Medico.com

Advocate of the Year Award

The Advocate of the Year Award: Our Cure Warrior is going to be Marilyn Smith, who retired last year after twelve straight years of leading this organization.

It starts in the most charming possible way, with a video feed of her son Noah Smith, which already makes me tear up. His face is enormous on the screens at the two sides of the room.

“Surprise, Mom!”

“I was injured about 15 years ago … and I’m just so thankful for what you’ve done and even though I’m not there yet I believe I will be.” (Oof ,that was emotional.)

Marilyn and Noah smile and make kisses to each other.

Marilyn: “Noah got hurt 15 years ago. He’d been home from college for Thanksgiving weekend and was driving back to school on the freeway when a truck on the other side of the median lost a wheel. If flew off the truck, bounced across the road, and slammed into his windshield. He was a quadriplegic.

There were six of us who started this thing, we called ourselves the Six Bionic Women — unfortunately I’m the only one of them here today. In the past 15 years I’ve met the most amazing, resilient, wonderful people. I’m so grateful to be part of this community. Noah, I’m so sorry you had to break your neck to have this happen. (He makes a face, and we laugh.) I wouldn’t wish it on anyone.

I’ve never met a more extraordinary group of people.. Thank you.”

The award is in the shape of a tennis racket, which Noah suggested because Marilyn is a tennis fiend. Matt gives it to her, talks about her tennis life, and then quotes Billie Jean King:

The main thing is to care, and to care hard.

Amen.

Thanks, Marilyn. We owe you.

Sabrina Cohen, Sabrina Cohen Foundation

(Note: I wish I could type just a little faster .. this is my best effort to capture what she said, but it’s by no means ALL of what she said. Find the video when it gets put up; you won’t be sorry.)Sabrina

From Injury to Advocacy

In 2005 I was first introduced to U2FP in Washington DC. What they do here is try to keep our community together.

When I was 5 yrs old, I already knew I wanted to do something important in the world. At the time I thought that meant becoming a social worker.

In August of 1992 I was an independent carefree, 14 yr old. I was a B student who loved to talk and schmooze too much. I was on my high school swim team, looking forward to things like dating. A friend died that summer, which seemed so wrong and unfair; little did I know it would soon be my turn to experience “unfair.” On Halloween night I spent the day with my best friend, Karen. Our plan was to meet some friends that night and go with them to downtown Miami. At 9:30 pm, in cutoff jeans and a white tank top, I kissed my mom goodbye and ran with Karen to meet up with four others, three guys and one other girl. Then we stopped at one of the guys’ houses to get another car., because he thought he might want to leave early. So there two cars, each with three people in them. I was alone in the back seat of a BMW, not wearing a seatbelt. Right away, these guys started drag-racing on a 30mph curvy street. The one I was in got hit at 90 mph.

I was a c3 quadriplegic, pulled out of the car because people thought it would explode. All the other kids walked away. I had surgery. I spent a month in ICU and then 2 more months in rehab. The first day they put me into a sip n puff chair and I slammed my poor mother into a wall. As I entered rehab the first thing I saw was some others in wheelchairs. i started to cry and wanted nothing but to go back to my room.

At home, I had to live downstairs. I went back to school, where I ate lunch in a private accessible bathroom so my nurse could feed me without anyone seeing. I spent hours every day in therapy and then doing homework. That was my life.

I never, ever gave up. The hope of walking one day never went away. i was asked to speak to a group of seniors about reckless driving, which I didn’t want to do. I did it anyway.  At graduation I was called first and positioned front and center so that all the students had to climb over me … there were more than 600 students so it took a long time. I thought, sitting there, that if I’d given up these people would all still be here. Life would go on, with or without me.

At the University of Miami I got a driver’s license, made new friends, joined a sorority, and had a social life … back in those days, no Siri, no Alexa. I graduated with a double major in advertising and psychology, and after another degree in copywriting I was finally done with school. I was terrified to go on a job interview. Who would hire me?  What if I dropped something? What if I needed help in a bathroom?

I made it to one or two interviews before giving up on that .. I decided to start my own company. After a couple of years of that I met a man named Bernie Siegal, who was head of the Genetic Policy Institute. I closed my business and took a job with them.

That led to deep involvement with the stem cell research movement, where I became a fierce advocate, with many, many public appearances.

I became convinced in those years that I needed to get strong, and it was during that period of intensive exercise that I fell and injured my foot, which led to hospital stays and pneumonia.

So that was in 2012, and I was very sick. I wanted to figure out what I could do to make sure I never got sick again. What I did is go to the beach. I wanted to go to the beach, actually. I couldn’t go there, because my chair and the sand were a bad combination. I thought that while science makes advances, I could focus on something else — a way to bring health and wellness to people with SCI. An adaptive playground. It’s fair to say that I now have a master’s degree in politics. Access may be a no-brainer to most people, but the idea of having disabled people in their backyards was NOT welcome to some of the citizens of my city.

In 2014, my idea for an accessible beach was chosen out of 400 applicants. With help from the Neilsen Foundation and the Christopher and Dana Reeve Foundation, we’ve served more than 2000 people. In two weeks we’ll be opening the first adapted beach playground so that all kids will be able to play near the ocean.

And we’re going to open the first fully accessible recreation center in the state of Florida.

30,000 people have heard me.

I’m a professional life coach.

I have a real estate license where I focus on universal accessibility.

I’m about to go and speak to thousands of real estate agents about why this matters.

Earlier this year I tried IVF .. which didn’t take, but I’m not giving up.

We’re all capable of adapting to whatever life gives. Be kind, caring, and understanding. Try not to take things for granted. Surround yourself with positive people. Less talk, more teamwork. Stay fierce and committed to what you love. My heart remains open to the possibility that one day, soon ….

Quotes Steve Jobs: No one wants to die. Even people who want to go to heaven don’t want to die to get there. And yet death is the destination we all share. No one has ever escaped it. And that is as it should be, because death is very likely the single best invention of life. It is life’s change agent. It clears out the old to make way for the new. Right now the new is you, but someday not too long from now, you will gradually become the old and be cleared away. Sorry to be so dramatic, but it is quite true. 

Your time is limited, so don’t waste it living someone else’s life. Don’t be trapped by dogma — which is living with the results of other people’s thinking. Don’t let the noise of others’ opinions drown out your own inner voice. And most important, have the courage to follow your heart and intuition. They somehow already know what you truly want to become.

Personally offers heartfelt thanks to an amazing list of people and organizations who have been there for her and for us. Brilliant woman, in the sense that she brings light.

For real.

Q and A with Dr Ferguson

Q: This is one of the most exciting things I’ve seen … one of the things that make us crazy is there’s so much duplication. Lots of $$ spent on things already done, which means things could move faster if that money knew where to go. Can your work help reduce duplication?

A: What happens now is that people send us questions and we have to query the data for them. What we want to do is make the tools that will make it possible for them to use the data to answer themselves.

Q: I have a premature question … could we imagine in the future that your tools will get us to a broader view. I’m dreaming of having a roadmap. Could these tools help to generate that roadmap for us?

A: Actually I anticipated that question so I have some slides ready … (we laugh) … he shows us an example of how you can take a single study with a very nice result that turns out to be a super outlier when looked at in context.

Q: How do you know how to understand the semantics of the data so that anybody can use it?

A: The partners that we have in the neuroscience world have ways of doing ontology about the data. The hope is to bring these things together so that the semantics get managed.

Q: Is anybody cataloguing retrospective patient data, or does that require an IRB that makes it impossible.

A: Well, maybe. The rule is that you can pool data together if it’s been de-identified.

Q: There’s a pilot going on now to bring together data from Europe and from Canada … (ok, not a question)

Q: Thank you for doing this. I’ve spent the last 6 months traveling, and it seems to me that the biggest progress is going to come from gathering big data and putting it to use. In the next 10 yrs 70-80% of jobs are going to be obsolete, but it’s okay. Where’s the gap to take this to the next level?

A: It’s cultural. The focus has been on paper-writing, not on data-sharing. NIH might try to make people share their numbers, but maybe they shouldn’t be spending time sorting and uploading their old data. Who do we give that job to? That’s a tractable problem.

Adam Ferguson, PhD, University of California

Big-data Analytics: Bringing “Dark Data” to Light for Enhancing Discovery and Translation in Spinal Cord Injury

I’ve been talking to people in this community for a few years, and I’m really excited to be here.

This falls under the category of “Big Data.” What’s that? Data that’s too complicated for us to just stare at and figure out what happened. The image that works is a giant tidal wave composed of zeroes and ones. There’s been a “datafication” of biomedicine. He has a graph that maps data size against number of data sets, with the high end of the curve being organized big data, and the skinny end at the right being unpublished, dark data.

AND 85% OF THE DATA IS INACCESSIBLE AND NEVER PUBLISHED.

Which is shocking, because that number represents $200billion in work we never hear about.

What’s more, the 15% that we DO see is the least useful, the most difficult to generalize. Which contributes to problems of reproducibility …. sometimes it works, sometimes not. But this seems to be an aritifact of the way we publish papers, based on what they guys in the 17th century came up with.

Inverted triangle on the screen, where lots of methods and data get filtered down through a process to become a tiny point called a published report.

Solution. DATA SHARING.

if everybody just published everything, we’d end up with an internet-sized pile of information. The solution is that it should happen symbiotically and not parasitically. The good news is that SCI is one of the areas where it’s routine to share data. I’ve gone to conferences in lots of fields over the last 7 years, and your guys are the ones who just hand it over.

Which means we now have 60 million datapoint from 4000 basic science and human medical records. We have 13 centers and counting. There’s an open data commons for SCI (ODC-SCI Initiative. They have a grant from the Neilsen Foundation to build this out. He’s showing us the faces of about a dozen people involved in this project and making a case for why they’re the right ones to do this work.

ODC-SCI.org.

That’s the website that’s going to go live in January — a giant resource for scientists and us. There’s a thing called TRACK-SCI that is gathering data about expected outcomes after injury, which is paart of their collection of resources.

So what? What are they going to do with all this data? Look at one thing (grasping function), which has a variety of things to measure … the problem is always to try to analyze and synthesize the information, like functional changes, plus surrogate biomarkers plus tissue changes. You can use machine learning tools to get a multidimensional set.

Systemic integration leads to precision in interventions. (Well, that sounds good.)

There’s a rotating three-dimensional cube full of dots, meant to represent a particular

Nelson et al, 2014, Journal of Neurotrauma is the paper that captures what he’s talking about.

Problem … hardly anybody understands this math stuff. Multivariate statistics are not for hobbyists. So what we need to do is crowdsource the discoveries. I met this guy called Gunnar who is a former chair of mathematics at Stanford University.. He explained to me how the tools google developed could be used to predict something like the difference between a group of rats who had good outcomes and those that didn’t. The machine learning tools showed that it was blood pressure, which was not something that could have been predicted. (Wow.)

AND, there’s bunch of data available at Wise Young’s lab from the MASCIS study of 1994, 1995 … which they went and got. (Picture of a dolly loaded with cardboard boxes.)

They’re already inputting that.adam ferguson

photo credit Brain and Spinal Injury Center, San Francisco General Hospital