The Princess Protein and the Pig


The October issue of NEW MOBILITY included a 12-page section sponsored by Unite 2 Fight Paralysis that previewed the organization’s annual Working 2 Walk conference. The pandemic forced the conference online for the first time in its 15-year history … but the event worked.

No airports, no hotels, no over-air-conditioned ballrooms — and yet the experience was familiar and motivating. I’d been anxious that they wouldn’t be able to reproduce the sense of power and excitement that comes with gathering our tribes, but I needn’t have worried. Over October 22–24, 245 people from 11 countries showed up for the presentations, which were crisply organized into compact and sensible groupings.

If you wanted exposure to both the big picture of the state of research and a sampling of how each aspect looks from down in the weeds, Working 2 Walk was the place to be. A glance at the main topics of the agenda tells the story: clinical research, pre-clinical research, industry, funding, community organizations — all leading to a final session on strategy. The only thing really missing was the loud party with the dozens of wheelchair users and the two free drink tickets — which, as a dedicated introvert, was never my favorite bit anyway. If you weren’t registered, the good news is that U2FP is putting the whole thing online at u2fp.org.

Cracking the ‘Pig Code’

For this piece, I want to drill down on a couple of talks from the second grouping of the first day, because they combine in a way I find helpful, and because they’re about research that could lead to a remedy for neuropathic pain. When my husband was injured in 2001, one of the more wretched surprises was what happened when something touched his skin lightly: his jeans sliding over his legs, the sheets on our bed, my hand — it was intolerably painful to him. About two-thirds of people with damaged cords live with some kind of neuropathic pain, and for a very unlucky fraction of those, it’s constant. There are no medications that can take it down completely, though some work for some people, some of the time.

Candace Floyd, Ph. D., who is associate professor and vice chair of research in the Department of Physical Medicine and Rehabilitation at the University of Utah in Salt Lake City, is working on something that could help. She likes pigs.

She likes them as creatures, but she also likes them as a vehicle for speeding up the translation of research aimed at healing the damage from spinal cord injury. Translation, in this context, means taking a potential treatment all the way from experiments in labs to doctors in clinics. The usual path starts with basic science, moves to pre-clinical work in animal models, proceeds to clinical trials with human volunteers, and then, if all goes well, arrives at your local doctor’s office with full insurance coverage.

Translation is notoriously slow, difficult and expensive. It also routinely fails.

The fact is, after that slow and expensive process, only 8% of potential therapies are even marginally effective — that means 92% of clinical trials don’t work well enough in humans to make it to market. At W2W, Floyd showed us how pigs might both reduce the time spent on those pre-clinical trials and lead to a much better success rate when therapeutics make it to human beings. She used the problem of neuropathic pain as one example of many possibilities.

Scientists trying to solve this problem have used rodents in pre-clinical work to see if their remedies might be effective. Specifically, they try to interpret rat behavior to see if it is in pain, and if so, how much pain and what kind of pain.

There’s no rat equivalent, though, of the pain scale most of us have seen at the doctor’s office. Think of the version often shown to children, who don’t have the language skills to explain how much it hurts. A rat can’t point to the orange face to indicate that it’s severe. A rat, under a light touch test, can only jerk its paw back, or not. And there’s the problem of spasticity, which makes it impossible to know if the rat is just having a spinal cord-mediated reflex or is responding to what it experiences as pain.

Enter the Pig

As Floyd explains in her presentation, pigs are quite capable of expressing themselves, and it’s possible to learn how to read them. She describes the moment she was inspired by her pet collie, an animal with an impressive vocabulary of barks that she’s easily able to differentiate and understand. What if this is possible in pigs, too? Cracking a “pig code” would mean having a very useful animal model for research that is both more expressive and closer in biological terms to people.

Learning to understand pigs has been the project of her lab in Utah, with the aim of, among many other things, creating a sort of pig-version of that pain chart. In terms of pre-clinical research, the pig could be a bridge between all those studies relying on rats and the much more involved and expensive primate studies. Time would be saved. Human outcome results would come faster and be more predictable.

The first part of this project sounded kind of fun — follow lab pigs around with video cameras and microphones to see what kinds of sounds they make and under what conditions. How does a pig signal its level of irritation or discomfort? It turns out that pigs have reliable ways to communicate their inner experience of distress, which means that once that code is broken, they may be able to shrink that timeline of pre-clinical work and help us understand where to invest scarce resources in human patient trials. They might show us, much better than rats can, what’s likeliest to work.

Once Floyd’s team was satisfied that it had developed a working knowledge of pig communication, it had the missing tool. They proceeded to use it to learn how closely pigs’ experience of neuropathic pain post-injury mimicked that of humans. Many people reading this will be able to visualize these tests: light touch, pin prick, vibration, heat and cold. The pigs, with common-in-humans contusion injuries, were given these common-in-human tests. Their responses, quantified and documented, provide a baseline that could allow scientists with medications ready for animal testing to quickly close in on proof of efficacy, or to face the lack of it.

Floyd is not making drugs or trying to do basic research on the cells, proteins, genes and molecules that will govern recovery from spinal cord injury. She’s creating a living tool set that scientists doing that work can access and use to assess the probable results of their own work.
Floyd’s ready to collaborate. What she needs is other scientists who have developed interventions they believe will work in people.

The Princess Protein

Neuropathic pain after spinal cord injury comes from exactly the same thing that causes loss of mobility — axons that used to connect and carry messages from body to brain and back again are unable to cross the injury site. The painful reaction to light touch happens because signals from nerve endings in the skin get distorted and amplified as they attempt to travel up to the brain. There’s a sort of chemical/physical barrier known as the glial scar.

If a scientist could develop a way to eliminate the glial scar, axons could grow more normally and recover lost connections. Then both sensation and mobility would return. That’s the theory.

Enter Molly Shoichet, Ph.D., of the University of Toronto, whose presentation involved an intervention that seemed like an excellent candidate for Floyd’s pigs. Readers of this column will be familiar with the protein known as ChABC, chondroitinase. Decades have passed since scientists first understood how powerful ChABC is in neutralizing certain molecules that gum up the post-injury spinal cord and build that glial scar. These scar tissue molecules are usually referred to as CSPGs because their complete name, chondroitin sulfate proteoglycans, is a mouthful.

When ChABC encounters CSPGs, the CSPGs dissolve. The problem is that ChABC, like many proteins, is fragile. I think of ChABC as a persnickety princess. Everything must be ordered exactly as the princess demands, or she simply folds her arms and refuses to eat. The temperature is one of those things that must be perfect.

What Shoichet’s team has done is deploy computational software and design tools to change the princess’s preferences — to create mutations that are less fussy. Many labs have attempted this over the years, because the promise of a molecule that can break down the scar surrounding an injury is enormous in terms of potential functional recovery. However, ChABC is a large, complex princess produced by a little bug that lives, among other places, in human intestines. It’s made up of 1,021 different amino acids, and occurs in at least 71 different varieties in nature.

Now, protein molecules like this princess can be re-designed, but how does one even begin to work through all the possible mutations?  Which of those 1,021 amino acids would need to be targeted? If only there were something like a Protein Repair One Stop Shop, where a spinal cord injury scientist could ask for expert help in sorting through the millions of options.

There is such a place, and Protein Repair One Stop Shop is actually its name. Using PROSS technology, Shoichet’s team identified the three most promising sets of mutations to ChABC. One had 37 alterations, one had 55 and one had 92. These mutations were carried out, and the new versions were tested in the lab.

ChABC-37 turned out to be the winner. The new designer molecule is both more stable under higher temperatures and more active for a longer time. It can destroy more scar, but before people can volunteer to have it tested in their bodies, it will need to be tested in relevant pre-clinical models. That’s the scientist way of saying, “We have to find some animals that can help us understand how well this will work in humans.”

Pigs would be a good candidate. Especially if a scientist had already taken the time and trouble to understand their language and was able to provide them as research subjects, ready to go.

This is the beauty and purpose of Working2Walk: Scientists who might not think of working collaboratively, who might not even know about one another, can be in the same room. As Matt Rodreick, U2FP’s executive director, put it in a letter sent after the conference, “Candace Floyd and Molly Shoichet … are now planning new ways to collaborate together.”

That’s a win.


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