The Silver Lining Nervgen Playbook. Part 1

Before he became a famed MIT professor and AI expert, Marvin Minsky was a graduate student at Bell Labs in the early 1950s. Stirring for a cultural metaphor that could be taken as a sign of the times, he contrived a totemic device, a box, one that was a small machine. Turn the machine on conspicuously, and a robotic arm from within the box reached out and turned the device off. No, really: that was its entire repertoire. Others would promptly riff on Minsky and emulate him in droves, perhaps most famously in the form of the so-called Kentucky do-nothing machine (rooted in fact in antiquity, as that device is actually a trammel of Archimedes). Famed sci-fi writer Arthur C. Clarke saw the device on Minsky’s desk and wrote: “There is something unspeakably sinister about a machine that does nothing—absolutely nothing—except switch itself off.” He got the nihilism vibe, but didn’t dig it. Herman Melville’s Bartleby the Scrivener comes to mind: “I would prefer not to.”

But what if the Minsky self-silencing machine had an unwitting correlate in nature, indeed in our very own neurological system? What if the system were trying to mount an appropriate response to an injury and then, surely as that got underway, kerplonkingly silenced itself? We get ahead of ourselves somewhat in our narrative, but isn’t the presence in us of so self-defeating a mechanism a desultory and lachrymose commentary, mud in the eye of any species pride? Surely you recall Prince Hamlet to Rosencrantz and Guildenstern:

“What a piece of work is man, How noble in reason, how infinite in faculty, In form and moving how express and admirable, In action how like an Angel, In apprehension how like a god, The beauty of the world, The paragon of animals.”

And didn’t Alexander Pope swooningly claim: “Whatever is, is right”? The truth is that what millions of years of evolution have begotten us is something far from perfect and something often at even greater remove from adaptivity. We know that teleological thinking always lacks merit, but the more we immerse ourselves in the secrets of the body, the more screwball we find them to be. Fearfully and wonderfully made? Certainly in many instances we are. But in other cases, fatuously and woefully constructed in slapdash fashion might be a better descriptor. We are works in progress, you see. And much of the labor the physician sets about doing is helping the body cope and compensate, wooing nature when its infinite wisdom veers off course. Medicine copes daily with how the most blood-demanding organ of the body, the heart, has the most parlously constructed blood supply (lacking collaterals! whodathunkit?). Our spinal columns did not come about with uprightness in mind, and many humans pay dearly for that inconvenient fact during most of their adult lives. How many lives have been claimed by futile, brazen anaphylactoid reactions serving absolutely no adaptive value for the organism? Mull these contradictions long enough and you are eventually driven to find great solace in an observation of Dutch-Jewish philosopher Baruch Spinoza: “For nature does not work with the end in view.” Enter from stage left the higher angels of our nature, projections of our neocortices, whereby we can invoke faculties of reason to heal ourselves….angels that can cope with the paradox that while the script of our species has had many iterative improvements, it’s still very much a rough draft. Doubt me? Then simply consider how bombastic and oversized the adrenal glands are compared with the frontal lobes that restrain their rash importunings! Yup, we’ve got a long way to go.

Among the most grievous injuries  a human body can suffer is trauma to that “silver cord” the spinal column. Evidence now is mounting that mechanisms are there to foster healing of injured nerves though many in science take it as article of faith that no such thing is possible. The body tries to heal….and does a Minsky, switching that urge off, confounding its very essence. Given world and time enough perhaps our bodies can evolve beyond this undesirable state of affairs, but this narrative is about where we find ourselves now: predicament, and solution. But let’s let the narrative catch up to us.

In 1992, Ross Perot ran for president (often regarded as crackpot, we can now safely say he’s been trumped). A clever political operative named Ed Rollins took over managing Perot’s campaign. Rollins had logged many hours sizing up the sociology of Perot. Behind closed doors, Rollins called a strategy meeting. Approaching the whiteboard, he took out a magic marker. Here on the left side of the board, Rollins wrote large: HOPE. He then strode to the right side of the board. Drawing a sigh, he again scrawled in large letters: KOOK. This was the Perot dichotomy with which they had to wrangle. For some Perot was certainly one, for others clearly the second choice, but for the teeming millions they just weren’t sure and they vacillated between the poles of their own senses of Perot. How to sequester, how to partition public sentiment around HOPE? Rollins never quite hit on a formula for doing so.

In 2019, lives in Cleveland a distinguished scientist named Jerry Silver. He’s professor of neurosciences at Case Western Reserve University. These days Silver often finds how people regard him as pingponging between the horns of a Perot-like dilemma.  Oh, don’t get us wrong. No one anywhere regards Silver as kook. But for a decade or more, Silver keeps running aground. “They don’t believe me.” Silver has been claiming, and competent others have validated his claims, that he can take critically spinally injured vertebrates newly bereft of hind limb function and restore gait in them. We’ve seen the data…..we’ve seen the video (you will too as soon as NervGen’s peri-IPO quiet period ends) and for us it abrogates even a vestigial crumb of doubt. But for other Silver observers, some of them peers, they get hung up: Who ya gonna believe?, the situation demands. The starched-lab-coat contingent over here with their hoarfrost-encrusted credentials? Or your lyin’ eyes? C’mon…which is it gonna be?

It’s not that others think Silver is lying. It’s not that they think Silver is pulling wool over their eyes. It’s not that they think Silver is some doddering incompetent man unfit to describe what he sees. They believe Silver believes in his own data, that such data is being served up be a guy pure of heart who wishes to boondoggle no one, least of all you. But they think….as the Queen apparently says when having a conniption fit….shurely shome mishtake has been made! Those animals appear to be walking….but  they can’t be because everyone knows you can’t walk after your spine is crushed.

“And so they give my grant applications low scores,” Silver says, ” and away I go, again a guy without any funding.” This is despite an uninterrupted success of golden papers in what one might call journals of apotheosis: Nature, Science, and other hotshot highbrow publications that reject more than 99.99 percent of the papers submitted to them as a lacking a je ne sais quois of academic bluebloodedness, scientific hauteur and iconoclastic elitism.

“It’s always the same for me,” Silver says, even as his work goes unfunded and his lab kept in business by soft departmental money from within Case Western and funds from well-wishers in other academic corners. Yet even as that status settles into ensconcement, already the signs are upon us that the establishment is going to have to countenance fundamentally Silver’s work again…and that this time it’s different. Why? Because this time it’s going to run the abbreviation gauntlet: IND, IRB, CRO, RCT. We may be going out on a limb, but we here conjecture that  when NervGen gets going therapeutically, that when its protocols call for newly spinally injured patients to receive its therapy (called ISP for intracellular sigma peptide), that crippled humans will be made to walk again. (We can practically hear Sister Elizabeth Kenny of Australia nearly a century earlier: “and they shall walk.” We’ll discuss Sister Kenny later.).

Upon spinal cord injury, cells that are supporting cast members, glial cells, for the main stars, the axons themselves, extrude gooey chondroitin sulfate. This viscous material not only snares and engunks the newly severed axon free ends, but it also  binds to a receptor sitting in the cell membrane of certain nerve cells. The receptor (and it IS a receptor, having a transmembrane domain and evoking intracellular signalling still being characterized) ligand, as it turns out IS the chrondroitin sulfate elaborate by glial cells; this is the first example we know of in which chondroitin sulfate has a proper receptor, and has vast implications.

Now, think in a Boolean algebra kind of way with me. It gets a little confusing. When chondroitin sulfate binds to the neural surface receptor we are speaking of, called protein tyrosine phosphatase sigma (PTPs), it does in a sense turn the receptor “on,” but turns it OFF as regards healing behavior. With me? For things to heal, it would be better that PTPs be left alone, and in fact Silver and associates have done elegant work in which they’ve bred colonies of PTPs knockout mice by homologous recombination. The complex truth is that PTPs-knockout mice can heal their own injured spinal cords. Even so, it’s not quite as simple, as we shall see in part 2 of this column, as to say PTPs is all bad. “Subtle is the Lord,” said Einstein, and nuanced is the molecular biology of the spinal cord.

The therapeutic intervention NervGen is propounding for humans is the same one Silver has propounded in laboratory vertebrates, intracellular sigma peptide (ISP), which he and colleagues invented based on 3-D stereochemical analysis to tease desired behavior out of PTPs. According to NervGen CEO Ernest Wong, PhD, ISP is about 35 amino acids, and “NervGen plans to optimize that pharmaceutically,” by which he means, subject to NervGen’s discretion it may optimize amino acid selection to improve performance and may add moieties to idealize pharmacokinetics (the intent is to dose ISP subcutaneously once daily for a defined limited period). ISP slides into a groove on PTPs, as it were, and serves as a modulator in the face of chondroitin sulfate having bound to PTPs. ISP drives neural healing and remyelination….and its actions, and results, have repeatedly transcended any form of neural recovery deemed possible by neuroscientists.

When we continue this column in part 2, we shall discuss Silver’s scientific work in detail, proceeding paper by paper through his accomplishments. We have reviewed his entire oeuvre, and find it relentlessly credible—just as we find Silver, after spending a day with him in Cleveland. “I have two brothers and no middle name,” says Silver. “None of us have middle names. My mom named us Jerry, Larry and Barry.”  Silver has social lightness of touch and swears no more often than you do. His easy manner and personality give us considerable confidence in investing in his work. But we want you to decide for yourself.

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