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A once abandoned drug compound shows an ability to rebuild organs (scientificamerican.com)
132 points by LinuxBender on April 2, 2019 | hide | past | favorite | 54 comments



I'm going to throw this out there not knowing much about the specifics in this case. Academic biologists suffer from tunnel vision when it comes to developing drugs.

Here's a script I've seen play out way too often. Molecule exhibits interesting behavior. Molecule is examined more closely in vitro and in vivo. Effects appear to be for real. More studies are done. Years go by.

And at no time was a single close analog made. Nor was a medicinal chemist ever consulted. Little to no structure-activity relationships were performed. The molecular mechanism of action remains mostly unknown as a result.

The thinking seems to be that drugs are discovered (by biologists), not developed (as in software through an iterative process). Some drugs are discovered, but most are developed.

The compound that biologists are interested in right now isn't the good part. The good part is the underlying mechanism and how amenable it will be to actual drug development.


Making the mechanism of action known open the door to alternatives and competition. If a firm pour millions into a project, they want exclusivity. In our current system it's more important than good science or choosing what's best for humanity.


But for the academics their prestige rests on publishing that mechanism of action. Determining x drug works via inhibiting such-and-such transferase via pi-pi interactions (for example) is how careers are made, and in cases where the learning is important enough to shutter away, typically the academic will license it out or go into business for themselves -- which is just fine because that means we get a drug out of it, if there was one to be had.

The problem is that the academic side isn't generally focused on things that matter about getting a drug to market(e.g. what happens when you swallow it? Does inhibiting such-and-such transferase actually do anything meaningful? What does it metabolize into? etc.) Lots more glitz and glamor (and lots cheaper) to make a compound inhibit something or kill cancer in a petri dish.

Its vaguely as if say computer science academics were studying code golf.


>> The thinking seems to be that drugs are discovered (by biologists), not developed (as in software through an iterative process). Some drugs are discovered, but most are developed.

>> The compound that biologists are interested in right now isn't the good part. The good part is the underlying mechanism and how amenable it will be to actual drug development.

You're not wrong, but some important drugs were actually discovered - Aspirin and Statins come to mind.

The reason for "drug development" is often due to a desire for a fresh patent to keep profits high. The reason a lot of those academic discoveries are not pursued is the lack of patentable derivatives. Go create a new opioid for example that's more addictive and see how much money it makes! There's no money in growing poppies.

Medicine does not require novelty, just results. Having said that, I do feel that understanding mechanisms is a good idea. But then look at all the psych medications where the mechanisms are often not really understood - SSRIs are an exception, though how serotonin actually affects how you feel is not well understood.


Most pertinent quote here is that the only reason it was not pursued was because it is not orally bioavailable:

"But because the drug comes as a liquid that needs to be injected every day, it was unlikely to be popular with patients who already had alternatives, such as pills, that were easier to take. Pharmaceutical companies did not pursue it."

There are many other molecules out there that have advanced properties but have difficult delivery methods, including some nootropics (semax, selank, cerebrolysin, etc).

There is a group though that has no problem injecting things into themselves: bodybuilders and athletes. Fortunately for us, they have brought some other abandoned molecules back from the dead, mostly ones that heal injuries.

For example, there is a molecule found in human gastric juices, known as Body Protecting Compound 157 (BPC-157). Part of the intestinal lining has to regenerate itself nearly weekly. This compound, isolated from there, and then synthesized, is used prolifically by athletes/bodybuilders with tendon/ligament injuries, but can also be used for repairing stomach issues. etc. It is widely available on the internet. Here is the science for you:

"As has been demonstrated for many organoprotective agents using different models of various tissue lesions, despite the poorly understood final mechanism, practically all organ systems appear to benefit from BPC activity. These effects have been achieved in many species using very low dosages (mostly microgram and ng/kg range) after ip, ig, and intramucosal (local) application. The effect was apparent already after one application. Long lasting activity was also demonstrated. BPC was highly effective when applied simultaneously with noxious agents or in already pathological, as well as chronical, conditions. Therefore, it seems that BPC treatment does not share any of the so far known limitations for 'conventional organoprotectors'. No influence on different basal parameters and no toxicity were observed. These findings provide a breakthrough in stress theory. BPC, as a possible endogenous free radical scavenger and organoprotection mediator, could be a useful prototype of a new class of drugs, organoprotective agents." https://www.ncbi.nlm.nih.gov/pubmed/8298609

"Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon." https://www.physiology.org/doi/full/10.1152/japplphysiol.009...

"BPC 157 may serve as a novel mediator of Robert’s cytoprotection, involved in maintaining of GI mucosa integrity, with no toxic effect. BPC 157 was successful in the therapy of GI tract, periodontitis, liver and pancreas lesions, and in the healing of various tissues and wounds." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333585/

" A novel stomach pentadecapeptide, BPC-157, improves wound and fracture healing in rats in addition to having an angiogenic effect. Therefore, in the present study, using a segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) that remained incompletely healed in all control rabbits for 6 weeks (assessed in 2 week intervals), pentadecapeptide BPC-157 was further studied (either percutaneously given locally [10 microg/kg body weight] into the bone defect, or applied intramuscularly [intermittently, at postoperative days 7, 9, 14, and 16 at 10 microg/kg body weight] or continuously [once per day, postoperative days 7-21 at 10 microg or 10 ng/kg body weight])...Pentadecapeptide BPC-157 significantly improved the healing of segmental bone defects." https://www.ncbi.nlm.nih.gov/pubmed/10071911

"BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase)...BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function." https://www.ncbi.nlm.nih.gov/pubmed/18668315


A recent paper seems to have solved this issue by doing away with the terminal amine and sulfate groups.

http://www.jbc.org/content/293/5/1517.full

Sidebar: I've spent way too much time reading about this compound and its target..


Nice find! Looks like they are exploring it for its copper chelating properties, specifically for use with Wilson's Disease (where copper accumulates).

The study you link further addresses the issue with a molecule being "undruggable" because it is not orally bioavailable:

"One of the major challenges faced by PTP1B-based drug discovery efforts has been to generate orally bioavailable inhibitors of the phosphatase. In fact, the lack of oral bioavailability of active site-directed PTP inhibitors was a major factor in industry describing these enzymes as “undruggable.” Our efforts with this class of allosteric inhibitors now provide proof of concept that these challenges associated with active site-directed inhibitors of PTP1B can be overcome...The combination of PTP1B inhibition and copper chelation presented in DPM-1001 reflects a new approach to the treatment of diabetes and obesity that we hope will re-invigorate drug development efforts in this area."

To me, it looks like they will still not utilize the full potential of the drug. But whatever can get DPM-1001 into production, I am for. (Group buy/synthesis anyone? ;)) It looks like their secondary observations of regeneration/restoration might be closer to the true potential for this molecule:

"In studying mice, DPM-1001 reduced liver complications, including enlarged cell size, irregular shape and arrangement in liver tissue."

https://www.cshl.edu/progress-toward-improved-wilsons-diseas...


Why is injection a problem for a magic healing elixer? Not one person with a severed tendon would ever say "I'd love some help knitting this baby back together so I can walk again, but injections, that's just not going to happen"


One is the injectable self-administration is difficult and the cost of a daily outpatient visit would be exorbitant, even with NPs doing administration. Plus in both cases compliance might not be adequate.


Compliance might not be adequate? How do you figure? Injuries to muscle, tendon, and ligament are extremely debilitating and don't normally heal well. I struggle to imagine someone who can't be bothered.


I used to work in pharma and you’d be shocked by the adherence statistics. Even just taking a tablet is difficult for most people, and a shocking number of refillable prescriptions are never refilled.

With injections it’s far worse, even when people know that it will be life saving.


I wonder, though, what the downsides are of this drug. If the human body can produce it and if there are only upsides, then why didn't evolution make the substance more abundantly available?


Things that cause growth are generally a very bad thing in biology, because they cause cancer. Look at a list of proteins key to cancer and you'll find tons of growth promoters, some of which have the word "growth" right there in the name (the G in EGFR, FGFR, VEGFR, IGFR).

Growth must be tightly regulated to not end up as cancer, so that's why it's not abundantly available.


The article makes the point that despite human trials originally, and later one-cell zebrafish embryo tests, no sign of carcinogenesis was detected. They further explain that given its limited range within the body, it only impacting damaged tissue and the short period of time it would be used, it’s unlikely to be carcinogenic.


Oh sure, this agrees with the "tightly regulated" constraint. Short time, localized application/expression qualify. I'm not sure that long term exposure would be good, and in reference to BPC-157 let's not forget that intestinal cancers do occur (though I'm not at all sure if there's ever been a link between BPC-157 and intestinal cancer).

It's great that the compound looks safe given the limited amount of information we have, but it sounds like there's not a whole lot of trials out there with the power to test the possibility that this could be cancerous long term. Happy to be proven wrong though!


Remember the initial human trials were using it systemically to control blood sugar, and specifically looked for carcinogenesis. Obviously there’s room for something to have been overlooked, but in the narrow case of this particular molecule I’d be hopeful. As for BPC-157 we’re very much on the same page, and I’d be very concerned about cancer.


Oh interesting, I'd missed that. Thanks for the note!


I suppose that many of the injuries would not be survivable before modern medicine, even if that chemical were produced. Major wounds that take more than a few days to heal and impair the ability to hunt would be almost always fatal. Torn ligaments require surgery to properly reattach them.


I've heard this referred to as the "no free lunch" principle, and it's a good tool to apply to any claims about a new way to improve human performance.


That's so sad. I'm hope some researchers are looking into better delivery methods? I know the nanotech industry has been making announcements for years.


Lipid encapsulation can be used to make things orally active.

https://scholar.google.co.nz/scholar?q=oral+bioavailability+...


You're missing the context: it was not pursued for obesity and type-2 diabetes because it was not orally bioavailable, so mightn't be competitive in those diseases, where tablets are already prevalent.

Totally agree that this wouldn't necessarily be a drawback for other uses, but they weren't known about originally.


BPC-157 has oral bioavailability.

I really don't believe bodybuilders are on the cusp of any breakthrough. Nor is what they are doing particularly useful to anyone else because of the dosages and confounding variables involved.


Yes there is some oral bioavailability, but for non-stomach the standard BPC-157 is not optimal. SubQ injections closest to the site of injury are preferred.

And what the bodybuilders are doing is useful because they find the effective human range for healthy adults. Obviously when it comes to growing muscle etc, it is usually the higher ends, but on the same forums are more modest users.

Most molecules are designed for people with diseases or disorders. For example, some of the SARMS were created to combat muscle wasting disorder for post-chemotherapy patients (cachexia). And before they got to cancer patients there are Phase I trials in healthy people, but they are not trying to actively gain healthy tissue with exercise. They are just taking it for safety/pharmacokinetics.

So when healthy bodybuilders/biohackers take these molecules while working out and eating right, we can see the true potential of whether or not the molecule is effective. One of the molecules was considered a failure because it could not overcome the effects of the radiation enough. The patients grew pounds of muscle, but it was not enough compared to the fact that their muscle is wasting away from chemotherapy. It is more germane to me whether it can work on a healthy person optimizing its effects/dosing/timing, what you call "confounding variables."

The bodybuilders are helping us explore these molecules and many times doing it in an open source, collaborative way. They will have blood work done and post it before and after the run. The community evaluates their bloodwork and can validate whether it worked, if the source was good etc. It's pretty impressive real-time, science experiments. And if you hang around and read all the science and see enough of those n=1 studies, the patterns and consensus that emerge are pretty clear.

And going full circle, it is helpful beyond the bodybuilders because when I go over to the longevity forums and what not, I see the older people whose bodies are wasting away naturally (sarcopenia) looking to do something closer to the original investigation of the molecule. They will usually do what is on the lower range of what the bodybuilders do.

So those older people are benefiting from the experiments and commercial availability of the more experimental and risk-taking bodybuilders. However, you'd be surprised because some of the people who are rapidly declining in physical and mental health have a similar risk profile of a bodybuilder who only cares about next month's competition.


> Yes there is some oral bioavailability, but for non-stomach the standard BPC-157 is not optimal.

Please post proof from a study. Some studies used the oral route in animals if I recall.

> SubQ injections closest to the site of injury are preferred.

According to who?

> The bodybuilders are helping us explore these molecules and many times doing it in an open source, collaborative way. They will have blood work done and post it before and after the run. The community evaluates their bloodwork and can validate whether it worked, if the source was good etc. It's pretty impressive real-time, science experiments. And if you hang around and read all the science and see enough of those n=1 studies, the patterns and consensus that emerge are pretty clear.

We have no way of knowing who these people are, what they are taking, or if they are underground labs posting to drum up business. The companies developing SARMs want to test them on people that have cancer cachexia. So yes, researching with bodybuilders is completely useless.


Do you have a non-paywalled version of this?


Related. I thought to myself “I used to read SA all the time, maybe I’ll subscribe, I wonder how much it is...” The price is $49.99 but the site refuses to tell you how often it’s billed. I can only guess that must be per year because, damn, that would be steep for a month. But really? You expect people to buy without knowing how often something is billed?



good site, is it paid? I mean, you have to pay for this website and you can enter the entrance of next posts? I try to find some clickable places, but can't find any. But why we can visit free like this URL?


Relevant study in zebrafish/mice with this compound (MSI-1436, aka trodusquemine): https://www.nature.com/articles/s41536-017-0008-1.


The compound looks like a detergent, something that would insert into cell membranes and disrupt them. Saying that it inhibits this or that kinase is really a long stretch.


I think that's a bit of a harsh dismissal. It's a sterol natural product that binds to PTPN1 allosterically. I've scanned the literature a bit and it seems reasonably well validated. It's termed as selective in many papers, but this is primarily referring to selectivity over a PTPN1 homolog, something which previous compounds had had trouble with.


I once worked for someone who had no clue about biology and had no critical faculties at all. She was like "but it inhibits target X", and you'd go like "and God know what else" because the compound looked far too much like a promiscuous binder. Then she'd tell you you were a pessimist. She had an Elizabeth Holmes portrait in her office until late 2016.

It was a complete shitshow, like the experience of the guy behind Org Prep Daily at his startup (starts here: https://orgprepdaily.wordpress.com/2017/08/21/breakin-bad-in...) minus the drug manufacturing, although I'm positive that the bosslady was on stimulants. After such an experience you get skittish.

Elsethread someone mentioned a supposedly copper-binding orally active derivative. Copper-binding in stomach acid? How much of that has been validated? Part 5 of "Breaking Bad in South Florida" might be relevant: https://orgprepdaily.wordpress.com/2017/08/24/breaking-bad-i...

David Lowe has something about supposedly selective compounds polluting the literature, but I can't fidn the blogpost right now. I agree with his sentiments.


Posting a paywalled article is pretty helpful /s


Can someone at least post the freaking name of the drug


What drug can I take to skip paywalls


If this drug has a 98% chance of having no effect, 1% chance of preventing heart disease, and a 1% chance of immediately killing me, it's still in the interests of someone with heart disease to take it.

It's definitely in the interests of humanity as a whole - a few hundred people might be killed in the cavalier hunt for effective drugs, but tens of millions every year will be saved.

Why are so many years of studies/paperwork needed? Why not just produce the drug and let people take it (who know the above risks)? That could happen as soon as this afternoon.

That wouldn't be a proper blinded study, but the results of it would be very strong indications for if the drug should go through the full process to become a standard treatment.


How do you determine those percentages? The reason all these studies are necessary is because biology is hard.

Example: cancers where Ras proteins are mutated are common and also predictive of poorer outcomes. Ras signals through several effector pathways including ones involving BRAF. So if someone develops a BRAF inhibitor, we should call it a day and people should just start taking these? Ooops, turns out this paradoxically enhances Ras oncogenic signaling.. Is it better to find that out 6 months when everyone who's taken these dies, or would these people be better served by doing your beta testing and "years of studies/paperwork" in cancer cell lines and mice?


> Why are so many years of studies/paperwork needed? Why not just produce the drug and let people take it (who know the above risks)? That could happen as soon as this afternoon.

We tried this and got snake-oil and Bayer Heroin. Anyone with questionable scruples who wants to make a buck will have a market of sick and desperate people who are quite literally dying to be told "maybe this will save/elongate your life".

There needs to be a check on perverse incentives, and rigorous research and clinical trials are the solution we've come up with.


Because it's super immoral?

Everyone's fine with human casualties as long as they're not the ones doing the dying.


It's immoral in a lot of cases, but is it immoral in every case? I don't think so.

Take a person who has a heart condition AND cancer that is 100% certainly going to kill him within a month and has no close family/friends to spend his dying days with. Would it be immoral for them to take a 1% chance of losing a couple crappy weeks to possibly make a huge step forward for science?

These things need to be wielded judiciously, but there are cases where the rewards outweigh the risks to a point a person of sound mind should be able to take the risk for the benefit of humanity.


I'm not involved in research, but recall that ethics review specifically looks for beneficence towards participants, the notion that participants themselves have risk minimized, and that one cannot pursue information to their detriment.


I’m a responsible adult who believes in personal responsibility. Provide the data around efficacy and risk, and allow me to make the informed choice myself.

I am okay dying if I make a mistake in my risk assessment. I would not make the choice for someone else.

Everyone dies. Progress is inherently risky, but necessary.


So long the "informed consent" really is truly informed, and not something that is slanted or otherwise concealing evidence or data. In that case, then I do not disagree with you.

However, considering what we know of how PR and Marketing works, I am inclined to err on the side of "Abundance of Caution and Due Diligence", even in the face of personal responsibility.


Definitely. Making the marketing of pharmaceuticals directly to consumers illegal would go a long way, as well as stronger oversight and governance by regulatory bodies.


Informed? How could you possibly make an informed choice without both a Ph.D. and an M.D. and a decade of experience in drug development in the exact same field? Even then, most developments considered highly promising by teams of people having that exact background end up producing nothing useful. And you just want "the" data around efficacy and risk and to make your own decision. Are you supposed to get real-time updates as each new data point comes in? It just makes zero sense to me.


You are basically not qualified to make that decision. There is no amount of informed consent for either the known unknowns or the unknowns present in say a clinical trial. It would also be a net negative to society because we would get no information outside of proper studies and it would be a huge waste of money.


As immoral as giving a placebo instead of a curative treatment to someone to fulfill the standards of a test?

In the case of medicine research, I think it's OK to let people dictate their own moralities. Try to reduce the chances of abuse, and start increasing results.


If they see a treatment working, the placebo group is almost always given the treatment.


I agree, but regarding this particular drug,

> it has already been shown to be safe.

> In 2007 this compound was tested in humans as a potential treatment for obesity and type 2 diabetes because it improves cell sensitivity to insulin. The studies, regulated by the U.S. Food and Drug Administration, demonstrated that MSI-1436 was well tolerated at high doses and did not harm patients.


That's a great sign, and a really nice target to choose to develop. This doesn't mean that it will be safe in another patient population (though it'll probably be okay), nor do these animal studies guarantee efficacy in humans. Humans have very different regenerative potentials compared to mice or zebrafish, or a more extreme example: axolotl. Additionally, drugs that target regeneration must walk a fine line between regenerating damaged tissue and overstimulating growth pathways (cancer).


Sure, we should do a study to find out what the percentage chance of immediately killing someone. If it's 1%, we'll go for it, if it's 50%, we'll skip endangering anyone with this drug...wait.


This line of thinking relies on social and mathematical assumptions. Those assumptions are both unrealistic.


> Why not just produce the drug and let people take it (who know the above risks)?

Because terrible things have been conducted in the name of research [1,2,3] which made humanity decide to form IRB and consider the actual impact on the participant. While you open up the "who know the above risks", what about child/prisoners/mentally disabled people? In current research, these are protected groups specifically because they can't really make these decisions for themselves. Furthermore, we don't know the longer term effects of things. Quaker didn't know radioactive oatmeal to track nutrient absorption in orphans would be harmful [3] and even made the case that "at least we were feeding them". Yes, again they are a protected group, but what if, say, this drug had the statistics you presented, but then 10-20 years later it was discovered that it gradually caused dementia? Simply saying "they knew the risks" is not enough.

In the end, human experimentation is a tricky gray area BECAUSE of the possibilities for misconduct. Someone could be coerced into doing something they didn't need/want to. This is both the annoyance and best thing about IRB. Yes, its annoying that I can't just experiment my novel teaching approach on a subset of students without their consent AND IRB approval, but it is ensuring that my control is getting equal learning opportunities AND my experimental is negatively learning.

[1] https://en.wikipedia.org/wiki/Unit_731

[2] https://en.wikipedia.org/wiki/Unethical_human_experimentatio...

[3] https://www.nytimes.com/1998/01/01/us/settlement-reached-in-...




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