A once abandoned drug compound shows an ability to rebuild organs
scientificamerican.com
scientificamerican.com
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.
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 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.
"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
Growth must be tightly regulated to not end up as cancer, so that's why it's not abundantly available.
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!
https://scholar.google.co.nz/scholar?q=oral+bioavailability+...
http://www.jbc.org/content/293/5/1517.full
Sidebar: I've spent way too much time reading about this compound and its target..
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...
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.
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.
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.
With injections it’s far worse, even when people know that it will be life saving.
Totally agree that this wouldn't necessarily be a drawback for other uses, but they weren't known about originally.
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.
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.
Everyone's fine with human casualties as long as they're not the ones doing the dying.
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.
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.
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.
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.
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?
> 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.
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-...
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.