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Hacker News reminds me of my first year of med school. Everyone is smart and fundamentally clueless about human pathophysiology. It's a wonderful thing, learning about the fruits of devilishly challenging science. But it's also a conspiratorial time. I suspect the reason is that first year med students suddenly feel empowered by the small amounts of knowledge that they have gained. HNers probably feel empowered for a different reason: that they are extremely good at rapidly acquiring new ideas and implementing them.

This is normally a great thing, but it opens up two risks: the blind leading the blind, and conspiratorial thinking.

The blind leading the blind is what happens when someone has an idea about a disease or treatment, finds one article in pubmed or one book by one author to support that idea, and proceeds to remain ignorant about the entire rest of the body of work on the topic. It's almost like a race: if the good information gets there first, people believe it; so too for the complete hogwash in Medical Hypotheses.

The second issue that plagues first year med students and HNers is conspiratorial thinking. This is largely a consequence of having little knowledge, and this finally brings me on topic.

This current article discusses how someone was denied funding for human trials of stem cell therapy despite the fact that it cured T1D in animal models. When I see this, I think, "Of course nobody would have funded that!" Here's why I think that:

Ten years ago, stem cell biology was far more limited than it is now. And I'm talking strictly about biology, not ethics or politics.

The first gene therapy trials resulted in the death of Jesse Geisinger; though stem cells are a different beast entirely from the viral vector used in that trial, this still cast a pall over the use of active biologics.

Using stem cells that do not come from the recipient may require immunosuppressive drugs. This is such a high burden to pay that it seems inconceivable that someone would take this risk. I'd rather inject insulin all day long than be on immunosuppressive therapy. Induced pluripotent stem cells did not become a possibility until Yamanaka discovered his factors.

There is the risk that stem cells will lead to tumor-like conditions. A woman died in 2009 from an unlicensed stem cell therapy that caused just that. Animals are the model in which we should fully understand these risks, subjecting humans to them only after we understand what the risks are, and why they might occur. Especially for T1D, which has very good, lifesaving therapeutics already. The human risk-benefit has to be there.

People often work on animal models for years, even a decade, before going to human trials. This fuy had a successful mouse model. So far, so good. But let's see primate work; let's see replication in other labs.

At the end if the day, this just doesn't seem like a conspiracy to me. Some small drug company would love nothing more than to completely disrupt the market for diabetes therapeutics. Sure, it might transform a $100 billion market into a $10 billion one - but they currently have 0% of the 100 billion market, and would have 100% of the 10 billion one.

Tl;dr - Stem cell biology is novel and poorly understood, especially 10 years ago. It is unsurprising that nobody wanted to fund a highly risky human trial for a disease that already has lifesaving therapeutics. I find conspiratorial thinking to be a trait shared by those early in their medical training and by HNers, and it can be frustrating to see great minds turn to those rarely-correct conspiratorial thoughts.




Well said. Another failing arises from just how complicated biology is, and how little we understand of it. Unlike in computer programming, in biology reliable layers of abstraction do not yet exist. The equivalent of changing one line of code in a cell's program (through a drug, gene, whatever) in a sense has unknown side-effects on every other line of code. A programmer's approach to working with or trying to understand such a system quickly leads to maddening (and unsupported) conclusions.


in biology reliable layers of abstraction do not yet exist.

In biology, reliable layers of abstraction do not exist. Period.

Biological technologies may arise with enough flexibility and processing power to deal with this situation. But situation itself won't change. Life simply evolved without fixed boundaries to its layers of abstraction. Every bit of evidence we have points to the genetic code as being more akin spaghetti coded assembly language than to any human-comprehensible programming language. Why would the genetic "programming" system respect any layers of abstraction understandable by humans? Life's been chugging away with 4 billion years of "whatever works".

Roge J. Williams' work early in the 20th showed how in just about every single biochemical system in the body, something like 20+% of the population and that with these outliers not correlating, every person's biochemical system actually work in somewhat unique fashion. That is hard manage and control from an engineering perspective, to say the least. See http://www.amazon.com/Biochemical-Individuality-Roger-Willia...


It seems inconceivable that, with random combinations of biochemistry and no "layers of abstraction", that anyone survives. Spaghetti code generated at random always fails, period.

I imagine "layers of abstraction" may not exist, but common nodes of behavior, clusters of biochemical solutions bound by genetics, MUST exist or we would all be still born.


While I can't really disagree with you, I don't think it's crazy to think that there are many influential people and organizations that have a strong interest in seeing that we avoid potential cures for common diseases. As such, I don't think this type of reaction is necessarily based largely in ignorance.

Then again, I'm largely ignorant on this subject so I'm certainly not making any accusations in this case.


One such case is of Barry Marshall and H.Pylori, he was awarded the nobel price in 2005 for discovering the cure to ulcers, (antibiotics) but he first discovered the cure in 1983 and after about 10 years of 'trying' to convince the medical community of which (Glaxo who was dominant in that market) was making 90% of their profits from Zantac (an anti acid treatment) - (known inside as the 'Zantac years'), they were accused of thwarting his discovery. Tired of the lack of interest, in about 1992 he did a live experiment on himself by swallowing a wapping dose of H.pylori and induced an ulcer, then proceeded to cure this with a course of antibiotics. He did this in the glare of the media and thereby changed the course of treatment worldwide for ulcers... How many would do that?

However, I agree with the point though that too many HNers often seem to be naive about the larger picture which I guess we could all be accused of in some way.


Barry Marshall did not have to convince Glaxo Kline Smith. He had to convince other doctors and scientists. I don't believe that companies can often keep genies in bottles, but dogma and groupthink is another matter.


He was also ignored totally by all the main stream publications, it was later alleged they had close ties to Glaxo and the editors were fully aware of the significance the impact would have had on Glaxo.

http://www.orc.ru/~yur77/pylori.htm


The article claims, without evidence, that Nature and Science didn't publish Marshall because of ties with Glaxo. Even if that's true, there are a lot of other journals out there. Are they ALL in Glaxos pocket?

I doubt it. But they're all reviewed by his peers, who made a living by giving endoscopies and prescriptions to patients every year or so.


Peer review is usually by scientist peers, and not professional peers. I doubt that most academic researchers in medicine were prescribing anything, really.


MDs do research all the time. Some MDs are also phDs. Marshall himself was a doctor/researcher.


This story seems to have at least the air of exaggeration around it. See http://www.csicop.org/si/show/bacteria_ulcers_and_ostracism_... for the history around the adoption of H. Pylori hypothesis.


There is nonsense in the above article:

"Perhaps more important was that the subject, who was none other than Marshall himself, failed to develop an ulcer. Note also that the disease resolved without treatment."

This story suggest that he didn't get an ulcer (but he did get all the first symptoms) and that he didn't treat it with (antibiotics) which he did and which eventually cured his own symptoms (and nearly cost him his marriage as his wife left him shortly after doing this).

http://www.intelihealth.com/IH/ihtIH/E/8270/22025/189048.htm...

"As with many tales of dedicated discoverers, you marvel at the tolerance of the family. When Marshall conducted his experiment on himself, he and his wife Ariadne, a psychologist, had four children aged between 10 and 3. He didn't inform Ariadne, or any of his colleagues, about what he was doing, mainly because he knew they'd object.

“I'm a selfish so-and-so”

“A few days after taking the bacteria I began to feel this heavy fullness after eating, and then on day five the vomiting started. One of the reasons I didn't tell my wife about it was that she had whiplash from a car accident. There was a lot of chaos in the family and in the middle of this each morning I would wake before dawn and run to the toilet to vomit. I had bad breath and I looked terrible. You have to admit I'm a selfish so-and-so to even go ahead with the experiment.”

Ten days after drinking the bacteria, Marshall had an endoscopy and other tests to show that his previously bug-free stomach was thoroughly infected and that he was showing the same signs as his patients.

“At that point I couldn't restrain myself; I had to tell the wife. She was speechless.” He laughs. “But it's easier to ask for forgiveness than permission.” She insisted that he took antibiotics to clear up the infection straight away, though Marshall wanted to continue until he had a full-blown ulcer."

http://www.timesonline.co.uk/tol/life_and_style/health/artic...

Also gastronome enteritis and related diseases was responsible for over 5k deaths (globally) -- a week -- during the period it was known but not accepted 1983 - 1997.

http://www.aips.net.au/97.html

"Marshall swallowed a culture of the bacterium. A week later, he began suffering acute symptoms of gastritis, and biopsies revealed that he had developed both infection with H. pylori and severe acute gastritis. Fortunately, the sequel was a successful case of "Physician, heal thyself"!

further:

"At this stage, bismuth subcitrate was commonly used to treat ulcers, although it was uncertain how the drug worked. Marshall surmised that it might kill the H. pylori bacteria, and he subsequently discovered that a combination of bismuth with antibiotics completely eradicated the bacteria. He then set out to test the hypothesis that elimination of H. pylori could result in a permanent cure of gastric ulcer."

"From 1985 to 1987, Warren and Marshall studied the use of antibiotics as treatment for ulcer. Their finding that 80% of patients were permanently cured of their ulcer if H. pylori were eradicated, proved a landmark in clinical gastroenterology practice. It resulted in a complete reassessment of ulcer treatment, and this therapy is now accepted as an essential part of the management of ulcer disease."


> I don't think it's crazy to think that there are many influential people and organizations that have a strong interest in seeing that we avoid potential cures for common diseases.

I do.

How about some evidence show that this has happened more than a handful of times in the last 20 years?

Note a company refusing to fund a competitor is NOT evidence of "avoid potential cure". Heck - a company refusing to fund something for eany reason is not evidence.

The act that you need to document must be someone going out of their way to block something, not merely refusing to help.


I was simply making a point that there are people that have a strong financial interest that a cure would compromise. That's simply a fact. I didn't go any further than that because I'm sure I'm less qualified to do that than many others here.

My cynical side might think that there are people that would go a long way to protect their financial interests.


I'm sure the shareholders of Eli Lilly, Novo Nordisk and others would like to squelch a cure for diabetes to protect their markets, just like any established company would like to squelch disruptive technologies. So what? What are they going to do about it if some startup cures diabetes?

That's all you really need to know about any story about big, evil companies supposedly suppressing new technology.


You seem to have assumed something over here. That,

a) A Start-Up has that type of money b) They'll be willing to invest in something so risky.

As others have pointed out there are StartUps with the money, but somehow we still don't hear about orphan drugs with potential to make it burst onto the scene. Why not? I think that the second factor is more at play over here. Ultimately it comes down to the cost vs. benefit analysis.

Imagine this you are a VC with a $100 mil. to burn will you support a long and twisted development process of something that might not even work at the end?

You might argue that the benefit is that you might become the up and coming Google of pharma, but try telling that to any smart VC.

This is why we need something more than a profit based industry for something that forms the basis of our society. On one hand people talk about freedom, and especially how it's related to the freedom of the markets, and on the other you trap them with the very failings of their bodies.

Perhaps, I am wrong, but this is something that we all need to think about. What do we value more as a species money or wealth? I wish I knew the answer.


>As others have pointed out there are StartUps with the money, but somehow we still don't hear about orphan drugs with potential to make it burst onto the scene.

Imatinib. It was developed as a cure for CML, a disease which only affects a few thousand people in the US. That's just the most notable. From wikipedia's article about orphan drugs,

"In the USA, from January 1983 to June 2004, a total of 1,129 different orphan drug designations have been granted by the Office of Orphan Products Development (OOPD) and 249 orphan drugs have received marketing authorization."

>Imagine this you are a VC with a $100 mil. to burn will you support a long and twisted development process of something that might not even work at the end?

The fact that pharmaceutical startups exist (google pharmaceutical startup or something like that and you'll find plenty of them) show that VCs, or whoever it is who invests in them, have different ideas about risk than you do.


>"In the USA, from January 1983 to June 2004, a total of 1,129 different orphan drug designations have been granted by the Office of Orphan Products Development (OOPD) and 249 orphan drugs have received marketing authorization."

Thanks. I realize my mistake now. I meant it as in how many new companies try something as risky as making an orphan drug? I shouldn't have leaped in with a bad example without checking it more thoroughly first.

Sorry.

>The fact that pharmaceutical startups exist (google pharmaceutical startup or something like that and you'll find plenty of them) show that VCs, or whoever it is who invests in them, have different ideas about risk than you do.

My point over here was that they fund them, but they might not fund something as risky as stem cell therapy. As far as orphan drugs and StartUps go; is there an data freely available online on the composition of companies that market orphan drugs?

Perhaps that would be more revealing?

(I found this site from the wiki article http://www.urchpublishing.com/publications/discovery__rd/orp... , but it's paid)


Here's a company that was started in 2006 with the intention of treating rare diseases: http://www.atonrx.com/background.php

They were just bought out for $318M. Not bad.

Treatments for rare diseases actually have fewer regulatory hurdles because of the Orphan Drug Act, which basically says that there's a lower standard of evidence for drugs that treat rare diseases.

>My point over here was that they fund them, but they might not fund something as risky as stem cell therapy.

Maybe not, but maybe that's a good thing, for reasons carbocation stated.

>is there an data freely available online on the composition of companies that market orphan drugs?

There's a list of drugs here (well, do a search on an empty string and you get a list) and the companies who make them, but it's not exactly predigested.

http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index....


>This current article discusses how someone was denied funding for human trials of stem cell therapy despite the fact that it cured T1D in animal models

Weissman is not "someone". He is one of the founding fathers of the stem cell field and has done amazing thing. He is a leader in the field and got really amazing results with animals. Sorry to say that but you sound like the first year student here.


Your comment comes off like a mix of appeal to authority with a touch of ad hominem. Do you disagree with what I've written? Is my failure to explain why 'this "someone" is a big deal' (which I felt was pretty well explained in the article itself) your primary concern?

In my other comments on this thread, you can see that I feel his work is important. So if you're concerned, as is implied in your language, about my respect for his work, you can rest assured.


There's one area where variations on Conspiratorial Thinking happens regularly and much of the population has their minds bathed in the result every day.

These ideas, conceived in the medical domain, apply, in some way, to the wider world of media reports.

Ever notice that when you really know an area, news reports about it nearly always get it wrong. Completely misunderstand what's going on. Often interpret it as one of a few stock, basely motivated, scenarios.

(You can debate whether the authors are all smart. I think that some of them are, but those still do it.)

So we have a society where the blind lead the blind down blind alleys as a matter of course.

Thank goodness that we have resources like Hacker News, to sometimes give a peek at more thorough thinking. (Chaotic though it may be!)


Would it follow from your argument that Weissman is either too foolish, disinterested, or arrogant to pursue the next step of animal trials that would have made human trials more likely?


My sense is that he followed the basic science, working deeply in stem cell biology and adding significantly to our knowledge. This is another important route to convincing people that they should pursue something like stem cells - if you know how they do what they do, then you can make educated guesses about how to prevent side effects, too.

So, to the contrary, I think he's done many things over the past 10 years to make human trials possible!


Do you think his research will result in type I diabetes being cured in humans in our lifetimes?


Stem cell therapy is not likely to be curative for Type I DM, although this is simply my opinion and I have no evidence to support it. Part of this is definitional. A true cure for Type I would involve stopping the autoimmune attack of the pancreatic islets.

A therapy that's as good as a cure (such as one that is stem cell based, or otherwise) does seem likely in the next 15 years to me. I've worked on this problem briefly; my role was miniscule, but the basic idea is that you can encapsulate beta cells in an artificially immunologically privileged space, such as an alginate capsule. If done just right, this will let you sense glucose, secrete insulin, and avoid immune attack.

At any rate, yes, I think that we're getting closer to meaningful "post-insulin" therapeutics. Whether or not that will be due to stem cell biology, I don't really know; to be honest, I don't really mind what technique is used so long as it is safe, effective, and maximizes the patients' quality of life.


For some reason I can't reply to carbocation, but in reply to his objection that stem cells wouldn't help due to the autoimmune issue, there's a lab that claims to have solved that problem in mice. Apparently, when you get rid of the autoimmune cells, the insulin-producing beta cells grow back. The lab claims to have had a successful phase I (human) trial. If they're right, stem cells are irrelevant. I don't know enough to really evaluate this, but these are definitely serious people.

Here's the lab: http://www.faustmanlab.org/index.html

There's research going on for MS, another autoimmune disease, which also involves getting rid of the autoimmune cells. Here's one approach: http://en.wikipedia.org/wiki/Tovaxin

If they can get this kind of thing right, we'll live to see many autoimmune diseases cured.


Excellent! This is the type of thing that gets me more excited, because it's treatment targeted at the cause of the disorder. (Stem cells will be so for certain diseases, too.) I hope they succeed.


It seems like we can also forget about MS being an autoimmune disease - but rather a mechanical issue caused by iron deposits in the blood vessels leading to the brain:

http://www.theglobeandmail.com/news/national/researchers-lab...

http://www.webmd.com/multiple-sclerosis/news/20031022/multip...


I wouldn't declare victory against MS just yet. Here's a skeptic: http://medicalmyths.wordpress.com/2010/04/10/kuwait-wastes-m...

And some patients report that it didn't help. http://www.thisisms.com/ftopict-12463.html

The jury is still out, at best.


Do you think his research will result in type I diabetes being cured in humans in our lifetimes?

Should it not be obvious that such a question exceed the ability of even the most sophisticated doctors and biologists today, not to mention anyone on HN. I'd agree that conspiracy and collusion is always part of human behavior but this doesn't prove that anyone knows the path that future efforts at cures will follow.


Nobody would have funded many bad ideas. That's when you turn to government to do it.


Suspicion or expectation of conspiracy can also be due to past exposure to evidence of actual conspiracy. Men colluding against others has been going on for thousands of years if history is to be believed. And yes one common motive to conspire is to gain large amounts of money to the detriment of another group, often involving lies and force. Are all imagined conspiracies real? Probably not. Do some exist? Of course.




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