I worked in diabetes for a decade so thought I'd chime in. This is an admirable project with very low prospects of making a difference in the lives of people with diabetes. I don't doubt this group will be able to show "success" in the form of simple clinical results.
I have the highest doubts that they'd have the resources to do the broad-based clinical trials required to go to market.
Basically, the increases in pharma regulation means it takes longer and gets more expensive to create a new drug each year.
This is a cool science project, but the reporting around it is sensational and not helpful to the millions of people with diabetes who have their cranks yanked regularly about miracle cures, cost-saving fantasies, etc.
To address some raised in sub-threads:
+ You can get extraordinarily cheap drugs in India, the rest of the developing world, and in parts of Europe. The "greedy" drug companies adjust pricing to what local markets can bear. So instead of letting poor people die en masse they mark the drugs down and pass the cost onto the developed world. Fair trade IMO.
+ The reason there are so few generic insulins is that they are hard to make consistently enough to please the FDA and European regulators. Companies like Teva and Perrigo are multi-billion dollar manufacturers of generic drugs who would love to get get into this game, but as noted, biosimilar drugs, especially ones as powerful as insulins, are a lot harder to copy than aspirin.
I'm a Pharmacologist and I've worked in a number of Biotechs. I have been part of pricing discussions to value our drugs and your assessment is correct — price discrimination, as in most industries, is based on what a particular market can bear. Factors that influence this are the way that healthcare systems are run (i.e. public healthcare, insurance based), the cost of compliance and competition. I wouldn't say that the industry subsidises poor countries via sales in the developed world, it's more a case of it's better to be paid something rather than be paid nothing. I personally, however, do like the happy side-effect this has for patients in poor countries.
Increased regulation costs more to comply with and that cost of course is born by the consumer. The cost of regulatory compliance also varies on the market you sell to, the US being one of the most expensive. Just as with software or hardware, the price reflects the cost of production and maintaining the product.
Notably with biologics (Insulin, any hormone ...) as opposed to small chemical entity (paracetamol, aspirin etc) is that broadly they are harder to keep in their stable active form. The are heat sensitive, chemically sensitive and have a tendency to stick to themselves. This tends to increase the cost of storage, logistics and compliance. It also means that if you can make a worthwhile biologic it will generally experience less competition.
> not helpful to the millions of people with diabetes who have their cranks yanked regularly about miracle cures, cost-saving fantasies, etc.
As a Type 1 Diabetic, this cracked me up. I regularly get sent articles and have conversations with friends about "research on such-and-such cure for Diabetes!" Ten-to-fifteen years, right? Add it to the pile. Call me when something's on the market.
Typically for most drugs it really just means they extract less profits from developing countries (slim margins), not that they sell for a loss, while making lots of money with large margins in developed countries.
The regulations might be partly in place to protect the big players from pesky small competition? I have no way to judge that, though. But if that's the case, perhaps the regulations can be changed.
This is definitely the case. There's a term called "Regulatory Capture" that describes this phenomena. I think it's less active scheming to stomp down startups and more a natural outgrowth of a world where the larger companies find it easier to comply with marginal increases in regulatory scrutiny than to fight the PR/lobbying war to oppose them.
You think big pharma encourages more regulation by the FDA? Jesus, they have a hard enough time getting approved under current rules. It would be a death sentence for them if they made them more stringent.
Every big pharma/biotech I've worked for has always pushed the FDA to make exceptions to the rules. They certainly aren't push for more of them.
The regulations are in place partly because as soon as any approved drug starts to show serious side effects, people (including Congress) start pointing fingers at the FDA and talk about their failure to protect the public.
Your comment seems to imply that said regulations are tougher than needed, and that if "FDA and European regulators" would loosen their standards, it would be a good thing.
That's my perspective. Regulators are heavily incentivized to prevent deaths, even small numbers, that will generate headlines and political pressure. There is no political voice for much larger numbers that would be aided by new drugs that come to market quicker in a looser regulatory scheme.
That said, I understand why the laws have been shaped the way they have.
Since we have already met our target $ for phase I, we opened up a stretch goal to fund phase II.
We are in the early stages of establishing the protocols for cutting and folding the proinsulin into its final, active form, and are looking into purification methods sufficient for research and potential pharmaceutical use.
Meeting stretch goals will help us purchase the reagents and equipment necessary to execute these protocols.
I have a really hard time taking this project serious. Plenty of people in my surroundings have diabetes so I can see the impact would be huge. If you asked for a few million then I would find it a lot more believable than the amounts that are requested in the crowdfunding campaigns.
If someone asked for $25000 to build the next electric car I'd not believe them either, there is more to making the next electric car in terms of process and design than being able to buy a battery and some motors.
it's not regulation, occupational health, and safety standards that keep the price higher. Drugs sold in india have just about as good standards as in the US. If it's made by Novo Nordisk, it probably comes out of the same plant that supplies the US supply. Even Indian generics manufacturers get themselves certified by the FDA because they want the lucrative US market.
Now if we could only convince India to move upmarket and develop new drugs instead of simply making generics. India would be richer and their population of 1.3 billion people would greatly benefit, as would little countries like the United States.
I remember reading in another HN thread about insulins (too lazy to search it right now) that plenty of prototype insulins have been developed, but most of them could cause nasty diseases, notably cancer. Hence only a low number of well-tested commercial insulins have been pushed to the market. Does someone knowledgeable have more info about those "good" vs. "bad" insulins?
biologically produced insulin starts as a monomeric protein (meaning it only consists of one string of amino acids) called preproinsulin. this amino acid chain must interact with itself to form stabilizing interactions and disulfide bonds.
once these disulfide linkages are created, this insulin precursor undergoes a multi step enzymatic cleavage which cuts off some bits and makes biologically active insulin.
There are many ways to create insulin synthetically, and some of them lead to product contaminated with misfolded proteins. Misfolded proteins may have no effect, but sometimes they can activate the IGF-1 signal pathway which has been associated with cancer. There is also a chance of an autoimmmune reaction to the misfolded insulin, which would also be very bad.
We are exploring a few different methods for our insulin production specifically with this concern in mind.
Misfolded proteins also cause Alzheimer's disease. They are the number one reason why cannibalism is bad. If you eat a human brain with misfolded human proteins (prions) it can cause your proteins to misfold. I think.
Yes, misfolded prion proteins(PrPsc) can 'infect' other correctly folded prion proteins(PrPc). Prions are glycoproteins found on the surface of cells, and they affect cell signaling from the exterior of a cell to the interior.
Insulin, on the other hand, is a free floating small molecule not anchored to a cell. Misfolded insulin is not 'infectious' like PrPsc.
The biological role of prions is still not well known, but one reason prion diseases are such a big deal is that prions are resistant to normal biological protein degredation. They are hard buggers to get rid of. Unlike insulin, which has a specific protease enzyme which breaks it down.
Insulin-like Growth Factors (IGF) have been implicated in some cancers. As the name suggests, these enzymes are very similar to Insulin -- so every time someone tweaks insulin there's concern that they might end up triggering whatever (as yet poorly understood) metabolic pathway connects IGFs to cancer.
That's on first glance a really nice project and goal but $12K to create a generic insulin is not going to cut it.
That will barely get you a kitchen, not a laboratory that will produce something that will pass FDA approval after you spend a very large multiple of that on tests.
There are already multiple lab spaces online with many active members participating in this project.
As far as FDA trials go, it is something currently outside the scope of this campaign. This is from the crowdfunding page:
"
$6,000 is needed to initiate Phase I of the project. In Phase I, the team will insert an optimized DNA sequence for insulin into E. coli bacteria, induce the bacteria to express insulin precursors, and verify that human proinsulin has been produced.
If we raise more than the minimum required for Phase I, we will proceed to establish the protocols for cutting and folding the proinsulin into its final, active insulin form, and develop purification methods sufficient for research and potential pharmaceutical use.
All protocols we develop and discoveries generated by our research will be freely available in the public domain. We will also be proactively investigating strategies to protect the open status of our work.
That still seems incredibly cheap to me. On another note, I'd be happy to back your campaign (I'd see it as contributing to your education rather than that I would expect you to succeed but that's just my totally un-informed opinion), but the requirement for becoming a backer are apparently that one signs up or uses facebook and that's a bridge I will not cross for any good cause. Is there some other way I can contribute?
It is indeed a low number as far as science research goes.
It's pretty staggering how inexpensive experimenting with DNA can be. Recent advances in DNA synthesis are outpacing Moore's Law. Creating genetic constructs for insulin is also cheaper because insulin itself is a relatively simple protein.
And fortunately there are also a ton of extremely qualified people on the team who seem to love working for free.
EDIT: you shouldnt need to use facebook. you can sign up for experiment .com with just an email addy.
I don't want to sign up for anything, I want to back your campaign. If your project has a direct way of receiving some funds let me know, email address in my profile.
What's the goal of the project, is it to produce cheap insulin, or is it to validate "open-source biohacking"?
If it's the latter, why start with such a hard molecule; isn't there a lower-hanging fruit?
If it's the former, it would seem grounded in the assumption that biosimilar insulin unavailability in the Western markets is due to the lack of a royalty-free production method. I'm not sure that is the case (and please, correct me along the way). Biosimilars face a more rigorous/expensive approval process than generics (as they should), they're more expensive to produce under GxP conditions, and they're more expensive to store/transport/etc—the upfront costs are higher, the production costs are higher, and the logistical costs are higher. A small portion of NRE costs in the beginning would seem to be a drop in the bucket compared to the rest. Are you planning to address the rest of the lifecycle? Also, there would seem to be a lot of handwaving over the folding problem… do you have direct plans to address it?
I don't intend for this to come across harshly—I'm genuinely curious and hope this comes across constructively.
> In Phase I, the team will insert an optimized DNA sequence for insulin into E. coli bacteria
That is an unfortunate naming choice. Phase + Roman numbers have a well defined meaning in drugs development (clinical trial phases). I saw you refer to phases elsewhere in the comments and misunderstood what you meant.
"Kevin Riggs, an instructor in medicine at Johns Hopkins University who co-authored an article about generic insulin earlier this year, doesn't think that Open Insulin will be enough to bring a generic insulin drug to the market:
“I don't think the major hurdle is that the companies don't know how to make insulin, because that part is reasonably straightforward,” he says. “The real hurdles are getting the drug approved by the FDA (and since insulin is a biologic drug, it requires a lot more original data than an application for a small-molecule generic would), and then upfront manufacturing costs (because making a biologic drug is different, so it requires different equipment).” "
I have type 1. In an emergency situation, when demand outweighs supply for life-saving drugs, I would think it useful that there be recipes available online for ambitious DIYers. I think about this from time-to-time since since reading Alas, Babylon in which the diabetic characters are the first to die (maybe I'm too paranoid).
My impression is that the production of biological drugs (as opposed to small molecules) is simply more expensive on a large scale. There isn't as much potential to save costs as with small molecule generic drugs.
This seems to be a small-scale expression and optimization, and I'd guess that this is not the expensive part of developing a generic insulin. Large-scale manufacturing and making sure you're producing the correct molecule reliable, and then demonstrating that to the FDA are probably orders of magnitude more expensive.
2) gave the open insulin guys the design they're using. I am a little bit dismayed that credit for the design is somewhat buried in the public facing materials, but whatever.
and
3) agree that it's mostly hype - both this project and 'biohacking' in general. I run a nonprofit that is working on an patent-free cancer drug. Raised 60k and I'm doing ok, about to launch into production phase pre- animal model study. I would hesitate to call myself a biohacker - I have a PhD in chemistry and two postdocs in biochemistry and molecular biology, so I'm not coming from the CS/IT side - although I do currently code for a living.
but
4) think that whatever, the project could be interesting.
As it is, the way insulin is manufactured is pretty terrible, it could be way cheaper, and it's with that in mind that I designed the scheme the way that I designed it.
Hey Issac. Sorry that we didn't make your design contributions clear enough in our promotional material. I was wondering if you might be willing to either write up a lab note for experiment.com or an article for our publication so we can point to it and do a better job of giving you credit.
I would try to write something up, but honestly although I studied biochemistry in undergrad, I don't have a clear enough understanding of the differences in the design you gave us vs. other strategies.
As someone who works in neuro lab who occasionally reads about "Neurohacking" I could easily dismiss it as 100% hype, but I won't (although I do call out when someone talks to me about any of the devices on the market having seen manufactures come through our lab and try to peddle their… stuff).
"A lot of biohackers (even PhD level biohackers ensconced in academia) are basically script kiddies – cut and paste these bits of DNA and cross your fingers and hope the result you expect pops out."
Same is true of Neuro phds: "scan brains in fmri/eeg that i have no idea how it works from a physics perspective", run this matlab script here, use this proprietary software there, calculate "connectivity|power|correlation" - "does this look good for my paper? yes, shiny grant coming right up! Will it move the field forward? Not anymore than the thousand other papers out there but the university pr office is on it!" (in no particular order).
I say this because if all this was more out in the open (methods, software, caveats on every level on a git repo) and more available to people in other fields/expertise to look at and source materials and parts, a lot could be moved forward in general from what I'm observing going on in academia now along the lines of:
"As I worked on insulin in grad school, I risked my job as a lowly postdoc, chiming in and pointedly telling him (in front of the program manager) why it wouldn’t work. Some of my coworkers speculated that I might not show up the next day, but I survived to tell the tale."
I see some well intentioned people fumbling around, being derided in private by academics (who play the same human status games in different ways) who are still willing to talk with such people (because $$$, and maybe because some other academic they "collaborate" with is talking with them), who are pretty smart in their field (who are finding alternative funding sources!) who I secretly hope burn a fire under the ass of what goes now, so I won't write it all off.
Author of the blog post here - to be a good sport, I gave the open insulin guys the design they're using. I think the chemistry is solid and it will work, but I can't say I'm confident the team will be able to get it together. Insulin is hard.
I could probably whip it up myself, but I'm already stretched thin doing two biology projects that aren't paying me anything - and in fact are costing me (my nonprofit and a startup) and I make barely enough on some part-time contract coding work that I am really lucky to have landed through roommate-nepotism.
As to why I'm not really that excited about helping the Open Insulin Project any further: I've become kind of wary about prevailing attitudes in the tech-to-bio transition field that basically takes an exploitative attitude following the Postdocapalypse... There's this investor class expectation that they can hire frustrated grad students and postdocs for cheap. I think this is true, but they better watch out, in 99% of cases they are going to get what they are paying for.
I've decided to quit impostor syndrome and accept that I am kind of a biochemistry badass (I redesigned an enzyme and made it 4x better on my first shot based on first principles), and that if anyone wants my expertise they have to pay $$ for it. The other week an ALS advocate showed me a drug candidate structure and I correctly identified the mechanism of action without knowing much about the target. I've never been terribly excited about bringing the marginal cost of scientific labor closer to zero, and the OIP is basically that.
> "I've decided to quit impostor syndrome and accept that I am kind of a biochemistry badass…"
I think the work you do is pretty awesome (at least from reading your posts here and on your blog) and can understand that you are stretched, but I can see that you also want to move the field forward (and not in the "lets shit some papers out and maximize for 'impact factor'" way).
>"As to why I'm not really that excited about helping the Open Insulin Project any further: I've become kind of wary about prevailing attitudes in the tech-to-bio transition field that basically takes an exploitative attitude following the Postdocapalypse... There's this investor class expectation that they can hire frustrated grad students and postdocs for cheap. I think this is true, but they better watch out, in 99% of cases they are going to get what they are paying for."
I can see where you are coming from about the whole Postdocapalypse economics… I see it heating up as well with mindfulness being the current carrying agent in moving the neural tech forward (some neuro phd i was talking to on twitter said this to when I was mocking the "run matlab on cluster for months mentality" and saying it could be done way faster (hours) and cheaper: "Sounds a little bit more complicated than just reporting what you did in a paper.", so yeah, the investors who fund people like that are going to get exactly what they are paying for), but I'm going to help people milk it for what its worth just to help foster something that can compete with the abomination that academia has metastasized into that masquerades such games as science.
> "…I've never been terribly excited about bringing the marginal cost of scientific labor closer to zero, and the OIP is basically that."
Yeah I can understand that, but I also think the way that resources are allocated as a society are in for a major shake up (esp with the whole crowdfunding bonanza across so many industries, and have people who worked for the UN and a gov agency in Turkey contact me about the software I wrote to track it on social media), which I think is why people aren't terribly excited on top of the personal stress all the uncertainty brings which I'm familiar with being a drop out who's in the neck of it up here in the boston area (and happen to be the only one it seems to have open-sourced a spacial beamformer in c++ for real time neural feedback for eeg that can be adapted for dual eeg/fmri). I do think though, because you aren't necessarily confining yourself to what things have to be (as defined by the status quo), you'll probably end up doing way more than you think you are capable of now.
Oh. Some bonus content (I hadn't read that blog post in quite a while). That DARPA program manager... About a year ago on pubpeer very credible claims emerged suggesting that all of her work in grad school was an instrument artefact. Her PhD advisor committed some ethically questionable actions overdefending it.
And after spearheading several bio-hacking-type calls within DARPA, and seemingly being groomed to take Arati Prabhukar's position, she seems to have suddenly disappeared from her position at DARPA altogether in the past few months.
DARPA is doing the same pretty much with some stuff going on at MIT in neuroimaging… so i hear… :P
And there's a lab in Wisconsin that's sucking up 10's million of dollars from private foundations of which a co pi of that lab visited ours to tell us about their soon to be created public outreach arm… on top of the questionable custom eeg head cap for dual/eeg frmi thats close to a million who knows nothing about e&m, who I confronted directly about that while getting the backing from the senior research scientist (who is on a visa…) in my lab whose phd is in soft condensed matter physics who worked on SQUIDs at yale, who is now conveniently "volunteering" most of the time doing mobile apps for some company attached to our lab who wrote most of the code for the system people saw Anderson Cooper hooked up too on CNN not too long ago… but you'll never hear about him over others trying to capture 100% of what they think is the only opportunity now.
#WhatAFuckingJokeThingsAre and this is why things are due for a shake up lol
And also ignoring all the commercial pharmaceuticals whose prices are being jacked up by orders of magnitude with no warning. Martin Skreli can make the mainstream news by jacking up the price of anti-infection drug pyrimethamine by 5555%. Cycloserine can go up 2160%. Isoproterenol, nitroprusside, tetracycline, and doxycycline went up abruptly.
When your quality of life, or even the remaining duration of it, is largely in the hands of a few executives at a single company, it's generally a good move to do whatever is necessary to reduce your dependence on them, before they realize that they can bleed you dry--along with those like you--with a few keystrokes in their inventory system.
It is inevitable that people made desperate by medical circumstance will do dangerous things with biology on a shockingly low budget.
For instance, did you know that some people are doing at-home fecal transplants using thrift-store blenders and over-the-counter enema kits?
How long do you think it will be before someone tries converting cells in their intestinal lining into beta cells, or implanting an artificial pancreas made from their own cells? It is very likely that any successes will be unknown, while the first person to inadvertently kill himself while attempting to cure his own diseases with garage-scale biotech will be criticized and demonized worldwide. And that will be the spark falling on dry tinder, as people realize that the cost of biohacking is now low enough to be within reach of ordinary people.
United States, insulin is very expensive—that cost was likely a large proportion of the $176 billion in medical expenditures incurred by diabetes patients in 2012 alone.
Well, the report itself says:
prescription medications to treat complications of diabetes (18%)
So this is up to $31.68 billion in 2012. I will assume for simplification that all of it goes for insulin.
I'm not sure which report you're looking at, but "prescription medications to treat complications of diabetes" means things like painkillers for neuropathy, antibiotics for infections, et cetera. Insulin falls under "antidiabetic agents", which treat diabetes itself, not the complications.
But most of the 20 million diabetics in the US are type 2 and do not require insulin; it's only Type 1s and the most severe cases Type 2s who take insulin.
Just throwing in my experience/numbers, for those interested.
I'm a type 1 diabetic (for ~30 years) and take Apidra (short acting) and Lantus (long acting) daily. I use about 5 vials of each per 3 months. I "think" the cost of each vial, if I was paying sticker price, would be about $250.00.
So... 2 * 5 * 250 / 3 = $833 / month
As it turns out, there's several mitigating factors:
1. I have insurance, so I pay much less than that
2. For those without insurance, the insulin creator has programs to help such people pay for the insurance (discounts for some, max out-of-pocket for others)
I'll have to admit it's a pretty cool project, but if you want to create a cheap source of insulin, you're really just creating a generics company.
And the reason why there isn't any generic insulin is because each new insulin is "next generation" and people would rather pay more for the added benefit than use the old stuff.
Because there's no(t enough) profit in it? Markets don't always create the stuff we need, even if they're not full of safety regulations because stuff that's being made is dangerous.
I have the highest doubts that they'd have the resources to do the broad-based clinical trials required to go to market.
Look up "Eroom's Law" which is "Moore's Law" spelled backwards: http://www.nature.com/nrd/journal/v11/n3/fig_tab/nrd3681_F1....
Basically, the increases in pharma regulation means it takes longer and gets more expensive to create a new drug each year.
This is a cool science project, but the reporting around it is sensational and not helpful to the millions of people with diabetes who have their cranks yanked regularly about miracle cures, cost-saving fantasies, etc.
To address some raised in sub-threads:
+ You can get extraordinarily cheap drugs in India, the rest of the developing world, and in parts of Europe. The "greedy" drug companies adjust pricing to what local markets can bear. So instead of letting poor people die en masse they mark the drugs down and pass the cost onto the developed world. Fair trade IMO.
+ The reason there are so few generic insulins is that they are hard to make consistently enough to please the FDA and European regulators. Companies like Teva and Perrigo are multi-billion dollar manufacturers of generic drugs who would love to get get into this game, but as noted, biosimilar drugs, especially ones as powerful as insulins, are a lot harder to copy than aspirin.