Artificial Pancreas Update (Jan 2015)

Sound track for this blog is "Living After Midnight" by Judas Priest, but performed by The Donnas:
http://grooveshark.com/#!/s/Living+After+Midnight+Judas+Priest/3ASqUY

Research into the Artificial Pancreas (AP) continues to move forward.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Metronic Starts Selling a "Step 2" Artificial Pancreas in Australia

The JDRF uses a 6 step model to get to the fully featured artificial pancreas that we wall want.  You can read about that model here:  http://jdrf.org/research/treat/artificial-pancreas-project/

Right now, Medtronic makes the only commercially available "step 1" artificial pancreas.  However, just recently they started publicising a "step 2" artificial pancreas in Australia.  The difference is that "step 1" APs cut off insulin if you are already too low, while "step 2" cuts you off before you get too low.    This is an important improvement in functionality, but it is also an important regulatory hurdle. The model number is 640G.  I can't find any press releases, or any notice on their web site, but karri on CWD posted this link to a promotional video:
https://www.youtube.com/watch?v=wl6WDkxXjBc
There are also several "Ambassador Reviews" on the Medtronic Diabetes ANZ youtube site.
It looks like they are taking orders for the device now.  However, I can't see anything on the web site related to the 640G.  Maybe they know I'm from the USA, and can't get it?

Of course, the next issue for us Americans is FDA approval.  Medtronic's "step 1" device took 31 months after European approval, before the FDA approved it!  It will be interesting to see if the FDA repeats that fiasco or not.  There has been a lot of progress, several meetings between the FDA and patient advocates (such as DOC, diaTribe, JDRF, etc.) and now we will see if any of that matters. But the clock is ticking now, and we will know a lot more when we see how long the FDA delay of approval is.


A Direct Single Hormone vs. Dual Hormone Comparison

In the past, I've tried to compare Single Hormone AP results to Dual Hormone AP results, by comparing similar results from different studies.  However, it's much better to compare the same result in the same study, rathern than combining data from different studies.  A group of researchers at Institut de Recherches Cliniques de Montreal, Montreal, QC, Canada (and elsewhere) recently did exactly this comparison.  They directly compared a regular pump plus CGM, to an insulin only AP, to a insulin and glucagon AP.  Patients (12 years or older) were treated for 3 24 hour periods.  The trial was not blinded. Funding was from the Canadian Diabetes Association, JDRF, and Medtronic (see above for involvement). They reported the following data:

Measure	Pump + CGM	Insulin AP	Dual Hormone AP
Time spent in target range	51%	62%	63%
Hypoglycaemic events	52	13	9
Symptomatic hypoglycaemic events	12	5	0
Nocturnal hypoglycaemic events	13	0	0

Opinions

I think the clear result of this trial is that the dual hormone AP is very slightly better than the Insulin AP, and they are both noticeably better than the current standard pump and CGM.  This result is similar to previous studies.

Abstract: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/fulltext
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT01754337

Many Articles in the January Journal of Diabetes Science and Technology

The Journal of Diabetes Science and Technology had a special issue on glucagon therapy.  There were a couple of articles on stable glucagon, which is required for a bihormonal artificial pancreas (such as Dr. Damiano is working on):

From this abstract http://dst.sagepub.com/content/9/1/8?etoc:

Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.

From this abstract http://dst.sagepub.com/content/9/1/24?etoc:

Data are presented that demonstrate physical and chemical stability under presumed storage conditions ([over] 2 years at room temperature) as well as “in use” stability and compatibility in an Insulet’s OmniPod® infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model.

Here is a diagram of their results.  Note that they are comparing their glucagon to standard glucagon, so their trial is successful if the same colored lines are close to each other, and they are:

Although both of these are animal trials, for this kind of test, I think results in animals are likely to mirror results in people.  They are really measuring the stability of the glucagon, and the test subject species doesn't have a big impact on that.  So my normal worries about "works in mice, fails in people" are pretty small for this kind of research.

Adding Physical Activity Measurements to Aritifical Pancreas Calculations

Also in The Journal of Diabetes Science and Technology, there is this paper:
http://dst.sagepub.com/content/9/1/80?etoc
(People in the San Francisco bay area will notice that the authors are mostly local: Drs. Stenerson, two Paynes, Ly, Wilson, and Buckingham.)

This paper attempted to use data on physical activity to improve an artificial pancreas's BG numbers. The idea is simple enough: we all know that physical activity lowers BG numbers.  If an artificial pancreas knew how active you were, could it do a better job of controlling BG numbers?   The kids in the study (average age 13), did a soccer workout ("football workout", in the rest of the world) on two separate occasions.  In one case, data from an accelerometer was used to help calculate real time insulin dosing, and in the other case, this data was not used.  BG and hypoglycemic events were measured both during the soccer, but also after it, until the next morning.  There were 18 kids in the study.

Overall BG numbers were similar in each group.  Hypoglycemia events were higher when not using the accelerometer, but the difference between groups was not statistically significant. (This is the scientific way of saying "close, but not quite".)

Discussion

From my point of view, there are a couple of ways to interpret this result:

1. One could say that the study was just too early and too small to interpret the results, and it's really more of a proof of concept of how accelerometers could be tested in the future.  The most that can be said is that more research should be done. 
2. Or, one could say that accelerometer data is not needed for an artificial pancreas, because it had no statistically significant effect here.  And this is a good thing, because it means we will not have to burden type-1 diabetics with accelerometers (in addition to pump(s) and a CGM), because the extra information they provide is not needed.
3. Or, one could say that existing algorithms and accelerometers are not good enough, and we need to develop better ones in order to take advantages of this information.
4. Or, one could sort of split the difference, and say that most people don't need accelerometer data (as also supported by the good BG numbers reported by other AP tests which don't use them). However, for serious athletes who do need this extra data, we need to develop better algorithms (or accelerometers), if we are going to successfully use this data. 
5. Or, we can view this research as answering the question "how much physical exertion is needed before an AP needs exertion data to work well?"  The idea is that, of course at some level of vigorous exercise, accelerometer data will be needed.  This trial just shows that the soccer exercises wasn't enough, and we need to do something even more vigorous until it does matter.

No matter which interpretation appeals to you, we are still very early in the testing of accelerator enhanced APs.  I'm sure there will be more clinical trials before there is any consensus on the proper way to integrate accelerator data into APs.  

Interview with Dexcom

Here is a two part interview with the CEO of Dexcom, a big CGM maker.  He talks about future development, both in terms of CGMs for APs and CGMs as a replacement for finger sticks.  I found part 2 more interesting than part 1, but here are links to both:
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-one-0001
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-two-0001

Another Summary

Here is another writer's summary of artificial pancreas progress for 2014.
http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/49342

Homebrew Artificial Pancreas

As Dave Berry used to say: I'm not making this up!

This project is being called "Hacking an Artificial Pancreas" or "DIY Artificial Pancreas", but in the tradition of Silicon Valley, I would called it "Homebrew Artificial Pancreas".  It looks like we have reached the point where people can cobble together a functional AP in their garage.

You can see pictures here (two quite different paths):
https://scottleibrand.wordpress.com/2014/12/15/how-does-a-closed-loop-artificial-pancreas-work-when-you-diy-or-diyps-closed-loop-is-working/
http://circles-of-blue.winchcombe.org/index.php/2015/01/11/wearenotwaiting-thanks-to-dexdrip-introduction/
https://twitter.com/stephenistaken

If you speak twitter: #DIYPS #WeAreNotWaiting #dexdrip

Less than $100 in parts. A little soldering (sometimes).  What could possibly go wrong?

When Steve Jobs and Steve Wozniak made the Apple I they were basically making something that they could not buy, and that's what these guys are doing.  Of course the Steves were not replacing  an organ of the body.

I want to thank Dominik for sending me this. I will never look at a Raspberry Pi the same way, again.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

A Cautionary Tale from Dr. Melton's Lab At Harvard

The soundtrack for this blog posting is the blues: Ball Peen Hammer sung by Joe Bonamassa:
http://grooveshark.com/#!/s/Ball+Peen+Hammer/2pulWL

This is a cautionary tale of research from Dr. Doug Melton's lab at Harvard.  I considered carefully if I should blog on this subject.  It is certainly a lot more fun to blog about successes, and new opportunities, than it is to blog about failures and mistakes.  However, I think it is critical to include both good news and bad news.  At the very least, so that people following type-1 research understand that mistakes get made, and that one of the strengths of the scientific method is the ability to recover from mistakes.

This posting is about Betatrophin, which I did not cover in my blog when it was first announced. The research was all done on animals, and I focus on human trials.  However, now that this research has gone full circle, I think it makes a useful scientific morality tale.  Obviously, lots of scientific research doesn't pan out for one reason or other.  Usually it dies a quiet and obscure death.  But this research was a little higher profile, and therefore it's death was a little higher profile as well, so more about it's life and death is known, than about your average research dead-end.

History

In early 2013 Dr. Melton's lab at Harvard released a "big news" research paper. They had identified a natural human hormone which caused beta cells to naturally regrow.  This one hormone, which they named "Betatrophin" had a huge impact in beta cell regrowth.  The research had been done in mice, and was published in Cell (a prestigious scientific journal).  Two big name pharmaceutical companies (Evotec and  Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson) paid millions of dollars for the rights to Betatrophin.  The lead author of the paper (Dr. Peng Yi) was hired by an important diabetes research center (Joslin) to do research, including future clinical trials focused on Betatrophin.

But about 18 months later, it all collapsed.  A research group working for Regeneron Pharmaceuticals found that Betatrophin did not cause beta cells to regrow, and submitted a paper to that effect.  When the paper was sent to Dr. Melton for peer review, he endorsed it, and wrote a "Perspective" stating that his own lab had been unable to reproduce it's own previous findings.  It now appears that the conclusion in the first paper was incorrect.  I want to stress that no one has suggested that there was any fraud or mistakes in the research; it is just that the conclusion turned out to be wrong.

Discussion of Fallout

Betatrophin was the big news from this lab in 2013, but what about the big news in 2014?  In 2014 Dr. Melton's lab released a "big news" research paper showing that they could grow large amounts of functional beta cells from embryonic stem cells.  (Again, I did not blog on this, because it was not yet being used in a clinical trial.  However I was asked about it specifically on CWD, and posted some comments.)  How does the failure of the 2013 news, affect how we view the 2014 news?  This is the question that should be in the front of the mind of everyone following research aimed at curing type-1 diabetes.  Does the collapse of Betatrophin suggest that the beta cell breakthrough might collapse?

There is no way for me to have any insight into that question.  A pessimist would say that a lab that is wrong with one thing, could easily be wrong about the next thing;  that whatever caused the first incorrect conclusion could still be there for the second one.  An optimist would say that testing Betatrophin is a very different technology than transforming embryonic stem cells into beta cells, and the fact that the lab was wrong about one does not mean it is wrong about the other.

Of course, this brings up this question: if a world class scientist, working at one of the most highly regarded universities in the world, publishing in one of the most prestigious journals in the world, can still be wrong, how are we -- everyday people affected by a disease, but without extensive scientific knowledge -- to know what is correct and what is wrong?  How will we ever know?  (I discuss this in the conclusion section.)

Discussion of Peer Review

One of the interesting "side issues" that this brings up is conflict of interest in peer review.  When the scientific journal Cell got the paper showing that the research done in Dr. Melton's lab was wrong, they sent it to Dr. Melton as part of peer review.  I was a little shocked by that; but it makes sense in a pure-science sort of way.  Dr. Melton is a world expert on Betatrophin (by virtue of being "senior author" of the paper discovering it's function) so it makes perfect sense to ask him to peer review this paper.  However, from a human point of view, it seems nuts to have a person peer review a paper that directly undermines his own paper.  Even if there is not a monetary conflict of interest, there certainly is an intellectual one!  We were all well served by Dr. Melton's ethical actions after he was asked to be a peer reviewer.  But the opposite can happen as well.

This policy, of having papers which contradict previously published papers (in the same journal) reviewed by the authors of the previous paper, appears to be common in scientific journals.  At least it used to be.  The big name journal Nature did this in the 1990s.  More shocking, it then did not publish the second paper, based on a bad review from the author of the first paper.  Two other reviewers gave the second paper good reviews. You can read the sorry tale here:
http://retractionwatch.com/2013/06/19/why-i-retracted-my-nature-paper-a-guest-post-from-david-vaux-about-correcting-the-scientific-record/

Corporate vs. University Research

There is the growing trend to ignore corporate research in favor of academic research, often under the guise of "conflict of interest".  Obviously, some of this is a well earned reaction to various corporate attempts to manipulate scientific research (nuclear, tobacco, and pharmaceutical industries, just to name the ones who have gotten caught at it).

However, it is important to not take that attitude to extremes.  There are pressures to deliver in academia and the non-profit world as well.  In this case the wrong results were from university research and the right results came from industry.  I think it is important to remember that, in the face of a growing "corporation = evil" narrative.

The Original Paper Has Not Been Retracted

An interesting question (at least it's interesting to me) is should this paper be retracted?  It hasn't been, and it doesn't look like it will be.  It is certainly wrong in it's conclusions, but is that enough to retract it?   There are two schools of thought here.   One says that publications should only be retracted if they are "in error", meaning there was an error in design, data collection or analysis, or if there was fraud or ethics problems.  The other school of thought says that being wrong is enough.  If the authors / editors / publishers are sure it is wrong, then it should be retracted.

This sounds like a good topic of debate in a college level ethics class, with a scientific bent.
But one of the existing complications, is that there is no global standard.  Each publication is free to make their own decisions about retractions, and even in one publication, they don't have to be internally consistent, if they don't want to be.

My Summary

First, the press:

I have a very low opinion of how "the press" (ie. mass market news web sites) covers science and medicine.  Among their other sins, I think they over hype certain medical news, based on buzz words in press releases.  Although these "over hype triggering buzzwords" change slightly over time, a good PR firm or savvy researcher keeps up to date, so they can use the trendy buzz words to manipulate the press coverage.to get more than their research deserves.

For the last decade, I think "stem cell" is one of those triggering buzz words, and I think "Harvard" is one, too, and reports from big name universities are generally over hyped, in relation to universities with less name recognition.

Second, how to determine that science is correct:

This incident reinforces my belief that the only way to be sure a scientific paper is correct, is to follow it's research for a period of years after the paper is published, to see what happens.  There is no way to look at a freshly printed paper and know that it is correct.  I know that a lot of people try to take short cuts, and they say (or think) things like "it is a peer reviewed paper [so it must be right]", "the researcher is one of the most famous people in the field [so it must be right]", "the researcher is at an ivy league calibre institution [so it must be right]", "it was published in the leading journal in it's field [so it must be right]", "the researcher's family is affected by the disease so he's totally committed to the research [so it must be right]", "he is so personable, so articulate, and the description of what is happening makes perfect sense [so it must be right]", "the researcher has a great history and a great reputation [so it must be right]", and so on.

For Betatrophin, every one of those statements was true, and yet the research was flat out wrong.

This case is a clear example where the only way to see if research was correct, was to wait and see what happened to the research over time, as people tried to capitalize on it, to build on it, and to productize it.  The take home point is simple: there is no short cut.  There is no way to know quickly if research is correct.  Only the passing of years will tell us with certainty.

Now, I certainly don't claim perfection in this regard. I'm sure I've fallen into this trap myself. But it still is a trap, and something to be avoided.  I do stress peer reviewed results in this blog, almost to the exclusion of non-peer reviewed results, but that is different than implying that peer review means the research is good.  I consider peer review to be a necessary component of good research, but not sufficient to prove good research.  Put another way: if research is not peer reviewed, then it is not worthy of serious consideration.  But even if it is peer reviewed, it still might be wrong.

Some people, optimists, might look on this example as a fluke, but I think that's a mistake.  Most research does not pan out.  Most phase-I clinical trials do not lead to a marketed treatment. Therefore, the failures described here are quite common.  Maybe even normal.  I'm posting about this particular case because it made a bigger than usual news splash.  I get emails from people asking "remember research project X from years ago?  Whatever happened to that?  Did the money making, type-1 conspiracy suppress it?".  Nine times out of ten, the answer is that the research just didn't pan out at the next level.  Like Betatrohpin, the first publication was in error, and nothing could be built on it.

I'm always very nervous about the number of people who assume because they have not heard of it, that means it was really successful, and was therefore suppressed.  It creates a mindset where failure is taken as evidence of conspiracy.  In a world of research, where most new ideas do not pan out, this is spectacularly dangerous logic.

To join the two parts of this conclusion, notice that news organizations have an impossible conundrum: they are judged on how quickly they get (incredibly superficial) articles about scientific research out on the web, yet the only way to know if those articles are accurate is to wait, often months or years!   Yet as long as we reward news sources for speed, and ignore their accuracy (the current situation) this is the news we are asking for.

More Reading

Betatropin news at the time:
http://news.harvard.edu/gazette/story/2013/04/potential-diabetes-breakthrough/
http://jdrf.org/blog/2013/discovery-of-new-hormone-may-impact-t1d/

The papers:
Harvard paper: http://www.cell.com/abstract/S0092-8674(13)00449-2
Regeneron Pharmaceuticals: http://www.sciencedirect.com/science/article/pii/S0092867414011763
The Perspective: http://www.cell.com/cell/abstract/S0092-8674(14)01177-5

Discussion and fallout:
Retraction Watch: http://retractionwatch.com/2014/11/10/i-kind-of-like-that-about-science-harvard-diabetes-breakthrough-muddied-by-two-new-papers/
Blog: http://www.ipscell.com/2014/10/the-betatrophin-blues/
Pubpeer: https://pubpeer.com/publications/8EAC9ED889CC6E498199B11B1BC135 and also https://pubpeer.com/publications/0F7B9DF45743305575A36FDBA7FC9A
Money issues: http://seekingalpha.com/article/1730632-companies-race-to-develop-the-next-novel-blockbuster-diabetes-drug-part-2

A note on titles: In the past I have not been consistent about it, but in the future, in this blog, I will attempt to refer to anyone with a doctorate (PhD, PharmD, DVM, etc.) or a medical degree (MD) as Dr. X Y the first time they are named, and Dr. Y thereafter.   (Sorry lawyers, on this blog, you're not doctors, no matter what your degree says. :-)

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Two DiaPep277 Papers Retracted

I had previously reported here:
http://cureresearch4type1diabetes.blogspot.com/2014/09/diapep277-development-canceled-due-to.html
that DiaPep277 development had been canceled due to serious allegations of misconduct.
The "second shoe" has now dropped.  A key paper on DiaPep277 has been retracted.  You can read about it here:
http://care.diabetesjournals.org/content/38/1/178.full

Additionally, a second paper has also been retracted:
http://care.diabetesjournals.org/content/38/1/179.full
This paper reported on an unexpected difference in two different C-peptide measurement schemes, during the DiaPep277 testing.  Since it used the same data which now is in question, it is retracted.

The paper's authors don't have any new information, but are retracting the paper based on the already published allegations.  For me, the interesting part of the retraction, is that only the authors not employed by Andromeda Biotech took part. The authors who worked for (or still work for) Andromeda Biotech were "unavailable for comment and therefore are not part of this retraction process".

This story include a sort of "collateral damage" warning about the impact of fraud in science.  The alleged manipulation was all targeted at the first paper.  The goal of it was to make the drug look more effective than it actually was, and that was what the first paper reported.  However, the second paper represents a dangerous side effect.  Because the data was manipulated (allegedly), the second paper gave an unexpected result.  If the alleged manipulation had not been discovered, then the second paper might have caused unnecessary research to try to explain it's results.  Even more worrisome, perfectly good research that used the measurement schemes discussed in the second paper might have been cast into doubt.  Luckily, none of that will happen now.

I encourage you to read my previous blogging on DiaPep277.
Unfortunately, science that turns out to be wrong is going to be a mini-theme, as I'm putting the finishing touches on a blog posting describing another incorrect paper which was also important to type-1 diabetes research.  That blog should go out in early January.


Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.