One Year of "Cured In Mice"

At the end of 2011 I started keeping track of all the treatments that were discovered to cure type-1 diabetes in animals.  Throughout 2012 I kept track of all these announcements, so now I have a full year's data on type-1 cures in animals, and this blog posting is a summary of that data and my thoughts on it.

You can see all these potential cures here: http://t1dcuredinmice.blogspot.com/

Summary of One Year of "Cured In Mice"

The big news is this:  Depending on how you count them, there were between 10 and 18 animal cures discovered in 2012.  That's a huge number.  Much more than I expected.

What kind of mouse cures were found?  Everything that I could imagine, and some that I couldn't imagine.  There were animal cures based on growing new beta cells in the pancreas and in other parts of the body.  There are stem cell cures, nanoparticles, parasitic infections, a natural/alternative/complimentary cure, all kinds of drugs, and biologicals.  Even "hyperbaric oxygen" made an appearance.

Here is the full list. More details (including web sites) are on the t1dcuredinmice blog.

Trial	Treatment	Animal	Results
ViaCyte	VC-01: encapsulated stem cells	diabetic mice and rats	Cure
Sheba Medical Ctr.	Ad-CMV-PDX-1	CAD-NOD mice	43% Cure
Feinstein Institute	ISO-1
NJ Medical School	intestinal parasite	NOD mice	Prevention
Karolinska Institutet	M2r macrophages	NOD mice	65% Prevention
U British Columbia	human embryonic stem cells	STZ mice	Beta Cell Creation
U North Carolina	non-depleting antibodies	NOD mice	80% honeymoon cure
U Florida	Adult Stem Cells + Beta Cell Growth Factors	mice	Cure
DRI	Hyperbaric Oxygen	mice	30% Prevention
KU Leuven	proinsulin autoantigen	NOD mice,	Honeymoon Cure
St. Jude  Hospital	Interleukin-35	NOD mice
U Colorado	CD40 inhibitory peptide	mice	Prevention and Cure
XOMA	XMetA	mouse model of diabetes	lower A1C
Hannover Medical School	Hepatic Insulin	IDDM and STZ Rats	Cure
Vanderbilt U	Brown Fat	STZ mice	Cure
U of Tokushima	anti-CD98hc	TZ NOD mice	Cure
Parvus	Nanoparticle	mice	70% Cure
Academia Sinica	Catenarin	NOD mice	Prevention

Notes on Animals

NOD mice have an autoimmune diabetes similar to human type-1 diabetes.  STZ mice have had their beta cells killed with a toxin, and therefore have no autoimmunity issues.  CAD-NOD mice are NOD mice where the type-1 was triggered with a toxin.

The Allure of Animal Research

One of the themes that I repeat over and over in this blog, is that animal research -- even really successful, animal research that sounds like a great idea and a sure winner -- is always a long way away from real success in people.  Reading this paper on Catenarin:
http://www.hindawi.com/journals/ecam/2012/982396/   (especially figure 2A)
really reminded me of the dangers of the siren-song of animal research.  How easy it is to sound really good, like a cure was just around the corner, even when it is not.  This paper shows a graph where untreated animals start to come down with type-1 diabetes at 12 weeks, and by 24 weeks every animal has type-1 (100%).  They give animals the smallest dose of Catenarin, and at 24 weeks only 70% of the animals have type-1; a medium dose results in 30% type-1 diabetes rates, and at full dose, no NOD mice get type-1 diabetes.  Even at 30 weeks, none of the full dose mice have type-1.  On paper it looks like the perfect preventative.  It looks so beautiful, so alluring. There is no reason why it shouldn't work; no reason why we should fund any other research.  So perfect.  And yet, so many treatments have shown this in mice.  Most wildly successful mice treatments never even start a human trial, and most of those that do, fail.   Reality is so hard, sometimes.  This is part of the reason I don't follow animal research very closely.  Too much heart-ache.  Even with human trials, there is too much, but with animals, it is even more.

The Future

How many of these animal cures are going to progress to human clinical trials?  I don't know.  So far the answer is none, but it's only been 8-20 months, and that's not a lot of time to translate into human trials.  But this is definitely the next piece of data to gather: out of the animal cures in 2012, how many turn into human trials in 2013, in 2014, in the next 5 years, or ever?  In looking over the research, I have a sinking feeling in my stomach, that very few of these are ever going to be tried in people.  But I'm really just guessing, and the whole point of gathering the data, is so I don't have to guess.

• The ViaCyte researchers are very specific about planning to start human trials in 2014.
• The lead Feinstein researcher (Dr. Al-Abed) "is now designing clinical trials" according to their press release. 
• I have heard some discussion about a human trial for the intestinal parasite tested at NJ Medical School, but there is widespread belief that very few people will volunteer for this, so there is little enthusiasm for starting the trial.

I'm not planning to continue the "Cured in Mice" blog, because I feel it has served it's purpose, and the extra work involved in keeping two blogs up to date is not worth it.  I may blog on animal research slightly more often here, but I don't think it's worth a second blog.

Joshua Levy -- Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail 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.

Data From A Phase-I Clinical Trial of Polyclonal Tregs

18 Month Data from a Phase-I Trial of Polyclonal Tregs

I previously blogged on this research here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs
so please read that blog posting for details of what is being tested, and who it is being tested on.

A quick summary is this: Dr. Trzonkowski and co-researchers at the Medical University of Gdańsk  remove one specific type of T regulator cell (called "CD3(+)CD4(+)CD25(high)CD127(-)") from a person with type-1 diabetes.  They use these cells to grow a lot more of them, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes. 

The previous data was from 10 children, who were treated within 2 months of diagnosis.  But this new data covers 12 children (aged 8-16), also treated within 2 months, and were followed for 18 months.  They were compared to a placebo (untreated) group.

The big news is simple: two of the treated children did not need to inject any insulin at all for 11 months.  The treated patients in general generated statistically significantly more C-peptide than the untreated group, which means they were generating more of their own insulin.  And obviously, two of the treated kids were generating a lot more insulin.  It is important to remember, that some honeymooners do not require insulin for some part of their honeymoon time.  However, I think that 2 out of 10 is far more than would be seen randomly, and I think that 11 months is longer than one would expect naturally.

A pessimist might say "It only works for honeymooners, it worked for less than 20% of the people, and it only worked for 11 months."  But I am an optimist.  I say "If it works for honeymooners now, maybe it will work for established type-1 diabetics in the future, or might work when combined with a beta cell growth factor.  Previously we had a prevention for no one; if this work pans out, we will have something that works for some people, and if we start out with 11 months, maybe we can stretch it longer with more research, or repeated doses.

So I think these results are very interesting, and well worth following.  I'm very happy that at least one other group (Drs. Gitelman, Bluestone, and Herold) also have a 14 person, phase-I trial going into this treatment.  However, that group is not expected to finish their trial until 2016. Hopefully Dr. Trzonkowski and his co-researchers will have a phase-II trial well underway by then; maybe even finished (if their phase-II trial gets funded quickly).   

Abstract: http://app.core-apps.com/tristar_ada13/abstract/9b942b88cb23351f1c62fdf808057354

Joshua Levy
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. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com

Data From A Phase-II Clinical Trial of TOL-3021

Data From A Phase-II Clinical Trial of TOL-3021 by Tolerion
(Previously known as BHT-3021 by Bayhill)

Tolerion recently reported results from a Phase-I/II clinical trial of TOL-3021.  This treatment started life as BHT-3021 under development by Bayhill Theraputics, so you can read my previous blogging on it under that name:
http://cureresearch4type1diabetes.blogspot.com/search/label/Bayhill

Background

The best results (most positive results) were seen in people dosed 1 micro gram, which was a middle dose in this trial, which tested a range of different doses.  Those are the results I discuss below.  This study was a true phase-I/II study.  The researchers started out dosing a few people to check for safety and to get early efficacy data for a very small number of people (the phase-I part). They then expanded into a larger group, which got four different dose levels (plus a placebo group).  The goal of the phase-II part was to find the best dose for future trials.  The people in this trial had type-1 diabetes for years prior to the start of the treatment.

Results

The researchers reported three interesting results:

1. Treated type-1 diabetics generated more of their own insulin, but only a tiny amount more.
The "top line" results for this study is that people treated with TOL-3021 saw a 28% increase in C-peptide production, which means a 28% increase in the amount of insulin their bodies were naturally producing. (I'm reporting on "spread" here: the treated group went up about 20%, the placebo group went down about 8%, so the spread was about 28%.)  On the one hand, this is a tiny amount.  So little that their insulin requirements did not change noticeably (ie. in a statistically significant amount).  On the other hand, any increase at all in well established type-1 diabetics is big news.  Even ten years ago, it was thought to be impossible.

2. Treated type-1 diabetics generated less autoimmune cells ("bad killer T cells"), targeting proinsulin.  The immune system generates cells ("killer T cells") that attack foreign cells.  In type-1 diabetes a small number of these killer T cells mistakenly attack the body's beta cells in the pancreas, which causes type-1 diabetes.  These are called "bad killer T cells".  These researchers specifically measured "bad killer T cells" (separately from other killer T cells) and found fewer of them in patients who got TOL-3021 as compared to those which got a placebo.  This is direct evidence that the treatment is working in the way the researchers expected.

3. Treated type-1 diabetics did not change their immune response to foreign cells.
One of dangers of immunology in general, is that you might damage the body's immune system. You might cure the type-1 diabetes, but hurt the body's ability to fight off disease in the future. These researchers specifically looked at the effect of TOL-3021 on the body's reaction to foreign bodies (the viruses, cancers, and foreign cells that the immune system is supposed to attack).  They found there was no change in the immune system's ability to do it's job of attacking these foreign cells.  This is interesting for at least two reasons: first, it's unusual.  Most immune treatments end up lowering the immune response across the board.   Second, it's important.  By showing this treatment did not effect the rest of the immune system at all, it puts TOL-3021 in a good position to move forward, because the safety worries will be lower and the potential doses can go higher.

Moving Forward

So what is the next step?  Well money, for one thing.  Or, better yet, a strategic partnership.  Since these are phase-II results, the obvious next step is either a phase-III study or another phase-II study.  Either path requires money.  Of the four phase-III studies I've followed in the past, three were funded via a strategic partnership with a "big pharma" company; only one was funded by a smaller company itself.

What are the problems to overcome?  The small results are a big problem.  They need to see a larger C-peptide production, if they are going to produce a treatment, much less a cure.  A second issue is duration.  The biggest results were seen 15 weeks into the treatment. since the treatment was given for 12 weeks, this is close to the point of longest duration of treatment.  That suggests to me that the treatment might need to be given for a longer duration, or given more often, or improved in some way, in order to be more effective in the long term.

What sort of clinical trial comes next? There are a lot of options here. Since TOL-3021 seems to lower the autoimmune attack, but does not create replacement beta cells.  An obvious trial would be to try it on honeymooners or even pre-diagnosis, high risk relatives of type-1 diabetics. Those people have more surviving beta cells, so the benefit should be more obvious. Another option would be to combine it with a treatment that stimulates beta cell regrowth. Simply repeating the treatment for a longer period of time would be interesting, as well.

Business News

The reason there was no news on TOL-3021, prior to these phase-II results, is that until recently this drug was known as BHT-3021 and was being developed by Bayhill Therapeutics.  Bayhill had all the trappings of a successful little pharmaceutical start up (several drugs in development, a deal with Genentech, about $50 million invested, etc.)  But it collapsed while BHT-3021 was in the middle of it's phase-II trial.  Luckily, the researchers focusing on BHT-3021 were able to rise, phoenix-like, from the ashes, and create Tolerion.

Some Discussion

One question I've heard is "why do they call this a vaccine" or "what is a reverse vaccine", and there is a simple answer to that.  Classic vaccines work by stimulating the immune system.  This product works by regulating (lowering) the immune system, so it acts like the reverse of a vaccine. It is similar to the way food allergies are treated.  For food allergies doctors sometimes give small amounts of what you are allergic to, so your body learns not to attack it.  The difference here, is that they are giving the body a specially crafted molecule, which is designed specifically to teach the body not to self-attack proinsulin.  Other researchers are giving small amounts of insulin to teach the body not to attack insulin, which is a related idea, but the hope here is that TOL-3021 will work better and more specifically than insulin.

Comparing TOL-3021 to BCG (ie. Tolerion's results to Faustman's results)

These two potential cures are similar in many ways.    Medically, they are both immunology based approaches.  They are both being tested on established type-1 diabetics (not honeymooners), and they both started clinical trials in the 2006-2007 time frame.   From a "marketing" point of view, their respective proponents each claimed that they targeted the exact cells that cause the destruction of beta cells in the pancreas.  They are not suppressing a whole class of immune cells, just the ones that are incorrectly attacking beta cells.

So with all those similarities, it makes sense to compare them in three different ways:
1: Effectiveness. The most important comparison would be C-peptide numbers. The BCG treated patients gained 22% of their C-peptide production, while the TOL-3021 group gained 28%. So TOL did slightly better.
2: Targeting.  One of the key advantages claimed by Dr. Faustman for BCG and by the Tolerion group for TOL-3021, is that they selectively target the bad T cells. Here the Tolerion group has published data supporting both sides of their claim: data showing bad T cells are lower when treated, and data showing other T cells don't change.  Dr. Faustman's trial found no difference in the number of active bad T cells, and did not measure the other T cells at all.
3: Research size/analysis. The TOL group was more than three times as large as the BCG group, which is always a good thing.   Finally, Tolerion's results were statistically significant as designed, which is different than Dr. Faustman's group.  They had to move a person out of the placebo group in order to get statistically significant results, and use different comparison groups for different measurements.

In a head to head comparison, TOL-3021 has better results across the board, and both treatments were tested in long established type-1 diabetics.

Note that Dr. Faustman's group reported C-peptide production in absolute numbers, while the Tolerion group reported as a percentage change. I did ask the Tolerion group for the absolute numbers, since that would make the comparison simpler, but that data is not publicly available. Therefore, I have converted Dr. Faustman's numbers into percentages in order to do the comparison. So the comparison is approximate. In my opinion, reporting absolute numbers (as done by Dr. Faustman) is the better way to go.

News: http://www.biospace.com/news_story.aspx?NewsEntityId=301263&source=news-email
http://news.yahoo.com/type-1-diabetes-vaccine-shows-promise-early-study-180404550.html
Press Release: http://www.tolerioninc.com/TOL-3021_press_release.html
Interview: http://www.bizjournals.com/sanfrancisco/blog/biotech/2013/06/type-1-diabetes-vaccine-stanford.html?page=all
Abstract: http://stm.sciencemag.org/content/5/191/191ra82
US Trial Registration: http://www.clinicaltrials.gov/ct2/show/NCT00453375
Company Web Site: http://www.tolerioninc.com/

Summary of ADA's Annual Conference

ADA just finished their annual conference. I enjoyed the summaries below. Remember that ADA covers both type-1 and type-2, so some of the news will be about type-2 diabetes:

http://www.integrateddiabetes.com/Articles/ADA%202013%20meeting%20notes.pdf
http://www.diabetesmine.com/2013/06/its-a-wrap-on-the-ada-scientific-sessions-for-2013.html
http://www.diabetesmine.com/2013/06/ada-scientific-sessions-part-2.html

Joshua Levy
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. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com

Possible Cures for Type-1 in the News (June)

Aldesleukin (Proleukin) Starts a Phase-II Clinical Trial

Called DILD1T, this is a 40 person clinical trial.  It started in March 2013, and is expected to finish in January 2015.  It is enrolling adults who have had type-1 diabetes for 3-24 months (so not just honeymooners) in Addenbrooke’s Hospital, Cambridge, UK.  Currently, it is only 12% enrolled, so they have a ways to go.  I'm treating this as a phase-II trial, because of it's size and because Proleukin has already been tested twice in type-1 diabetics (that I know of).

I think that this study involves only one subcutaneous injection (like an insulin injection).

Here is the justification for the study.  The quote is from the researchers, but I've removed some of the medical language:

The vast majority of genes that contribute to susceptibility to type 1 diabetes [are related to] immune regulation and function. In particular, ... the interleukin 2 (IL-2) pathway that regulates T cell activation .... Aldesleukin (Proleukin) is a human recombinant IL-2 product .... There is substantial [research data in tissues/petri dishes, animals, and humans] that ultra low dose IL-2 (aldesleukin) therapy can arrest the autoimmune mediated destruction of pancreatic beta cells by [encouraging] functional T regulatory cells.

The researchers view this study as looking for the optimal dose as a prelude to doing a large phase-III trial.  This is a classic goal of many phase-II trials.  This trial is funded by the Welcome Trust (a big UK operation), JDRF, and the NHS Foundation Trust (which I think is the UK government).

Here are links for this new research:
Web sites: http://www.clinical-trials-type1-diabetes.com  http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13846
News: http://www.wellcome.ac.uk/News/Media-office/Press-releases/2013/WTP052844.htm
Facebook: https://www.facebook.com/ClinicalTrialsType1Diabetes
Twitter: https://twitter.com/t1diabetestrial
WHO Registration: http://www.controlled-trials.com/ISRCTN27852285/
US Registration: http://www.clinicaltrials.gov/ct2/show/NCT01827735
Wikipedia on IL-2: http://en.wikipedia.org/wiki/Interleukin_2

I also think it is important to remember that IL-2 has been tested in humans twice before, and has failed both times.  I previously blogged on those trials:
http://cureresearch4type1diabetes.blogspot.com/search/label/IL-2
Clinical Trial Records:
    http://www.clinicaltrials.gov/ct2/show/NCT00336674
    http://www.clinicaltrials.gov/ct2/show/NCT00525889


DiaPep 277's Results from an Extended Phase-III Trial:
No Longer a Cure?

I've been following DiaPep 277 for as long as I've been following type-1 diabetes cures.  When I started, it was already in phase-II trials.  Recently Andromeda Biotech Ltd, the company developing it, has published some phase-III results, and (most recently) some extended phase-III results.  These extended results are from people who were in the phase-III trial for two years, and then continued with the treatment for an additional two years.  The two year extension was "open label", meaning that the patients and doctors knew they were getting the treatment; it was not blinded.

Unfortunately, the results are decidedly mild.  People's A1C numbers dropped by 0.6 (from an average of 7.6 to an average of 7.0.  In terms of improvement of treatment, that's not bad.  I think there is a market for a drug that would lower A1C numbers that amount, but it is not a cure.  There is always hope that future improvements in the treatment will lead to even better A1C improvements (which I think is likely), or even improvements so great they lead to a cure (which I think is very unlikely).  But currently, this is an adjunct treatment, not a cure.  So I expect to stop covering DiaPep 277, unless I see results much larger than are seen here.

news: http://www.globenewswire.com/news-release/2013/06/05/552188/10035325/en/Andromeda-Announces-the-Results-of-an-Extension-to-Its-Phase-III-Study.html

The previously announced results from one of their phase-III trials, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2011/11/andromedas-diapep277-succeeds-in-phase.html
were similarly mild, and much more like a treatment than like a cure. 

Phase-I Trial Resets the Immune System in MS Patients

This news comes from a human trial in multiple sclerosis (MS) patients.  Basically, researchers were able to "reset" the body's immune system, to lower the autoimmunity reaction (the body's attacking it's own cells) by  50%.-75%.  This was in a 9 person phase-I trial in Germany.

To understand why that is important, a little background is needed.  Most researchers believe that MS and Type-1 are related diseases.  In both cases the immune system mistakenly attacks the body's own cells.  In Type-1, it attacks beta cells in the pancreas, and in MS it attacks the myelin sheaths of nerve cells, however the underlying autoimmunity reaction is similar.

Prior to testing on people, this method was tested in mice who had MS and in mice who had type-1 diabetes, and worked on both groups of mice.  However, the human trials were MS only.  But obviously, trials in type-1 diabetic people could be done as well.  In my opinion, should be done.

The idea of resetting (or rebooting) the body's immune system has been tried on type-1 diabetics, and it was successful.  Some of the treated type-1 diabetics did not have to inject insulin for years afterwards.  However, the risk involved is high enough, that these treatments have never moved forward.  At least three different teams (in Brazil, Poland, and China) have run similar trials and gotten similar results.  I have blogged about them before:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Although it is hard to draw a direct comparison, it sounds like the procedure being tested here is much safer, but slightly less effective than the procedure used by Burt, Snarski, Li, etc.  Of course, it might be refined over time to make it more effective or safer, or both.

news: http://scienceblog.com/63715/big-multiple-sclerosis-breakthrough/

Personal Note

In the past, I've posted on my blog what I call a "non-conflict of interest statement" which is this:

• I don't work for a company involved in medical research; I never have.
• I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything.
• None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for, nor have I gotten anything free.  (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

I'm now adding a fourth bullet point:

• My daughter has type-1 diabetes and participates in clinical trials.  She usually gets some money for participating. I sometimes report on trials that she participates in.  For several reasons, I don't generally reveal what studies she enrolled in (or tried to enroll).  

Why not, you ask?  A couple of reasons.  First  of all, her participation is a two step process.  My wife and I decide the research is safe and that she can participate, and then she decides if she wants to participate.  Therefore, she selects different studies than I would select.  For example, she prefers studies in the summer, and studies that pay well.  I don't want people coming back to me and saying why did she participate in study X rather than study Y?  Second, I get important information from researchers.  I don't want researchers thinking, "his daughter was in Dr. X's trial, but not mine, why is that?"  (Truthfully, the answer is usually, Dr. X paid better, or required less time, or was more convenient, but I don't want to be explaining that.)  Thirdly, I don't want readers of this blog to be thinking "Joshua's daughter isn't in trial X, why should my child be in that one?" or the reverse "Josh's daughter is in trial X, I should get my kid in there, also!"  Our kids are different, and participating in a trial should always be personal decision.  And finally, even participating in a trial might make public health information about my daughter that I don't want public.  For example, enrollment might only be open to people who have a particular side effect, or don't have that side effect, or who are still generating some insulin, or whatever. 

In the last 5 years, I have only blogged on one study that my daughter participated in.  I would expect to blog on only a couple in the next 5 years, so this is a rare thing. 

Joshua Levy
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.  My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

The Root Cause of Type-1

Some researchers in Boston made a big splash recently by claiming to find the "root cause" of type-1 diabetes.  I've gotten at least two emails asking for my thoughts on the research, so here they are.

One thing that I try to do, is to read the original paper, or at least the abstract, and then describe what the researchers did, what they found, and why it is important.  I've found that the original research often contains valuable information that doesn't make it into press releases, news articles, blog postings, etc.  So I try hard to find that original work.

Unfortunately, I can't do that for this paper.  I've read the abstract a couple of times, and I can't make heads or tails of it.  The abstract assumes a level of knowledge way beyond me.  One thing that did make me nervous was this: it looks like this research was done on people and mice who had transplants to treat type-1 diabetes, and they studied how those people's bodies attacked the transplanted cells.  This makes me nervous because the immune system's attack on a transplanted organ is proper.  It's a foreign invader, after all.  This is different than the immune system's attack on it's own pancreas, which is an error.  I'm not sure learning about the causes of one, is going to teach us what causes the other.  On the other hand, I might be totally misunderstanding what they were doing.  The abstract is opaque to me.

How important is this?

I don't know.  I don't think anyone knows, as yet.  It often takes a few years to confirm that a breakthrough really is the big breakthrough that everyone hoped it was at the start.  Even after we know that this is a big breakthrough, we don't know if it will lead to a cure or not.  The discovery of the smallpox virus (for example) did not lead to the discovery of a cure for smallpox  (and the first smallpox vaccine predated knowledge of the smallpox virus).

In the future, if this leads to a cure (or preventative) for type-1 diabetes, then we will be able to look back and say, "this really was that important".  But there is no reasonable way for us to look into the future and know that this discovery is that important right now.

(I know that's kind of depressing.  Some people react to that by not donating money to research, because they never know which research is going to lead to a cure.  I view it the exact opposite, that it is important to give money to research, so that as many different options can be funded as possible, specifically because we don't know which will lead to a cure.)

What does this mean to me?

I care about a cure for type-1 diabetes, so what does this discovery mean to me?  Basically, a lot more research.  In order to get from a discovery of root cause to a cure, at least three things need to happen.  (a) they need to be sure the discovery is correct and use that discovery to figure out a cure. (b) they need to test that cure in petri dishes, tissue samples, and animals. (c) they need to test it in people.  Now (a) often takes a few years, although sometimes less, and (b) can take anywhere from years to decades, and (c) takes at least 10 years.  So making a few reasonable guesses, I would expect any cure that comes from this discovery to arrive in 15+ years (for an optimistic guess) to 25+ years (for a more reasonable guess).  If this discovery pans out as being important.  And that is a big "if".

One last word.

Curtis Lomax said "This one smells like a lot of hype."  I agree, and I couldn't put it better myself.  In fact, I'm linking to the Lynyrd Skynyrd song "That Smell" as the theme song for this posting:
http://www.youtube.com/watch?v=sV_toedW2L0

Links to the news coverage:

• http://diabetes.diabetesjournals.org/content/early/2013/01/10/db12-0242?utm_campaign=Diabetes%20transplant&utm_medium=6/2013&utm_source=vector&utm_content=Transplant&utm_term=Tripp
• http://www.bostonmagazine.com/health/blog/2013/06/13/boston-childrens-hospital-found-the-root-cause-of-diabetes/
• http://vectorblog.org/2013/06/silencing-immune-attacks-in-type-1-diabetes-without/#more-8597

I think this is the paper's abstract:

• http://www.ncbi.nlm.nih.gov/pubmed/23315496

Joshua Levy
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 I sometimes blog on. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

No Data on Environmental Causes of Type-1

I'm not completely happy with this posting, but I've been working on it for many weeks, and at this point I think it is better to publish what I have, than to continue to struggle with it.  Maybe in the future, will post an improved version.

This posting is a little different from my usual fare.  Instead of discussing specific research results, I'm going to discuss, in more general terms, a subject that has come up repeatedly:

What is causing the increase of type-1 diabetes?

Every six months or so we get a study, government report, or newspaper article claiming that there must be something in the environment which is causing the number of type-1 diabetics to go up, way up. These articles usually follow the same path:

1. Description of type-1 diabetes as having a genetic and environmental cause [d0].
2. The number of type-1 diabetics is going up (way up!)
3. The number of younger type-1 diabetics is going up even more than older ones.
4. So there must be an environmental cause (usually a toxic chemical) which is growing, and causing the numbers of type-1 diabetics to grow.

They often contain a quote like this one:

Despite a strong genetic component to the susceptibility of T1DM, this marked increase in incidence in different populations within a short period of time cannot be explained by increased transmission of T1DM susceptibility genes. So what is the cause? [r1]

Or like this one:

Essentially all researchers agree that changes of this magnitude cannot be explained by genetics alone. [r6]

(The d-numbered footnotes refer to extra discussion and r-numbered footnotes refer to references, both are at the bottom of the posting.)  Before you get too worried about such news reports, it's best to think about what should be happening.  The simple answer is: of course the rates of type-1 diabetes are going up, and we should all expect that.  Why?  Type-1 diabetes has a large genetic component.  Before 1920, most people who were diagnosed with type-1 diabetes died before they had children.   Now, those people are living longer, happier, richer lives, with children and grandchildren of their own.   So the genetic component of type-1 is becoming more common, and of course the rate of type-1 diabetes is going up [d1].  We certainly would not expect it to be going down or staying the same.

So the the correct response when someone says the rate of type-1 diabetes is going up (way up!) is to yawn, and say "Of course, I would not expect anything else" and "Isn't it great that what was previously a fatal disease is not any more".   However there are still some issues which need some more discussion:

1. Referring to age at diagnosis: why is the rate of very young type-1 diabetics going up more than the rate of older diabetics?
2. Is there something in the environment which is contributing to the increase of people with type-1 diabetes, and especially a toxic chemical of some kind?  Even if some of the growth rate is caused by genetics, maybe some of it is not?  
3. Are sentences like "the increase is too high to be explained by genetics alone" (or similar) supported by the data we have, or are they fear-mongering?

Why are more children getting diagnosed at a younger age?

I'm not going to review it in detail, but I think there is pretty strong evidence that more children are getting diagnosed with type-1 diabetes at a younger age than previously.  For example [r1,r2] both show this. The percentage diagnosed between ages 0 and 5 is going up faster than the more traditional diagnosis between 10 and 20 years old.

The first thing to realize here, is that you would expect this behavior based on the genetics and impact of type-1 diabetes.  Type-1 is not (usually) caused by a single gene.  It is caused by complex groups of genes which, acting together, make it more likely that you will get type-1, and other groups of genes that make it less likely. It is likely [need to specific references here] that there are gene groups that tend to cause type-1 in younger kids, and other gene groups that tend to cause type-1 in older kids.  Prior to the 1920s, everyone who had type-1 diabetes died very close to diagnosis.  So if you had the genes for the age 0-5 type, you had zero chance of having children.  But if you had the genes for a 10-20 year old diagnosis, then maybe you would have children (especially in earlier times, with younger parents).  Obviously, this would be a very small number of births, but it would be higher than zero.  So the genetic "filtering" that type-1 death caused, was stronger for those "younger" genetic variants.  Therefore when the genetic "filtering" is removed, we should expect type-1 diabetes to rise more quickly in younger kids than older kids.  And that is exactly what is seen.

Summary: faster growth in type-1 diabetes diagnosis in younger kids is something that we should be expecting based on the known genetics and lethality of the disease.

Is there something in the environment causing more type-1 diabetes?  
Maybe a toxic chemical?

Obviously, there are a huge number of chemicals out there, and any one of them might increase the incidence of type-1 diabetes.  Even if we proved 1000 (or 10,000) chemicals do not cause type-1 diabetes, it might always be caused by one we have not tested.  So the possibility of chemicals causing type-1 diabetes will always be with us.  But I think there are two important points that should be made here:

First, it is easy to show that a chemical causes type-1 diabetes.

We have an animal model of type-1 diabetes.   It's called the NOD mouse, and has been in widespread use for decades [d3].  The number of these mice who will naturally come down with type-1 diabetes, and when it happens, is well known.  And some of these mice won't come down with the disease, even if most do.  Therefore, any chemical you want to test, you can just give it to these mice, and see if the rate of type-1 diabetes goes up, or if the mice get it more quickly, than the untreated mice. [d4]

This is the kind of mouse-based research that is done all the time, and it isn't even that expensive.  Running a test on 300 mice is vastly cheaper and faster than running a test on even 1 person.

So if anyone really believed that they know which chemical or drug caused type-1 diabetes. They could become famous quickly, easily, and inexpensively by testing their theory in mice. The fact that no one has done this suggests to me that none of the common chemicals sometimes suggested as a cause of type-1 diabetes, really do cause it [d5].

Now, some people will make excuses.  They are likely to say "we can't test chemical X because no one will fund it", but that is untrue for a number of reasons.  Most obviously: non-profits, environmental groups, and government agencies often fund safety research.  But also, companies that produce competitors to a chemical have a strong economic motivation to fund research that the other chemical is unsafe, since that would lead to higher sales of their (competing) chemical.  Finally, remember that fame is an important motivator (in addition to money), and providing strong evidence that a common chemical is unsafe is a sure path to fame in the university, non-profit, and government worlds.

Here are examples of experiments of that kind (could show chemical danger in NOD mice) but did not find any problems:

Trichloroethylene (TCE): http://www.ncbi.nlm.nih.gov/pubmed/18958647 [d6]
Mercury: http://www.ncbi.nlm.nih.gov/pubmed/11529910  [d7]
Bisphenol A (BPA) is a more complex case, which I may cover in a future posting (time permitting).

Second, not a lot of chemicals fit the dosing/timeline profile.

The second problem with blaming a toxic chemical, is that the chemical needs to have a use profile that matches type-1's growth profile, in those countries where we have good data on type-1's growth profile.

For example, it couldn't be DDT.  Because in the USA, DDT use skyrocketed right after World War II, and then dropped to nearly zero in the 1970s.  But the rate of type-1 diabetes continues to grow at a pretty constant rate.  There was no big increase right after WWII and no dropping off in the 1970s.  Similar arguments can be made against lead, PCBs, BPAs, and many other toxins [d9].

But it turns out that type-1 diabetes growth appears to be pretty constant.  More kids are diagnosed each year, but the increase is linear, and there are no big troughs or hills.   (Although [r6] shows some small bumps up and down.)  Indeed, if you look at the whole time period from 1920 to 2012, the growth is pretty constant the whole time (as much as we have data for). [Need to add specific references for this.]  I think that suggests that there is no chemical environmental cause, because the environmental chemicals common to the 1920s are not common now, and visa-versa.  I just don't see a good candidate.  However, since testing the chemical is cheap and easy (see previous discussion), the moment someone does identify a chemical who's use has been steadily growing for the last 90 years, without any large troughs or hills, that chemical could be quickly tested.  And if it happened to match the small ups and downs in the [r6] data in the same countries where that data was gathered, that would be even stronger evidence.

Based on all this, if there is an environmental factor, a toxic chemical is not my leading contender.  I think something like the "hygiene hypothesis" is more likely, or maybe something in the diet, or something related to affluence [d8].

The increase is too high to be explained by genetics alone.

Think about this claim for a minute.  This sentence is based on three pieces of data:

1. We know how much type-1 diagnosis is increasing.
2. We know how much it should be increasing, based on genetics.
3. Therefore, we can see that there is a gap, which must be filled with an environmental cause of growth.  

Of these three statements, only the first is true.  See [r1,r2, r6] and other studies.  Even there, our knowledge is imperfect, but we do have some data about the overall change in the rate of type-1 diagnosis.  But for the next two, we have nothing; absolutely nothing.  Not all the genes that lead to type-1 diabetes have been identified.   Not all the genes that protect against type-1 have been identified.  How these genes interact to cause or avoid type-1 diabetes is not known.  In short, we have no idea, what the levels of type-1 diabetes "should" be, based on genetic susceptibilities.  Obviously, since we don't know 2, we can't know 3.  In my opinion, people who say "there must be an environmental cause for the increase in type-1" are fear mongering, or looking for more research funding. 

Remember: I agree that there is an environmental cause of type-1 diabetes, but I'm also saying that there is no evidence that it is growing. Put another way (with double negatives): I'm not saying that there is no environmental component that causes type-1 diabetes. We know there is [d0]. Rather, I'm saying that there is no evidence that this environmental component is causing the increase in type-1 cases. It is not growing or causing more cases of type-1 diabetes.

Summary:  There is evidence that an environmental component exists, but there is no evidence that the environmental component is causing growth in type-1 diagnosis.

Looking at Genes Specifically

As far as I know, no researcher is looking at the overall genetics of type-1 diabetes to see if the overall genetic change is causing the overall type-1 diagnosis change.  However, there are a couple of studies that look at a single gene specifically [r7].  These studies both looked at a gene highly associated with type-1 diabetes [d10] and they both found that specific gene had become less common in the population.  Not more common, as would be expected.  One study looked at the period from the 1960s to the 2000s, and the other compared the 1980s to the 2000s (roughly).

Proponents of an environmental cause to increases in type-1 diagnosis can point to these studies as support for the idea that the growth is not caused by genetics.  However, these studies provide only the tiniest support.  Neither of these studies actually looked at the total genetic change affecting type-1 diabetes.  Indeed, they couldn't do that, because we don't yet know all the genes that affect type-1 diabetes.  It's like trying to guess if the value of pocket change is going up or down, based on the number of nickels in people's pockets, when you don't even know all the kinds of coins in circulation.

So while these two studies are scientifically interesting, and should form the basis of more research, they are nowhere near the level of knowledge we need to say that the current growth in type-1 diabetes diagnosis is caused by an environmental factor.

Discussion

[d0] We know that the cause of type-1 diabetes has a genetic component, because it is more common in people with relatives who also have type-1 diabetes.   In particular, the closer a relative who has type-1 diabetes, the more likely a person is to have it.  This is a classic sign of a genetic component.  However, we know that there is an environmental component as well, because of "twin studies".  For a purely genetic condition, there should be no cases of identical twins, one with type-1 diabetes and one without.  However, there are.  In fact, in less than half of identical twin pairs do both twins have type-1 diabetes.  It is more common that only one does [r3].  This difference in disease between identical twins is a classic sign of an environmental component.  So it is clear that type-1 diabetes is caused by a combination of both genetics and environmental causes.

[d1] No matter how I phrase it, some people read those last two sentences, and think I'm "blaming" parents for their children's type-1 diabetes.  I'm not, and that's a silly idea in any case.  I'm discussing genetics.  It has nothing to do with blame.  No one decides what DNA to pass to their children.  And it is completely unreasonable to think "well something might go wrong with my kid, so I won't have any."  If people thought like that, no one would ever have children, because something can always go wrong.

[d3] Technically, we have at least three animals models for autoimmunity-based diabetes.  Another is the BB ("Biobreeding") rat [r4], and the third is an animal that given a small dose of a beta cell toxin.  The beta cell die off somehow triggers autoimmunity.  This last technique is quite different that given the animal a large dose of a beta cell toxin (which is more common).  Giving a large dose kills the beta cells, but does not trigger autoimmunity.  It can be used to test insulin replacement, but not autoimmune effects.

[d4] I know a lot of people are frustrated with NOD mice, because cures that work in those mice have failed when used on people.  However, in this case, we are using NOD mice to show danger, rather than improvement.  The "standard of proof" is much lower to show danger, as compared to showing safety and effectiveness.  To show safety and effectiveness most people would require several tests in animals followed by several tests in people.  On the other hand, to show danger, even one or two tests in animals would be enough to convince most people that a chemical was unsafe.  The big frustration of NOD mice (that cures don't work when tried in people) doesn't affect this kind of danger testing, because if the chemical is found unsafe in mice, it's done: no tests in people are needed.

[d5] Basically, the first time I hear someone say that chemical X might cause type-1 diabetes, I look at a calendar.  I then wait a few years.  If no one has published results for the obvious test in NOD mice, then I'm pretty sure chemical X does not cause type-1 diabetes.  I then wait a few more years.  By that point, if no one has published results, then I think it's settled that chemical X does not cause type-1.  A logician will continue to chant "absence of evidence is not evidence of absence," but in the real world, it is.

[d6] A quote from their abstract:

To test whether TCE [Trichloroethylene, a chlorinated hydrocarbon] can exert similar deleterious effects on organ-specific autoimmune diseases, non obese diabetic (NOD) mice were given 5 mg/ml TCE via the drinking water for 12 weeks. ... Contrary to what has been found in systemic models of autoimmunity, TCE did not accelerate the diabetes of NOD mice and may have a protective effect.

[d7] A quote from their abstract:

We found that three weeks of treatment with mercury was also able to significantly suppress the development of insulitis and postpone the onset of diabetes in these mice. Thus, mercury-induced immune activation can counter-regulate the Th1 cell-mediated autoimmune responses and confer a partial protection against autoimmune diabetes in NOD mice.

(Although I don't think people will line up for a clinical study injecting mercury or TCE to delay onset of type-1 diabetes. :-)

[d8] I am not saying that I think the "hygiene hypothesis" is correct. I am saying something much weaker: that the evidence we have for the "hygiene hypothesis" is stronger than the evidence we have for any single, specific chemical causing type-1 diabetes.

[d9] This line of reasoning also tends to exclude breast feeding as an environmental protective against type-1 diabetes.  Breast feeding rates were high in the 1920s, dropped to their lowest in the 1960s, rose in the 1970-1990s, and have been drifting higher since then [r5].  None of that is reflected in type-1 diabetes rates.  If breast feeding protected against type-1, then the type-1 rate would be dropping slightly right now, not rising.  Also, it would have been much higher in the 1960s, than in the 1980s, but the reverse is actually seen.

[d10] I'm not a geneticist.  Both studies dealt with something called "HLA class II".  One study looked at a gene called "HLA-DR, DQ" , while the other looked at a genotype called "HLA-DR3/4-DQB1*0302".  I'm not sure if they were both looking at the same gene, or slightly different genes.  But in either case, they are clearly only looking at a tiny part of the genetics that lead to type-1 diabetes, which is my main point.

References

[r1] Incidence of childhood type 1 diabetes: a worrying trend by Ronald C. W. Ma and Juliana C. N. Chan
October 2009
http://www.nature.com/nrendo/journal/v5/n10/full/nrendo.2009.180.html

[r2] Type 1 Diabetes in Urban Children Skyrockets, Increasing by 70%
Jan 22, 2013
http://www.newswise.com/articles/type-1-diabetes-in-urban-children-skyrockets-increasing-by-70-in-children-under-age-5
http://vitals.nbcnews.com/_news/2013/02/01/16811346-type-1-diabetes-rising-in-kids-study-shows

[r3] http://www.ncbi.nlm.nih.gov/pubmed/22569240
This Italian twins study found:

Genetic contribution to type 1 diabetes susceptibility was 40%, and the shared and individual-specific environmental components were 51% and 9%, respectively.  [I removed the confidance intervals from this sentence, but they are in the original abstract if you want them.]

[r4] Wikipedia on BB rat: http://en.wikipedia.org/wiki/Biobreeding_rat

[r5]
From 200-2008: http://kellymom.com/wp-content/uploads/US_BF_rates.png
From 1850-2000: http://www.historyandpolicy.org/papers/policy-paper-89.html (see Figure 3)

[r6]
http://www.diabetesandenvironment.org/home/incidence/historical

[r7]
http://www.ncbi.nlm.nih.gov/pubmed/18356404
http://www.ncbi.nlm.nih.gov/pubmed/21307077

Possible Cures for Type-1 in the News (April)

Unfortunately, this is bad news.  But here it is:

Canakinumab and Anakinra Both Fail Phase-II Trials in Honeymooners

Canakinumab (brand name Ilaris, previously known as ACZ885) and Anakinra (brand name Kineret) are different drugs, but they have a lot in common.  Both target IL-1, which is part of the immune system.  Canakinumab is already approved in the US for the treatment of cryopyrin-associated periodic syndromes. Anakinra is already approved in the US for the treatment of rheumatoid arthritis.  Unfortunately, both failed Phase-II trials for type-1 diabetes.  Here is the quote from the abstract:

Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes.

A previous, smaller test of Anakinra had also failed.  

Discussion

I occasionally hear arguments that testing drugs on NOD mice is the wrong approach.  That we should not bother to do that, and just go straight to human testing.  People who make this argument are quick to point out that NOD mice are commonly cured of type-1 diabetes, but none of these cures have worked in people.  They often go a step farther and suggest that maybe NOD mice are so different that they are leading researchers astray.  That a successful mice cure means it won't work on people, and conversely that drugs that work on people might not work on mice.

However, both of these drugs were tested initially in people.  They were never tested (alone) in NOD mice.  And they both failed.  Of course, two examples don't prove anything.  However it does support the idea that curing type-1 diabetes is tough no matter if you test first in mice or first in people.

Abstracts:

http://www.lancet.com/journals/lancet/article/PIIS0140-6736%2813%2960023-9/abstract

http://www.ncbi.nlm.nih.gov/pubmed/21518168?dopt=Abstract

Clinical Trial Records:

http://clinicaltrials.gov/ct2/show/NCT00947427

http://clinicaltrials.gov/ct2/show/NCT00711503

http://clinicaltrials.gov/ct2/show/NCT00645840

Wikipedia:

http://en.wikipedia.org/wiki/Canakinumab

http://en.wikipedia.org/wiki/Anakinra

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog. 
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/