A new series of pro- and con editorials in the Am J Res Crit Care Med discusses the question why in some instances mouse models have “misdirected resources and thinking”. You may have noticed that I have only rarely used animals for research; the authors of this editorial have collected empirical data on the exploding use of murine models. Despite their attractiveness from a technological point, they are useless because
- mice do not have asthma as even the most hyperresponsive strain does not show spontaneous symptoms
- mice do not have allergy – although sensitization can be manipulated by high intraperitoneal allergen/adjuvant injection, this does not involve immediate and late airway obstruction.
- immune reaction in mice is quite different – the interfering of some substances like vitamin D cannot be reliable tested, there is no pure Th1 and Th2 reaction in human and less stronger IL-13 response
- mice typically can not be challenged with the complex (and interacting) human exposure – oxidant stress, viral infection, obesity, diet, smoke, pollutants, ….
- time course is difficult to mimicking in the mouse, there is no longterm model
- structure of mouse airways is different – there are fewer airway generations, much less hypertrophy of smooth muscle
- inflammation in mouse is parenchymal rather than restricted
- humans are outbred, mice are inbred
- many promising interventions of mice pathways failed in humans (VLA-4, IL4, IL5, bradykinine, PAF,…)
I am sure there are even more arguments – I suggest that the authors have deserved the Felix-Wankel price.
15 Dec 06: The BMJ has 6 more examples about the discordance between animal and human studies: steroids in acute head injury, antifibrinolytics in haemorrhage, thrombolysis or tirilazad treatment in acure ischaemic stroke, antenatal steroids to prevent RDS and biphosphonate to treat osteoporosis.
19 Dec 06: Another pitfall paper
31 Dec 06: A blog on animal welfare
25 Apr 07: Call for better mouse models
Clemens von Pirquet (1874-1929) was the first to introduce “Allergie” into clinical medicine by characterizing an altered immune reaction of the body to foreign substances. The famous paper was published 1906 in the “Münchner Medizinische Wochenschrift (MMW)” Volume 53, page 1457-1458.
AB Kay published a nice essay on “100 years of Allergy: can von Pirquet’s word be rescued?” that includes an English translation of the above paper. The MMW has a contemporary obituary of Meinhard von Pfaundler (1872-1947) who was one of the earlier directors of the Münchner Haunersche Kinderspital.
Finally, the “Wiener Klinische Wochenschrift” has a CV of Clemens von Pirquet, showing his way to Baltimore and Breslau back to Vienna until his tragic end by committing suicide together with his mentally ill wife.
Just found at the HUM MOLGEN bulletin board a link to Fable, a new automated literature extraction system. Fable is pretty fast and can output gene lists. Sure, the screenshot below shows only those genes that I mentioned in the abstract, but this is not so bad as the most important genes wil be placed there.
BTW, the number of reviews on asthma genetics have been falling to less than 50% after closing the Asthma Gene Database. Maybe this new service will help to re-establish the former output of reviews ;-) yea, yea.
I am interested in 5q31 and the IL4 cluster since I met David Marsh in the lobby of a hotel in Heidelberg around 1993. David was one of the founding fathers of asthma genetics and I renember how he vividly told me that he has a forthcoming Science paper on the IL4 cluster and IgE. The cluster is still one of the best allergy regions where the signalling through IL4 and IL13 now gets more interest than the work of any of his competitors.
Nature genetics now has an update on the 3-dimensional resolution of the genomic region. It is not cristallographic work as might be expected but a nice study of the chromatin structure that is leading to a coordinated expression of these cytokines. SATB1 (special AT-rich sequence binding protein 1) is thought to anchor specialized sequences letting DNA loops come into interaction. I wonder if there might be even a direct physical interaction of the IL4 and IL13 promotor and if there will be any SNP influencing that interaction? David (who died of brain cancer in 1998) would have really liked this work. Yea, yea.
The Hotel Dieu in Paris has been one of the first pediatric hospital in the world (see my photo of the hospital entrance). I recall from the detailed history of allergic diseases by Schadewaldt that at the beginning of the last century it was difficult to presen the students a case of the Bostock hayfever.
The disease was so rare that it took more than one week to find a child with the typical symptoms. Yea, yea.
I am detailing in a forthcoming paper in “Allergy”, that the contradicting results found with ADAM33 (the first positionally cloned asthma gene) probably results from a rather poor design of all follow-up studies.
It does not make so much sense to repeat over and over the same few SNP marker; instead a full resquencing of the linkage region would be necessary. From the analysis of public LD maps it is even possible that neighboring genes may be responsible for the observed associations.
I have also doubts if the SNP-centric view is always leading to success. BTW there is a new database of over 400,000 non-reduandt indels of which 280,000 are validated by comparison with other human or chimpanzee genomes (see Mills et al., the indels are available in dbSNP under the “Devine_lab” handle).
Folllowing up numerous emails to my recent review about allergy and vitamin D exposure, I wonder if there could be a quantitative relationship if we look at the vitamin D system as a major biological hub. This is not so much about connecting different playgrounds but of integrating signals (as shown in the hourglass blog). The East-West German difference, the farming studies as well as numerous other studies would even allow a quantitative effect. Yea, yea.
Biospektrum will publish in their next issue a summary of the vitamin D story.
4-07-2007 The list of vitamin D dependent genes that are associated with allergy (IL12B, IL12RB, SPP/OPN, CD14, CD23, VDR, TNF, GC, IFN, IL1RN, IL8, ADRB2, CARD15, IL4R, ALOX5, FLG, SOCS3) is expanding: TSLP and CD86
A new study now shows directly that personal exposure of particles is linked to asthma symptoms. Children carried pollution monitors in their backpacks on the way to school where PM2.5 ranged from 20 to 50 micrograms per cubic meter. Although only around 10 percent of the total mass of particles was diesel soot, it was this that was most closely linked to the children’s asthma. This nicely complements results of our study in Munich in 1989/1990 which was the first survey indirectly linking car exhaust and airway symptoms in children. Mechanisms how this happens are not very well known – for a discussion of the biphasic response see our paper of a mouse model, yea, yea.
Having read again Beutlers 2004 TLR review, I am always fascinated by the flexible response and the hourglass response effect. On the outside there is the microbial universe and inside are the many strategies to fight infection, but all goes through a single bottleneck. What is the reason behind? To calm down but strike when necessary?
Asthma in Africa: I will touch this issue in more detail in a forthcoming editorial in PLos Medicine. Africa has fascinated me since childhood when I read books of Paul White, Albert Schweitzer and tried to get everything our library had about David Livingstone and Morton Stanley. Here is a further link that we couldn’t place in the editorial – a 2 month helicopter trip from Hamburg to Kapstadt including daily GPS data to watch a heli flying in Google Earth, simply the best, I have seen in the internet this year, yea.
-moblog- A new nature medicine paper describes a deficient induction of interferon beta (gene is on chr 9) and interferon lambda (gene is on chr 19). The author concludes that genetic polymorphisms are an unlikely cause as genes are on different chromosomes. What a misunderstanding – does the author really believe in a single asthma gene? Yea, yea.
If you are invited to a party just mention genetically modified (GM) food and you will be center of the crowd. There are many national and internationally bodies that deal with GM food (see the dissertation of Scholderer). As far as we do not know what makes and allergen and allergen, I would always care when introducing any modification. There is a way round, however, that GM food can also have less allergen content – just found a preprint of a gene-silenced tomato. This German-Spanish group managed by RNAi silencing to reduce protein Lyc e 3 with led to reduced skin reactivity of tomato allergic probands. BTW – do you renember our fake food hypothesis? Yea, yea. BTW The best tomato bread can be found in Barcelona.
The CD14 / allergy story never ends – after many years and numerous contradictory reports. A new comment in the AJRCCM concludes that “further research is required” – at this time “research into the area of gene-by-environment interaction where large-scale studies, advanced assessment of environmental exposure of and experimental investigations of interactions are needed”. Is there any sense with neverending loops (except playground for hamster)? Nay, nay.
JCI has a paper about resurrection of vitamin D deficiency (more about the author at 1, 2 and 3). The author uses references 46-59 to underpin his opinion that rickets has again become an epidemic. These references are from 1992, 1984, 2005, 2000, 1987, 1987, 1989, 1994, 1989, 2001, 1998, 2001, 1987, 2006. So nothing really new – no prospective study, no systematic survey, just a few isolated reports. Sure, that there might be a rickets problem in a selected areas or in minority groups, but there is no world-wide epidemic. He argues also that many (if not all) studies show “low” serum 25-OH-D3 values. Is this chasing a phantom? A more systematic study concludes that rickets in Africa is more a disease of calcium deficiency. The JCI article is particular poorly written when it comes to immunological effects; asthma is misquoted from the Camargo study (which is subject of my review at Pediatric Allergy. Nay, nay.
German news magazine SPIEGEL ONLINE writes of an ongoing trial in Berlin where 1 to 6 month year old newborns are given some kind of “oral LPS vaccination”. You might know my opinion about LPS and will therefore understand my hope that newborn gastric acid pH will prevent them from any LPS side effect. Yea, yea.