On mice and men with asthma

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.

Addendum

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

Why dog and cat can´t marry

or in more scientific terms: Why are F1 hybrids so often sterile or lethal? The Dobzhansky-Muller theory says that there is an incompatibility between genes with reduced fitness that have diverged between species. So far nobody has ever observed a D-M gene but a new Science paper describes two genes that separate D. simulans and D. melanogaster: lhr (lethal hybrid rescue) and hmr (hybrid male rescue). Yea, Yea.

For the first time two human genomes compared

Another “first discovery” in this nature genetics preprint although the analysis could have already been done some years earlier. The CNV specialists from Toronto now compare the Human Genome Project sequence with the Celera sequence – the gap between the two compilations was obviously bigger than the intra-sequence gaps. Of course both sequences are still mosaics from several individuals but the analysis nicely exemplifies how difficult it will be to compare the genome of two different human beings.
The authors employ a whole battery of alignment tools BLAT, MEGABLAST, GCA and A2Amapper. Of course results depend on the strategy, definition and implementation. As show by FISH analysis most of the discrepancies are true and can be classified into a few categories – insertions or deletions if seen from the second genome (has somebody ever thought about a minimal human genome?), mismatches and inversions. We are getting here a preview of the diagnostic workup in a patient in 2026. This blog contains forward looking statements while the responsibility rests solely with the reader. Yea, yea.

The mind has a thousand eyes

The night has a thousand eyes,
And the day but one:
Yet the light of the bright world dies
With the dying sun.

The mind has a thousand eyes,
And the heart but one.
Yet the light of a whole life dies
When love is done.

Francis William Bourdillon

(found 7/12/06 on the inside cover of an old book with title “Perdita” in the patient library of a university clinic)

Assets minus debts

Slashdot reports a United Nations study that

the richest 2% of adults in the world own more than half of all household wealth… Most previous studies of economic disparity have looked at income, whereas this one looks at wealth – assets minus debts.

Looks similar to science budgets, yea, yea.

Addendum

An interview with Richard Münch in Laborjournal 12/2006, p.23 confirms this: 17 out of 100 German universities consume 50% of all funds provided by DFG. He furthermore believes that SFBs and research networks are a kind of ideological framework; projects are not assessed retrospectively; there is an overkill of management costs where a considerable part of third-party funding is used to get more third-party funding.

Headline: For the first time 2 human genomes compared

What sounds brand new in a current nature genetics preprint, could have even been done already a couple of years before. The CNV specialists from Toronto compare now the Human Genome Project sequence with the Celera sequence. Was the gap between these two compilations bigger than the intra sequence holes? Both sequences are of course mosaics from several individuals but the analysis nevertheless exemplifies how difficult it may be to compare even the genome of two related individuals. The authors employ a whole battery of alignment tools BLAT, MEGABLAST, A2Axxx, GCA. Of course results are different depending on strategy, definition and implementation used. As show nicely by FISH analysis most of the discrepancies are true and can be classified into a few categories – insertions with and without corresponding fragment or deletions if seen from the second genome (has somebody ever thought about a minimal human genome?), mismatches and inversions. We are getting here a preview of the diagnostic workup in a patient in 2026. This blog contains forward looking statements while the responsibility rests solely with the reader. Yea, yea.

New LD measure

There is a new way to calculate LD that may overcome the limitations of D’ and R^2 that are not easily generalizable to multiallelic markers (or haplotypes) and depend on the distribution of SNPs (or haplotypes).
The paper is at BMC, the sources at the authors’ website. I have slightly modified the program to allow input and output file names on the command line before compiling it. Use at your own risk, yea, yea.

100 years of allergy

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.

pirquet2.png

Tit-for-tat or altruism in science

No, this essay will not deal with altruism in science but with the science of altruism. There are two new papers from the Fehr group (one in Science on Nov, 3 about diminished reciprocal fairness after magnetic stimulation of the right prefrontal cortex and a second in Nature on Aug, 24 about altruism in two indigenous groups in Papua New Guinea). I was, however, much more impressed by their recent review of human altruism.
Cooperation between genetically unrelated groups is a typical human behaviour (otherwise seen only in ants, bees and the naked mole rat) where there seems a strong reciprocity between selfishness and altruism. Cooperation is rarely stable and may deteriorate under worse conditions. Altruistic rewarding and reputation seeking seem to be the most powerful determinants of future donors’ behaviour where effects of punishing behaviour seem to be underestimated: Cooperation in larger group continues only if punishment of defectors and non-punishers is possible.

punish480.png

An utter refutation

I am slow in commenting on a paper that has already been published earlier this year – Joe Terwillingers vivid refutation of the fundamental theorem of the hapmap proponents that

if a marker is in tight LD with a polymorphism that directly impacts disease risk, as measured by the metric r^2, then one would be able to detect an association between the marker and disease with sample size that was increased by a factor of 1/r^2 over that needed to detect the effect of the functional variant directly

I cannot comment on the statistical proof but fear from my recent experience with Crohn and asthma tags that he may be right with his assumption: Even marker in high LD with the functional variant may not show any association at all. These may be bad news for all those currently running large screening programs with hapmap based variants believing that P(A|BC)=P(A|Bc)=P(A|B), yea, yea.

Addendum

Tag SNPs also do not work with CNVs

Who will survive?

When looking at gene variants in a population we may forget that even having a perfect sampling scheme this will not be an unbiased view of the human genome. Earlier studies suggested that up to 75% of conceptions are lost during early development; a further indicator of an biased view are unexplained cases of departure from Hardy-Weinberg equilibrium.
Selective survival during early pregnancy is still a terra incognita and except of studies in the Hutterites I am not aware of any (modern) study that looked at selective survival.
A study of Grant Montgomery now shows fresh data on genomewide allele sharing in 1,592 DZ twins from Australia and 336 DZ pairs from the Netherlands.
It is somewhat disappointing that there is no excess allele sharing in the HLA region nor somewhere else in the genome. Maybe further studies can do that a high resolution than with just 359 microsatellite marker?

Prevention of fraud

Donald Kennedy is writing in this week’ Science editorial about Responding to Fraud. The editorial is even more about prevention of fraud: The external reviewers ask for future risk assessment of potential fraud. Science will think in the future

… which papers deserve particularly careful editorial scrutiny. Papers that are of substantial public interest, present results that are unexpected and/or counterintuitive, or touch on areas of high political controversy may fall into this category…

I appreciate such an initiative and I agree that science is based on an assumption of trust – no procedure will be immune to deliberate fraud. However, looking both at people and at papers could be worthwile. I would give extra score points for

  • too ambitious institutional environments
  • large and anonymous organizations
  • poor social and scientific interaction at a local level
  • limited scientific qualification or background of researchers or department heads
  • time pressure, too many projects, no longterm goals
  • direct financial compensation in return of scientific impact
  • past history of minor misconduct

Looking at papers will also reveal inconsistencies

  • contradictory numbers
  • suspicious modifications of figures
  • original data not public available
  • original documentation not public available
  • constructs, cell lines, animals not public available
  • inadequate point by point response to review
  • insufficient documentation of IRB and authorship

Another option is to pay reviewers – the review process is becoming more and more time consuming – and even to plan on-site evaluation. An option probably not feasible is to delay publication until the main findings are independently reproduced.

Finally, I see a large gap between the attempts of Science and Nature to improve their performance while some average impact journals never respond if you ask them to correct or withdraw a highly distorted paper. Yea, yea.

Addendum

Guide to promoting integrity in scientific journals published by the Council of Science Editors

I agree with everything you said

“I agree with everything you said that was correct, and I disagree with everything you said, that was incorrect” (Adlai Stevenson according to AJRCM 2006;174:1056) – a nice comment that fits every situation.
The German Spiegel has an interview with Tim O’Reilly about the quality of internet resources. It seems that everybody can voice his or her opinion while the final decision about a feature or a patch is done in the “inner circle”. Entry to the inner circle is limited to those who qualify by previous contributions – probably a very similar system in science. O’Reilly talks in this interview also about Jaron Larnier’s warning that Wikipedia may be dangerous for creating mono-culture-knowledge. He agrees that Wikipedia has been abused in the past but believes that the mechanisms behind Wikipedia to identify abuse are much better than in any political system, yea, yea.