Ab initio creata sum

13.02.2007 admin

Hymne an das Ewig-Weibliche / 19. â€“ 25. März 1918 – Verzy / Teilhard de Chardin / An Beatrix / Ab initio creata sumâ€¦(Proverbs 8:22)

Seit Weltbeginn bin ich erschienen. Vor den Ewen (Äonen) ging ich hervor aus Gottes Händen â€“ umrißhaft, um im Gang der Zeit an Schönheit zu gewinnen, Mitwirkerin seines Werkes.
Alles im Universum erfolgt durch Vereinigung und Befruchtung â€“ durch Zusammenschluß der Elemente, die zueinander suchen, paarweise verschmelzen und neugeboren werden in einem Dritten.
Gott hat mich in das ursprüngliche Viele hinein ergossen als die Kraft, die verdichtet und den Dingen zu ihrer Mitte verhilft.
Ich bin das einigende Antlitz der Seienden â€“ bin der Duft, der sie herbeilockt und sie in Freiheit und Leidenschaft mitzieht auf den Weg ihrer Einigung.
Durch mich gerät alles in Bewegung und ordnet sich zueinander.
Ich bin der Zauber, der in die Welt gemischt ist, auf daß sie sich sammle â€“ das über ihr schwebende Ideal, auf daß sie emporsteige.
Ich bin das wesenhaft Weibliche.

Teilhard de Chardin was one of the few theologians who had also a sound scientific background. He worked in the paleontology laboratory of the Musée National d’Histoire Naturelle; in 1913 he took part in excavations in the prehistoric painted caves in the northwest of Spain – more information at

His verses reminds me to Jeremiah 1:5 who already expressed 628 BC a clear view of our pre-existence: Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee. Is there really so much difference to what we currently believe about meiotic events?

Philosophy

Meeting abstract versus full paper

13.02.2007 admin

JACI has an interesting letter comparing the number of meeting abstracts and the subsequent publication of a full paper. It seems that there is a large variation from from 11% to 78% – does this really mean that at some meetings half of the talks is not worth to write them up? This would explain why at some conferences nobody is taking notes – I am usually playing sudoku, backgammon or go but have also interesting podcasts with me.

Allergy

Say no

13.02.2007 admin

German Ärzteblatt has some important suggestions “Mehr Mut zum Nein-sagen” how the German healthcare system may be improved. In brief,
(1) patients need to be empowered to make their own health decision – Norwegians have on average only 3 but Germans 16 physician contacs per year
(2) during professional contact patients need more trust in doctor, nurse, pharmacist and physical therapist
(3) more money for the ill, less for the health people

Genetics

NHANES R data parser

12.02.2007 admin

NHANES is a great ressource for doing epidemiological research. As the NIH website provides only data import for commercial software here is my rewrite in R. First load from their site

adult.exe
youth.exe
lab.exe
lab2.exe
exam.exe

put everything in one directory and expand the self-extracting archives. Then create from each SAS file a new variable content file that will only contain variable name and tab separated start position in the .dat file. Adult.var for example would read like this:
SEQN 1 DMPFSEQ 6 DMPSTAT 11 DMARETHN 12 DMARACER 13 ... HAZNOK5R 3345

Then start the following R job with the datasets and variables that you are interested in

|wj_nhanes.R|

Genetics

Undo button

11.02.2007 admin

â€“Day 7 of Just Science Weekâ€“

WouldnÂ´t it be nice to have also a CTRL+Z action in the laboratory? For example when you have confused pellet and supernatant during pipetting? Biology at least seems to have some kind of undo action – see a series of nice papers in Cell Research. ItÂ´s not about demethylation of the parental genome, it’s about stopping and rebuilding the zygotic transcription program during the first meiotic division (that creates the haploid set of chromosomes that will be passed to the progeny).

At present there are 3 hypothesis around, how transcription is being silenced – simply by the speed up of the cell cycle, by active inhibitory (transcription) factors, or the passive deficiency of critical factors. Sun et al. now show that there is a genome-wide disscociation of chromatin factors leading to a naive state in preparing the new life cycle. Critical transcription factors and regulators remain separated for a prolonged time period and become reassociated only after pronuclear formation. It is still unclear if the second or third hypothesis fits best this process as the absence of even 1 essential transcription factor can inactivate transcription. Deletion of TBP for example will inactivate both PolI and PolII; TBP is found to dissociate among other factors.

Only a couple of structural proteins remain bound persistently (HP1alpha, HP1beta, TOPIIalpha and AcH4, with acetylated histone 4 as a positive control. Of course methyl-binding proteins, topisozymerases, and other heterochromatin binding stuff is required for normal chromatin structure where it would be nice to know which of these remain bound during this reprogramming step. So, this looks more like a reinstalling the OS than a simple undo action.

Thanks and good bye to all guest readers of the science week.

Joke

Random news, oxymorons and paper generator

10.02.2007 admin

â€“Day 6 of Just Science Weekâ€“

No idea, what to write in your next scientific paper? Use the random medical news for some ideas. Here are also some expressions ready for cut & paste. Or you may want to go directly to SCIGEN (thanks to Christine for that link).

This page took 0.134 seconds of computer labor to produce. No computers were harmed in the making of this page. Some browsers whose name starts with Internet may be though (from Matt s blog).

Philosophy

Poll: Are most published research findings wrong?

9.02.2007 admin

â€“Day 5 of Just Science Weekâ€“

John Ioannides has published a rather influential paper (that will not so often be cited as read): “Why Most Published Research Findings Are False”. In principle his arguments are (numbering by me):

1. a research finding is less likely to be true when the studies conducted in a field are smaller
2. when effect sizes are smaller
3. when there is a greater number and lesser preselection of tested relationships
4. where there is greater flexibility in designs, definitions, outcomes, and analytical modes
5. when there is greater financial and other interest and prejudice
6. and when more teams are involved in a scientific field in chase of statistical significance

According to good scientific practice, this could be tested – the only problem is to recognize if the result of a single study is wrong. To be continued in 20 years…

{democracy:2}

Genetics

My compliments

8.02.2007 admin

My compliments to Nicole, the latest Ph.D. student from our lab who succesfully passed her final exam today in Freising at TU München-Weihenstephan. Here is the semi-official document:

The title of her thesis is High-resolution snp scan of chromosome 6p21 in pooled samples from patients with complex diseases , a topic that has recently attracted new interest.

We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn’s disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.

Genetics

The master animals of LinnÃ©

8.02.2007 admin 2 Comments

â€“Day 4 of Just Science Weekâ€“

Quicklink to www.biolib.de (thanks to Sigrid for the link). You will find at Kurt Stübers Online Library 440 scanned historical biological books. Many of these books are currently out of print and even hard to obtain from public libraries or book sellers.

Philosophy

Less is more

7.02.2007 admin

–Day 3 of Just Science Week–

Peer review certainly plays a major role in assuring quality of science. There are many positive aspects of peer review (plus a few disadvantages like promoting mainstream). Systematic research on peer review, however, has been largely absent until 2 decades ago; after 5 international conferences on peer review there is now also the WAME association of journal editors. Over the years, I have experienced the “cumulative wisdom” thrown at my own papers and of course developed my own style when doing reviews. Last week PLOS medicine published an interesting study who makes a good peer review:

These reviewers had done 2,856 reviews of 1,484 separate manuscripts during a four-year study period, and during this time the quality of the reviews had been rated by the journal’s editors. Surprisingly, most variables, including academic rank, formal training in critical appraisal or statistics, or status as principal investigator of a grant, failed to predict performance of higher-quality reviews. The only significant predictors of quality were working in a university-operated hospital versus other teaching environment and relative youth (under ten years of experience after finishing training), and even these were only weak predictors.

The first finding may be unimportant for non-medics but the second may apply to a larger audience. What I fear – and that is usually not mentioned in the current discussion – that the peer review system is slowly suffocating. The willingness to do this (unpaid & extra) work is going down as papers (at least in my field) are produced more and more an industrial mass production level. I am getting a review request nearly every second day while I do need between 30 minutes and 3 hours for a paper. So, less is more.

Addendum

For a follow up go to sciencesque, a scenario how science in the post-review phase will work.

Genetics

Genes on the move

6.02.2007 admin

–Day 2 of Just Science Week–

Most people think that human genes are static entities inherited from generation to generation. They may be right, there are no jumping genes in humans.

In 2000, when defending my thesis in epidemiology, I even had to answer the question of the faculty: “How can allergy have a genetic cause as most allergy cases date back only 1 or 2 generations?”. I explained the concept of susceptibility genes (that were always there) plus some new environmental risk factor (that came in only recently) and passed the colloquium.

Maybe this concept was not completely wrong. By today, however, I could offer more explanations – human genes are on the move and even within 2 or 3 generations. You may still wonder – are we talking about T cell receptor recombination? Yes, this may be a possibility, but not a really new one. More noteworthy are (1) abolished purifying selection (2) population admixture and (3) increased spike in mutations. These are all are independent paths that may combine freely.

Lets start with “abolished purifying selection”. At the beginning of the last century there were much larger family sizes and a much higher infant mortality. In Europe, mortality under the age of 5 has been about 250/1.000 live born children in 1900. It dropped to 50/1.000 around 1950 and is now about 5/1.000 – the effect of improved sanitary conditions, vaccines and antibiotics. Geneticists would describe it as a reduced selection – giving immediate rise to some variants in the gene pool.

The figure is Â© Copyright 2006 SASI Group (University of Sheffield) and Mark Newman (University of Michigan). Thanks to John Pritchard from the Worldmapper Team to let me post it here. Territory size shows the proportion of infant deaths during the first year of their life in 2002

Second, think of population admixture. This usually refers to the composition of a population by descendants of a few founders. Except for major migration periods population composition has been kept rather stable over centuries which can be nicely seen in humans living in isolation and having enriched some diseases – examples from Finland, Hutterities, South Tirol, East Adria or Iceand. With current decrease of admixture also the prevalence of diseases frequently seen in these populations will go done. However, some people even expect that other diseases will rise – as unusual allelic variants will meet other unusual allelic variants (which has not been balanced before). This theory is still vague but has interesting aspects that may be followed up.

A third possibility why human gene variants may change within short time comes with the ever increasing age of fathers at reproduction. I came across this only very recently by a paper of Ellegren. With each additional year of the father the number of pre-meiotic cell divisions increases – leading to a permanent (germline) increase of mutations. Most of these will be irrelevant but some may spike in random genes leading eventually to health effects. Crow asks: “Is this a problem? Surely it will be eventually, but probably not immediately”.

Human genes are therefore on the move, yea, yea.

Genetics, Software

Human genome variation

5.02.2007 admin 3 Comments

Being a former curator for a genetic disease database, I received a PM that explained why the foundation of the Human Genome Variation Society did not include most of the HUGO Mutation Database Owners — most did not join as they found it difficult to pay for membership. This reflects the overall frustration in obtaining funds for databases projects that are between research and service. Now, a new initiative for the Human Variome Project (HVP) is started to create a focus pulling the whole vision together and to assist in fundraising. Meeting details are at www.humanvariomeproject.org. I strongly support this initiative. All genetic variation databases are sharing a high interest in the community but zero interest at funding bodies (more). I have a dream…

the flyer…

Philosophy, Software

Anything better than impact factors?

5.02.2007 admin

Here is a nice inside view from the BMC journals – you can watch how often your own papers are being downloaded.

Hopefully these hits are not only generated by search engine spiders, yea, yea.

Genetics, Philosophy

Curiouser and Curiouser

5.02.2007 admin 3 Comments

–Day 1 of Just Science Week–

… said Alice in the Wonderland. Curiouser an couriouser all these gene X – trait Y – value P – association studies that are so often not reproduced. Science magazine now publishes letters of 3 independent groups contributing 6 essentially negative studies. This does not come unexpected – maybe we should look again at the original paper?
The introduction seems to be somewhat misleading — obesity is not primarily associated with another disease but with over-eating — and a heritablity of 70% is hard to believe. BTW I wonder why neither the editors, reviewers, or authors noticed the editorial errors (page 281: the 1775 cases in the text appear as 1835 cases in table 3; table 3 itself is redundant and misses genotype counts as well as the 923 FHS individuals from page 280). However, that does not explain why the association cannot be reproduced by other groups. So what could be the reason that the initial results were not be replicated?
Looking more closely at the case-control definition it seems that obesity is defined in different ways in the different populations – the German sample by cutoff BMI>30, the Polish by 90th to 97th percentile, the Nurses’ trait is never explained and the Africans are split by quartiles. How would a consistently defined look across all these populations? There seems to be also no proof why SNP rs7566605 somewhere 10000 bases away from a gene should have any biological function. Just because it “is an attractive candidate gene … [as it] … inhibits the synthesis of fatty acid” ?
More general, I believe that it is not adequate to make any conclusions about causal interference from a statistical association alone. There are many known fallacies; reasons for non replication may be simple errors during phenotyping or genotyping, inadequate statistical power, a biased analysis, selective reporting, population stratification or population unique effects. My six criteria for a meaningful association are:

sufficient strong association, stable in subgroups and in populations of the same ethnic background
importance of the tagged mutation leading to regulatory or structural protein change while excluding any confounding LD effect
functional importance of the resulting protein with the trait of interest
known genetic background and interaction with other genes and proteins
known time of onset of functional change and interaction with relevant pathway
known interaction with the environment, possibly also in an animal model

Quite simple ;-), yea, yea.

Joke, Software

Laptop stolen – phoning home

4.02.2007 admin 2 Comments

Scientists are frequent travellers – hopefully you have always your harddisk encrypted. There are many companies that offer to trace your computer like Computrace(R), zTrace(R), LapTrak(R), BoomerangIt(R), LoJack(R) and PC-Guardian(R). Save your $/€ for your next experiment, here is the trick: During the next boot your laptop will send out a http request to any server you like. You simply need to watch the server logfile if your stolen laptop is phoning home…
For installation please download LaptopService.cmd, LaptopService.reg and two small binaries from the windows ressource kit. Adjust path and server name before running LaptopService.cmd. VoilÃ , that’s it – for a good joke look at Slashdot.

|wj_LaptopService.cmd|