Category Archives: Noteworthy

Bullet points for future allergy research

Maybe this is a difficult task – defining an agenda for future research. Here are some thoughts as we don’t know the reasons for the allergy epidemic even after 100 years of research. And we don’t have any cure yet, there is some relief of symptoms and there are some limited curative efforts but we don’t have any real understanding of what is going on. The following research areas may therefore be identified in NON-therapeutic research: Continue reading Bullet points for future allergy research

Finally! 23 and the FDA warning

Quite some time passed already since my last post (to be exact, more than 5 years) but now there are good news. The FDA issued a warning letter on the 22nd

… The Food and Drug Administration (FDA) is sending you this letter because you are marketing the 23andMe Saliva Collection Kit and Personal Genome Service (PGS) without marketing clearance or approval in violation of the Federal Food, Drug and Cosmetic Act (the FD&C Act) … However, even after these many interactions with 23andMe, we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses … Therefore, 23andMe must immediately discontinue marketing the PGS until such time as it receives FDA marketing authorization for the device …

The response is quite flimsy. Yes, there may be negative side effects of genetic testing and of course tests need to validated first. Slate may be correct that the FDA’s battle with 23andMe won’t mean anything in the long run but now at least, we are set back to science, yea, yea.

LIMIT TO 5! What about a maximum of 5 papers per year per scientist?

Undoubtly, there is an avalanche of poor research – as the Chronicle wrote last June, “we must stop the avalanche of low-quality research

the amount of redundant, inconsequential, and outright poor research has swelled in recent decades, filling countless pages in journals and monographs. Consider this tally from Science two decades ago: Only 45 percent of the articles published in the 4,500 top scientific journals were cited within the first five years after publication. In recent years, the figure seems to have dropped further

Also Genomeweb writes

Pedro Beltrao at the Public Rambling blog says there never seems to be enough time to keep up with all the literature researchers keep churning out. In 2009, 848,865 papers were added to PubMed, he says — that’s something like 1.6 papers per minute.

Continuing a discussion Continue reading LIMIT TO 5! What about a maximum of 5 papers per year per scientist?

Science success sucks (sometimes)

Leo at zenhabits has a great new piece:

Why I don’t care about success. ‘Try not to become a man of success, but rather try to become a man of value.’ (Albert Einstein)
A lot of people in my field write about how to be successful, but I try to avoid it. It’s just not something I believe is important. Now, that might seem weird: what kind of loser doesn’t want to be successful?
Me. I’m that loser. Continue reading Science success sucks (sometimes)

A passion for precision

The title is borrowed from  the opening Lecture of Theodor Hänsch on July, 7th, 2006 at the The Euroscience Open Forum in Munich and the Nobel lecture on December 8, 2005 [video] – one of the real science heroes.

(essay written 1/10/2009)

With a never ending stream of genetic association studies in allergy research we are facing severe problems as most of these studies are never reproduced 1. The Lancet editors already think that genetic association is “in danger of becoming a rather dirty word” 2 with even consensus recommendations are not being able to dam up this flood 3, 4. Should we rethink about reasons and consequences 5,6 ?

The Inevitable. The many contradictory results are frequently explained by genetic heterogeneity across populations. There are indeed good examples where populations differ in genetic terms. Lactase variants for example show a clear European South / North gradient. Estimating the genetic risk in an additional populations for replication, however, may have only limited value if population specific risks are of such an enormous importance  – which may be particular relevant for founder populations  and for rare variants. A recent family study 7 found a rare mutation in filaggrin (FLG) associated with atopic dermatitis (AD). Every replication study will depend on the fact that we are sampling enough FLG carriers from the population as well as enough AD patients while replication would fail in black-skinned AD patients (where FLG variants are absent). Non-replication therefore does not necessarily refute a true association while on the other hand replication in a further sample does not sort out a biological relevant association from a chance finding.

Another frequently invoked argument for non replication is phenotypic heterogeneity in complex diseases. Lacking precision in how outcomes are defined and how they are validated may explain non-replication in particular when the phenotype under interest relies on a simple diagnosis only and ignores the underlying QTLs. But there may be less doubt about a positive association like that of FLG and AD when looking at linkage scores, functional properties of the truncated profilaggrin, the general skin physiology, other irritant effects and finally the itchy and dry skin in these patients. Many genetic associations, however, are ignoring the biological context (as well as all Bradford-Hill criteria of causality) and have entered the (never) ending replication loop. Curiously, some associations being published also in high impact journals do not received any interest at all 8. Replication of genetic studies is not an art 9 – it is science or no science at all.

The evitable. Even if we assume for a moment that nature leaves us a detectable genetic risk in complex diseases (that is being worthwile to be found) the field is plagued by studies that are poorly planned, biased sampled, sloppy analysed and botchy reported. Although being accepted on a theoretically level 10, 11 these problems are tacitly ignored. While running a reference database of genetic association  over many years, we recognized an increasing number of studies lacking precision in reporting.

No doubt, errors occur while writing and typesetting of manuscripts, however, it seems that careful writing and copy-editing of printed material has become unfashionable. As a consequence a recent commentary 12 defined scientific misconduct in a new way – as a continuum ranging from honest errors to outright fraud. While the impact of fraud in the field of genetic association studies will be low (due to its low prevalence), the impact of inappropriate research conduct is being high (due to the high prevalence). There are many ways how genetic associations are being distorted by ignoring previous work, insufficient reporting of methods, suppressing inconsistent own data, poor adjustment of confounders, unreported multiple testing, frouzy tables, wording, and references. Accurate reporting may be an ethical duty as this “is not merely a failure to satisfy a few highly critical readers. It not infrequently makes the data that are presented of little or no value.” ( Unfortunately the overloading of referees with ever increasing review requests may be a reason that these errors are not being detected anymore. The number of publications doubled during the last decade while the number of journals basically remained the same.

Decades ago, the bulk of scientific work was done by single researchers. The dusty folios in the libraries that survived from that time list just one author (at the end and not at the beginning of a paper) who had the ultimate responsibility. He would get all credits for his achievements – or all malice for the failure. When researching the obvious errors in some current association papers I have found an “impersonation” effect: The first author moves his responsibility to a statistician who claims that the data administrator had failed while the data administrator does not feel to be responsible for genotyping and so on: “Success has many fathers while failure is an orphan”. It is unacceptable that even papers withtwo dozen errors are never retracted13.

A solution. The field probably requires a greater investment of resources and more careful attention to details. A way out could be joint MD/PhD programs where investigators will learn to deal with clinical protocol, the laboratory work, the data analysis, how to interpret and validate the conclusions. It can be taught in the class room (and by example) how to ask the right clinical question, to perform accurate laboratory work, to check the integrity of data, to perform an optimal analysis, to develop a proper interpretation and to adopt a good writing style 14. We need quality assurance courses covering all critical steps but also teaching scientific accurateness and research ethics.

Also post-publication strategies could be discussed 15. As already mentioned most erroneous papers are neither corrected nor retracted, a bias called by Jim Giles to be “reluctant to have my name attached to negative comments” 16. The comment function in BMC journals, the respond button at BMJ and the eLetter function at PLOS journals nevertheless may be a some first step into a more open discussion of research failure.

It is timely to develop, implement and supervise good scientific practice also for genetic association studies in allergy research. The hunt for impact has compromised the field in an unfortunate manner where the “public´s trust in science and scientists is deteriorating” 17. Most researchers agreed during a recent web survey that most published research findings are wrong 18. We need more passion for precision to get back the trust in our science.

Cited References
1. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306-309
2. Lancet T (2003) In search of genetic precision. The Lancet 361:357
3. NN (2005) Framework for a fully powered risk engine. Nat Genet 37:1153
4. Cordell HJ, Clayton DG (2005) Genetic association studies. Lancet 366:1121-1131
5. Buchanan AV, Weiss KM, Fullerton SM (2006) Dissecting complex disease: the quest for the Philosopher’s Stone? Int J Epidemiol 35:562-571
6. Edwards JH (1999) Unifactorial models are not appropriate for multifactorial disease. Bmj 318:1353-1354
7. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. (2006) Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337-342
8. Zhang Y, Leaves NI, Anderson GG, et al. (2003) Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 34:181-186
9. Kabesch M (2009). The art of replication. Thorax 64:370-371
10. Spilker B (1991) Guide to Clinical Trials. Lippincott Williams and Wilkins:24ff
11. Skrabanek P. M, J. (1990) Follies and Fallacies in Medicine. Prometheus, Buffalo
12. Nylenna M, Simonsen S (2006) Scientific misconduct: a new approach to prevention. Lancet 367:1882-1884
13. Kabesch M, Peters W, Carr D, Leupold W, Weiland SK, von Mutius E (2003) Association between polymorphisms in caspase recruitment domain containing protein 15 and allergy in two German populations. J Allergy Clin Immunol 111:813-817
14. Anonymous (2005) Good data need good writing. nature immunology 6:1061
15. Bracken MF (2005) Genomic epidemiology of complex diseases: The need for an electronic evidence-based approach to research synthesis. American Journal of Epidemiology 162:297-301
16. Giles J (2006) The trouble with replication. Nature 442:344-347
17. Neill US (2006) Stop misbehaving! Journal of Clinical Investigation 116:1740-1741
18. Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2:e124

A longe fuse

Mutation accumulation in the human genome is a largely neglected research field. Most mutations have a very small effect (if any) and may be compensated by environmental improvements. I have already argued in that way in my 2003 Triple T paper and will reiterate it soon in PLOS medicine (just found that James Crow 1997 in PNAS and 2000 in nat gen rev had the same opinion). In principle, the improvement of sanitation and better medical care is leading to a retention of mutations that would be otherwise subject of purifying selection.
Another important factor seems to be the increase of parental age in Western societies. A 20 year old man had about 150 chromosome replications while a 40 year old had about 610 replications. To count the number of your somatic mutations, you need to add all events of your lifetime plus the age of your father at birth minus 9 months … Even with the high fidelity of polymerases, DNA replication remains an error prone process leading eventually to an increase of germline mutations (as may be seen with achondroplasia, Apert syndrome, neurofibromatosis and prostate cancer). With the increasing age of fathers we are now nearly doubling the absolute number of mutations every generation – and we keep them in the pool in contrast to previous centuries. Crow in PNAS 1997 even said

I do regard mutation accumulation as a problem. It is something like the population bomb, but it has a much longer fuse


Addendum 20 Nov 2013

In another post, I detailed the 3,93 figure derived from cancer tissues. The best human estimate at the moment is in this Cell paper that shows a rate between 2.0 and 3.8 x 10^-8 cells. Sperm sequencing may not represent a good model as there are too many degenerate cells.

Addendum 1 Jan 2021

Here is a new nature medicine paper on cell turnover.

What I do not understand – shouldn’t we  have a much higher leukemia rate in the population? Leukemia is only  on the11th place.

Addendum 29 Apr 2021

Another Nature study shows

Differentiated cells in blood and colon displayed remarkably similar mutation loads and signatures to their corresponding stem cells, despite mature blood cells having undergone considerably more divisions. We then characterized the mutational landscape of post-mitotic neurons and polyclonal smooth muscle, confirming that neurons accumulate somatic mutations at a constant rate throughout life without cell division, with similar rates to mitotically active tissues …

this could be the answer to my previous question

These mutations may result from the interplay between endogenous DNA damage and repair that occurs in cells at all times. The similar mutation burden and signatures in granulocytes and hae- matopoietic stem cells, despite a different divisional load, could also be consistent with a time-dependent rather than a division-dependent accumulation of somatic mutations during haematopoiesis

although it will need independent corroboration before making any conclusion that damage repair is more important than replication.

Is religion a natural phenomenon?

I do not want to discuss the rather polemic view of Daniel Dennetts “Breaking the spell” or promote other books of the new secularism. The Guardian digital edition writes on 29th Oct 2006

Secularism is suddenly hip, at least in the publishing world. A glut of popular science books making a trenchant case against religion have soared up the bestseller lists both here and in America. The phenomenon represents a backlash against a perceived rise in religious fundamentalism and recent crazes for ‘spirituality’ by way of books such as The Da Vinci Code. Secularists are now eager to show that the empiricism of science can debunk the claims of believers.

More interesting is the question if human morality is an inborn trait or not. Nicholas Wade has a nice essay in the NYT:

Marc D. Hauser, a Harvard biologist, has built on this idea to propose that people are born with a moral grammar wired into their neural circuits by evolution. In a new book, “Moral Minds” (HarperCollins 2006), he argues that the grammar generates instant moral judgments which, in part because of the quick decisions that must be made in life-or-death situations, are inaccessible to the conscious mind. People are generally unaware of this process because the mind is adept at coming up with plausible rationalizations for why it arrived at a decision generated subconsciously. Dr. Hauser presents his argument as a hypothesis to be proved, not as an established fact. But it is an idea that he roots in solid ground, including his own and others’ work with primates and in empirical results derived by moral philosophers.

I renember also an article by Roger Higfield in the Washington Times (24th March 2003) than unfortunately vanished from the internet:

Scientists are hunting for a “God gene” that underpins our ability to believe. The idea of genes linked with beliefs does not look far-fetched, given the influence of genetics on the developeing brain.

Higfield is refering to an empirical twin study:

To investigate the heritability of religiousness and possible age changes in this estimate, both current and retrospective religiousness were assessed by self-report in a sample of adult male twins (169 MZ pairs and 104 DZ pairs, mean age of 33 years). Retrospective reports of religiousness showed little correlation difference between MZ (r=.69) and DZ (r=.59) twins. Reports of current religiousness, however, did show larger MZ (r=.62) than DZ (r=.42) similarity. Biometric analysis of the two religiousness ratings revealed that genetic factors were significantly weaker (12% vs. 44%) and shared environmental factors were significantly stronger (56% vs. 18%) in adolescence compared to adulthood. Analysis of internal and external religiousness subscales of the total score revealed similar results. These findings support the hypothesis that the heritability of religiousness increases from adolescence to adulthood.

Time on Oct 17, 2004 referred to a book of Dean Hamer “The God Gene”

Chief of gene structure at the National Cancer Institute, Hamer not only claims that human spirituality is an adaptive trait, but he also says he has located one of the genes responsible, a gene that just happens to also code for production of the neurotransmitters that regulate our moods. Our most profound feelings of spirituality, according to a literal reading of Hamer’s work, may be due to little more than an occasional shot of intoxicating brain chemicals governed by our DNA. “I’m a believer that every thought we think and every feeling we feel is the result of activity in the brain,” Hamer says.

This looks very much like a completely physical view of spiritual affairs (Hamer became famous for his failure of the “gay gene” before abandoning science).

So we may better turn to the question if there is any theological background? I renember a famous guest lecture in Marburg 1980 about the Epistle to the Romans by Herbert Braun (Braun is a Bultmann scholar. Ernst Fuchs was in Marburg too; together with Ernst Käsemann and Günther Bornkamm they are all famous scholars of Rudolf Bultmann. Käsemann and Fuchs both wrote a “Commentary on Romans”).

Fuchs highlighted Rom 2:14 in King James translation saying:

13 For not the hearers of the law are just before God, but the doers of the law shall be justified.
14 For when the Gentiles, which have not the law, do by nature the things contained in the law, these, having not the law, are a law unto themselves:
15 Which shew the work of the law written in their hearts, their conscience also bearing witness, and their thoughts the mean while accusing or else excusing one another;

Science and theology are not far away here. Maybe it is even common sense that most humans have an inherited deep feeling of religiousness.