Genome Medicine - Latest Comments

Appreciation of special susceptibility through metabolomics

Heikki Savolainen — 2012-07-10T16:39:12Z

Dear Editor,

The review correctly points out that the use of metabolomics is already in the clinical routine (1).

By applying the idea of individual susceptibility, it was found that carriers of slow N-acetyltransferase activity may excrete more slowly the amine metabolites of organic diisocyanates (2). If this trait was associated with a heterozygous antitrypsin phenotype, the risk of developing an occupational asthma in work involving diisocyanates was threefold (Confidence interval 1.2-8). Thus it seems that the combination of traits is even more important than specifying single changes.

1. Robinette SL, Holmes E, Nicholson JK, Dumas ME. Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations. Genome Medicine 2012, 4:30

2. Berode M, Jost M, Ruegger M, Savolainen H. Host factors in occupational diisocyanate asthma: a Swiss longitudinal study. Int Arch Occup Environ Hlth 2005, 78:158

Thumbs up for the authors, but you overlooked ...

Kristina Spiller — 2011-08-04T12:16:55Z

...there is actually already one such data sharing model, known as GISAID (www.gisaid.org). It successfully addresses all the principles & procedures suggested here. Based on a collaboration of bonafide researchers from various disciplines and coordinated/backed by the vision of an influential media executive, the most significant influenza sharing platform proves fittingly the viability of all 7 principles prescribed by the authors. Now hosted by the federal office for agriculture & food in Germany it has emerged into a public-private partnership supported by international cooperation. We need more of these examples to move science forward. The days of public-domain databases as we know them, and their failure to provide transparency of access and usage and accountability are indeed numbered. Harvard's Winhide succinctly summed it up in October 2010: http://winhide.wordpress.com/2010/10/31/a-right-to-access-and-a-duty-to-reciprocity-gisaid-sets-the-paradigm

Complementary publication (cloud computing for comparative genomics)

Dennis Wall — 2010-09-02T17:05:31Z

Nice paper! Have you seen this http://www.biomedcentral.com/1471-2105/11/259.

sample sizes

James Timmons — 2010-04-19T10:29:13Z

I would like to thank Dr Bossola for their interesting comments. When studies using the same approach we did find strong evidence that ICU patients - patients with severe imobillity and inflammation - that the pathways mentioned by Dr Bossola were indeed activated as described. In contrast, using the same technology we did not find such pathways activated in this type of cancer related cachexia (Frederikson et al PLos One 2008). Thus we know the technology is valid.

Many molecular profiling studies in patients versus controls often use only a handful of patients. This has led to great confusion in the diabetes field, for example, with respect to gene changes in muscle insulin resistance. The same is true of cancer cachexia. the majority of studies using molecular profiling have relied on only small case-contorl sample sizes.

In our present study we utilise the relationship between modest and severe weight loss and not simply a case control analysis. Further, the sample size far exceeds previous studies and we profile 3 distinct muscle groups in humans, across two clinical centres, to find common mechanisms. I believe these reasons may explain the differences in the studies mentioned in the points made by Dr Bossola.

Role of ubiquitin-proteasome in cancer cachexia

Maurizio Bossola — 2010-03-17T09:36:27Z

Sir,

we read with much interest the article by Sthepens et al recently published in Genome Medicine (1) that shows, among other results, that the mRNA expression of the E3 ligases MURF1 and MAFbx, examined by qRT-PCR, was not related with weight loss in the skeletal muscle of patients with cancer of the upper gastrointestinal tract. According to the authors, this result would suggest that the ubiquitin E3 ligases do not play the same role in human cancer cachexia as that previously demonstrated in animal and cell studies and that any support to the findings of previous human studies (2-4) could be found. Indeed, few studies have investigated the ubiquitin-proteasome pathway in the skeletal muscle of cancer patients (2-5), but none of these have assessed the expression of E3 ligases. In our first study (2), northern blot analysis of the skeletal muscle revealed a significant twofold increase of the mRNA levels for ubiquitin in gastric cancer patients with respect to control subjects. The levels of ubiquitin mRNA did not correlate with age, BMI, percent weight loss, serum albumin and total lymphocyte count but were higher in stage IV than in stages I-II-III. In a second study (3), we found that the three proteasome activities (chymotrypsin-like; trypsin-like and peptidyl-glutamyl-peptidase) significantly increased in the skeletal muscle of gastric cancer patients with respect to controls and that advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher chymotrypsin-like activity but had no influence on trypsin-like and peptidyl-glutamyl-peptidase. The results of the study of Khal et al (4) demonstrated that the expression of mRNA for proteasome subunits C2 and C5 was three to five times higher in cancer patients with weight loss than in control subjects. It seems that an increased expression and activity of the ubiquitin-proteasome proteolytic pathway occurs in cancer patients when compared with controls who are not affected by comorbidities. Thus, it could be interesting to know if, in the study of Stephens et al, there were differences between cancer patients and controls in the expression of E3 ligases, although we are aware that the controls were few and significantly younger. It remains that the role of the ubiquitin-proteasome pathway in skeletal muscle of cancer patients suffering weight loss and/or cachexia needs to be further investigated and elucidated.

1. Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, Ross JA, Guttridge DC, Lundell L, Fearon KC, Timmons JA. . Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med. 2010;2:1-12
2. Bossola M, Muscaritoli M, Costelli P, Grieco G, Bonelli G, Pacelli F, Rossi Fanelli F, Doglietto GB, Baccino FM. Increased muscle proteasome activity correlates with disease severity in gastric cancer patients. Ann Surg. 2003;237:384-389.
3. Bossola M, Muscaritoli M, Costelli P, Bellantone R, Pacelli F, Busquets S, Argilès J, Lopez-Soriano FJ, Civello IM, Baccino FM, Rossi Fanelli F, Doglietto GB. Increased muscle ubiquitin mRNA levels in gastric cancer patients. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1518-23
4. Greenhaff PL, Karagounis LG, Peirce N, Simpson EJ, Hazell M, Layfield R, Wackerhage H, Smith K, Atherton P, Selby A, Rennie MJ. Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab. 2008;295:E595¿604.
5. Jagoe RT, Redfern CP, Roberts RG, Gibson GJ, Goodship TH. Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. Clin Sci (Lond). 2002;102:353¿361

Response to Dr. Tarynn M. Witten's comment

Peter Csermely — 2010-01-27T09:14:06Z

We would like to thank for the comment of Dr. Witten to our paper. First, we would like to apologize for Dr. Witten for not citing any of the listed contributions. Indeed, the 1984 Mech. Aging Dev. paper represents one of the first uses of network theory in aging, which deserves citation, as we will do in our later papers. This work is extended by its sequel, the 1985 Mech. Aging Dev. paper. In 1984 the complex network structure of the cell was obviously unknown, and therefore, the centrality of the critical elements defined by Witten is rather a general central position of a systems theory-type network than the refined versions of betweenness and other types of centralities of the interactome or metabolic type networks attracting the focus of research today. Obviously at that time Witten¿s general notion of centrality could not be tested on a real network, and, therefore was not attached to any types of essential genes. However, the early idea to use network theory to the identification of critical cellular elements is indeed, important.

The recent PLoS ONE paper of Managbanag et al. is a nice representation of the graph theoretical tools to identify longevity genes. Similarly, the Witten-Bonchev Chemistry and Biodiversity paper gives an important contribution to the topics of longevity-networks also described by others simultaneously. We consider it a very unfortunate oversight not to cite these papers in our review. We will certainly cite these contributions in our later, relevant publications.

As a final note, carefully re-reading our paper we did not find any statements inferring our role as originators of any ideas covered by Dr. Witten¿s publications. Since our paper was a review paper the references ¿ including self references ¿ gave the source and verification of the given statement, and could by no means regarded as any claim for priority. The limitation of references and the focus to the most recent papers published makes it generally very difficult to cite all primary references in these, not extensive, but mini-reviews.

On behalf of all co-authors: Peter Csermely

sodium control problems common to bipolar disorder and schizophrenia

Gregory Marlow — 2009-12-08T14:41:16Z

One should considered that the genes responsible for the sodium level control system may be the ones responsible for bipolar disorder and schizophrenia. Both these illness have a ten fold higher frequency of hospital admissions with hyponatremia compared to hyponatremia in all other admissions. I believe that most hyponatremia in psychiatric patients is incorrectly attributed to polydipsia. Instead it should be looked at as a possible underlying cause. Patients with hyponatremia can display many mental symptoms common to bipolar disorder and schizophrenia. In addition there is a mechanism that links sodium to the circadian rhythm. In the evening the body lowers blood sodium levels in preparation for sleep. If the individual already has a low level due to some hormone problem, the evening lowering may cause levels to become hyponatremic.

History of Research in Aging Networks

Tarynn Witten — 2009-12-04T14:49:00Z

While an interesting paper, this paper ignores the significant previous literature in the field of aging networks, reliability theoretic applications to aging networks and purports to be the first to generate the ideas of using hubs and other network concepts to understand the behavior of aging processes. Unfortunately, the ignored literature significantly overlaps the results in this paper.

The work of Witten, as far back as the early 1980's represents the actual first publication of the concepts of central elements and centrality of networks using graph theoretic concepts in aging.

Witten, T.M., A return to time, cells, systems, and aging: II. Relational and reliability theoretic aspects of senescence in mammalian systems, Mech. Aging and Dev., 27 (1984) 323--340.

This work documented the idea of what is now called essential genes (Witten called them critical elements) and highly connected hubs. This work was followed by a number of publications applying network and reliability theory to aging networks:

Witten, T.M., Reliability theoretic methods and aging: Critical elements, hierarchies, and longevity---Interpreting survival curves, (in) The Molecular Biology of Aging (eds.) A. Woodhead, A. Blackett, and R. Setlow (Plenum Press, N.Y. 1985).

Witten, T.M., A return to time, cells, systems and aging: III. Critical elements, hierarchies, and Gompertzian dynamics, Mech. Ageing and Dev., 32 (1985) 141--177.

More recently, these methods were extended using the Bonchev-Witten algorithm to determine potential longevity-related genes in longevity-gene networks.

Witten, T.M. and Bonchev, D.G. (2007). Predicting aging/longevity-related genes in the nematode C. elegans. Chemistry and Biodiversity, 4: 2639-2655.

The following paper provides a history of the work:

Witten, T.M. (2007). (M,R)-systems, (P,M,C)-nets, hierarchical decay and biological aging: Reminiscences of Robert Rosen. Chemistry and Biodiversity, 4 (10): 2332-2344.

Most recently, Witten's doctoral student Managbanag along with the research team at U of Seattle, using the methods developed by Bonchev and Witten published the following paper:

Managbanag, J.R., Witten, T.M., Bonchev, D.G., Fox, L.A., Tsuchiya, M., Kennedy, B.K. & Kaeberlein, M. (2008). Shortest-path network analysis is a useful approach towards identifying genetic determinants of longevity. PLoS ONE, 3 (11):e3802. doi:10.1371/journal.pone.0003802

It is extremely disturbing to discover that all of these works were ignored in the reference list of the Simko et al (2009) paper [also ignored in other papers published in other locations] and that the current paper Simko et al (2009)purports to present the idea that they are the originators of ideas whose core was published by Witten over 20 years ago. We hope that this lack of attention to the core literature in the field of networks in aging will be rectified in the future by these and other authors.