August 5, 2012

An unusual and relevant protein structure.

A recent paper [BBC coverage] regarding work conducted at the MRC centre for human reproductive health in Edinburgh has revealed a role suggested a role for the proteoglycan Decorin in prostate cancer. The paper describes observational work looking at the presence and production of 5 proteins (including Decorin), and their distribution within different cell layers in the developing rat prostate. Looking at differential expression of Decorin during prostate development is an entirely reasonable thing to, given Decorin’s previously hypothesised role in organogenesis (development of organs) and tissue differentiation [REF].

In the recent paper, Henke et al also show that levels of Decorin are often significantly reduced in prostate cancer, and this is suggestive that Decorin might be a tumour suppressor gene – i.e. remove Decorin, and you may remove a barrier that prevents normal cells from becoming cancerous. Potential mechanisms are discussed in the paper, and it seems entirely plausible that decorin might function in this way – its role in organogenesis requires that it regulate cell division in some way – failure of this regulation of this might result in unchecked cell division – i.e. cancer.

Anyway, this all served to remind me of the small leucine rich repeat proteoglycans, or SLRPs – pronounced, ‘slurps’.

Decorin was the first SLRP (of the 17 known in the human genome) to have its structure determined [ PDBe | Pubmed ], by Jordi Bella and Paul Bishop, working at the University of Manchester (disclosure: I work there now).

SLRPs are pretty unusual looking structures – officially their fold is called a “beta-alpha-right-handed-superhelix”, and it looks a little something like this:

Each leucine rich repeat forms a single helical turn of the “beta-alpha-right handed superhelix” – the hydrophobic (water-hating) leucine residues form a continuous beta sheet (the rainbow coloured arrows in the figure below) which makes up the concave face of the protein. The convex face of the protein is made up of hydrophilic (water loving) loops.

The fact that this large concave hydrophobic face exists and is exposed to solvent is energetically unfavourable – however, in both the crystal structure, and in solution, Decorin exists as a dimer (2 Decorin molecules non-covalently bound to each other), and formation of this dimer hides this hydrophobic concave face from the solvent, making it thermodynamically more favourable.

Hopefully it is clear in the above figure that the concave faces of the protein are packed against each other, preventing them from having to interact with solvent.

It’s a neat example of how the primary (amino acid sequence – in this case rich in hydrophobic leucine residues), secondary (beta-strands) and tertiary (beta-sheet) structure of a protein influences its quaternary structure – in this case its oligomeric state.

Psorinum therapy – homeopathy for cancer?

January 31, 2011

A quick look at another paper doing the rounds

There is an update to this blog post that follows the original post

These papers [1], [2](pdf) have recently been pimped around twitter by various homeopaths, apparently as proof that a homeopathic remedy can cure cancers, including the very nasty pancreatic cancers. Paper 1 (published in a sensible-looking oncology journal) is just an abstract from a meeting, and paper 2 (published in Evidence-Based Complementary and Alternative Medicine) is the actual paper with all the juicy details – but they essentially detail the same study.

Taken on face value, the results are pretty amazing, with 5-year survival rats of around 40% for patients with stomach, gall bladder pancreatic and liver cancers (paper 2, table 3).

Compare these with current 5 year survival rates for stomach and pancreatic cancers of roughly 12% and 2% respectively.

So, if kosher – these results would be a fantastic addition to the arsenal in the war on cancer.


… the studies were conducted without any controls whatsoever. The mind boggles. Why bother going to the effort of a 5 year study, and not including a control arm? Whether it be an ‘untreated’ arm, a placebo arm or a comparison against current best practices and therapies, a control arm would have increased the viability of this study no end. Even if they failed to recruit any more patients, and just split the patients into to two randomised groups with 20-odd patients in each arm, the power and impact of the study would be massively enhanced. To not control anything is just a massive fail.

This massive fail is then compounded by a failure of peer-review at eCAM. Did the reviewers not ask themselves where the controls in this study where? However, this was published in eCAM and this is clearly labelled as a prospective study – maybe I am being too harsh.

However, for those totting this paper as evidence for homeopathy curing cancer,  let’s make this absolutely clear: the only conclusions that can be drawn from this study are that the study is ultimately a waste of 5 years and is utterly meaningless in it’s current form. It should have been designed properly 5 years ago, and it should have contained some sort of control arm, and should have been properly randomised and blinded.

The authors are clearly aware of this and allude to it themselves in the final sentence of the paper:

“…randomized double-blind clinical trial, detailed molecular, pharmacokinetics,and pharmacodynamics studies should be conducted for further scientific exploration of this alternative cancer treatment to determine if it can be integrated into the mainstream oncology.”


It is perhaps telling that in this final sentence in the paper, that the authors mention “detailed molecular, pharmacokinetics,and pharmacodynamics studies.” That use of the word ‘molecular’ is the only appearance of the word molecular or derivatives thereof in the entire paper, maybe unsurprising given that this is a homeopathic study.

The wonder remedy that the researchers are testing out is ‘Psnorium’ – a homeopathic remedy made from the fluid from scabies blisters (yuck) – that apparently has indications for a large number of symptoms, including, “generalities; sensitive; to pain” – well, that rules out the ~48 people on the planet that suffer from CIPA, then…

Of more note to people with an interest in molecular mechanisms (myself included), is the fact that the dilution factor used in the study is only 6x. So, 1 in 1,000,000.

Wait a minute! That’s cheating! There is an outside chance that Psnorium 6x actually has “something” in it!

Let’s assume for a minute that the results are genuine, and Psnorium 6x has had an effect on these cancers. The fluid from scabies blisters will likely contain serous fluid – but depending upon the exact contents of the blister it could contain all manner of biochemical goodies.

Given that scabies blisters are apparently intensely itchy, there may be some histamine around. The fact that the scabies mite (a foreign object) has penetrated the skin, means that some sort of immune response will have been mounted, and therefore it is inconceivable that scabies blisters would not contain some cytokines or chemokines. Was the remedy prepared from crusted or normal scabies? Because patients with crusted scabies secrete higher levels of cytokines IL-5 and IL-13, and lover levels of IFN-gamma than normal patients [3]. Other studies have shown that scabies mites, or extracts thereof alter secretion levels of a whole range of cytokines:

Active mites on the surface of the HSE induced secretion of cutaneous T cell-attracting chemokine, thymic stromal lymphopoietin, interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1ra), IL-6, IL-8, monocyte chemoattractant protein-1, granulocyte/macrophage colony-stimulating factor, and macrophage colony-stimulating factor.

So, biochemically speaking, scabies blister fluid likely contains some very interesting molecules, some of which may have an effect on cancer cells. Oral administration of Interleukins has been shown to have physiological effects in some studies, and cytokine therapy is an avenue being explored in the fight against cancer.

<Insert vaguely witty sub-heading here>

Let’s assume that the DBRCT has been done properly, and it shows a clear, statistically significant effect in cancer patients. What next? Would it be the killer blow that shows that skeptics have been wrong and homeopathy works? Sadly not – because of the likely presence of actual molecules of something. That being said, if there is an effect to be seen, it does at least give us the possibility of conducting an interesting experiment to test homeopathy:

  • Take the scabies blister fluid.
  • Give one-third of it to a homeopath, get them to make up their remedies as usual, with all the serial dilutions and succussion.
  • Give another third to a competent postgraduate student. Get them to make a 1 in 106 dilution of it, but without the homeopathic rituals like succussion.
  • Give the final third to a well-equipped, well-staffed biochemistry lab. Get them to fractionate the fluid by HPLC or FPLC, and then test the fractions for biological activity in a suitable assay, and identify the molecules present are responsible for the effect, (assuming it’s not some arm-wavy, unsubstantiated guff about the vital force or EM fields) they will presumably isolate one or more fractions that contain the molecules responsible for the therapeutic effect. These molecules could then be purified for trial in patients.

If only the homeopathic remedy recapitulates the results of the DBRCT, then homeopathy works. Elseif, science works, and someone just got lucky feeding diluted extract of scabies blister to cancer patients.



A blog post at Anaximperator that I was alerted to by a pingback is well worth a look as it contains a rather interesting graph from the conference presentation that was not included in the publications –

“Psorinum+Allopathy+Homeopathy” does not look significantly different from “Psorinum+Allopathy”. “Psorinum+Homeopathy” comes a distant 3rd. The authors of the study apparently didn’t think to include an “Allopathy” or “Homeopathy” alone group. Looking at this, I would suggest that psorinum gives little, if any, benefit above and beyond the conventional treatment that patients were receiving. You will note that the only group without conventional/allopathic treatment fared significantly worse than those groups receiving it. As the anaximperator author wryly observes –  “It appears that conventional treatment is necessary for homeopathy to work.” 😉