Friday, August 3, 2007

A bad memory

[Please forgive the double posting here - it is also on my regular blog www.philipball.blogspot.com - and also forgive its informality, for the same reason. But it seemed relevant to put this up here too.]
I have just read all the papers on ‘the memory of water’ published in a special issue of the journal Homeopathy, which will be released in print on 10 August. Well, someone had to do it. I rather fear that my response, detailed below, will potentially make some enemies of people with whom I’ve been on friendly terms. I hope not, however. I hope they will respect my right to present my views as much as I do theirs to present theirs. But I felt my patience being eroded as I waded through this stuff. Might we at least put to rest now the tedious martyred rhetoric about ‘scientific heresy’, which, from years of unfortunate experience, I can testify to being the badge of the crank? I once tried to persuade Jacques Benveniste of how inappropriate it was to portray a maverick like John Maddox as a pillar of the scientific establishment – but he wouldn’t have it, I suppose because that would have undermined his own platform. Ah well, here’s the piece, a much shortened version of which will appear in my Crucible column in the September issue of Chemistry World.

************************************************************

I met Jacques Benveniste in 2004, shortly before he died. He had tremendous charm and charisma, and I rather liked him. But I felt then, and still feel now, that in ‘discovering’ the so-called memory of water he lost his way as a scientist and was sucked into a black hole of pseudoscience that was just waiting for someone like him to come along.

This particular hole is, of course, homeopathy. In 1988, Benveniste published a paper in Nature that seemed to offer an explanation for how homeopathic remedies could retain their biological activity even after being diluted so much that not a single molecule of the original ‘active’ ingredients remains [1]. It is common for homeopathic remedies to have undergone up to 200 tenfold dilutions of the original ‘mother tincture’, which is quite sufficient to wash away even the awesome magnitude of Avogadro’s constant.

Benveniste and his coworkers studied the effect of dilution of an antibody that stimulates human immune cells called basophils to release histamine – a response that can provoke an allergic reaction. In effect, the antibody mimics an allergen. The researchers reported that the antibody retains its ability to provoke this response even when diluted by 10**60 – and, even more oddly, that this activity rises and falls more or less periodically with increasing dilution.

The paper’s publication in Nature inevitably sparked a huge controversy, which turned into a media circus when Nature’s then editor John Maddox led an investigation into Benveniste’s laboratory techniques. Several laboratories tried subsequently to repeat the experiment, but never with unambiguous results. The experiment proved irreproducible, and came to be seen as a classic example of what US chemist Irving Langmuir christened ‘pathological science’. (The details are discussed in my book on water [2], or you can read Michel Schiff’s book [3] for a deeply partisan view from the Benveniste camp.)

Benveniste remained convinced of his results, however, and continued working on them in a privately funded lab. He eventually claimed that he could ‘programme’ specific biological activity into pure water using electromagnetic radiation. He predicted a forthcoming age of ‘digital biology’, in which the electromagnetic signatures of proteins and other biological agents would be digitally recorded and programmed into water from information sent down phone lines.

Homeopaths have persistently cited Benveniste’s results as evidence that their treatments do not necessarily lack scientific credibility. Such claims have now culminated in a special issue of the journal Homeopathy [4] that presents a dozen scientific papers on the ‘memory of water.’

In at least one sense, this volume is valuable. The memory of water is an idea that refuses to go away, and so it is good to have collected together all of the major strands of work that purport to explain or demonstrate it. The papers report some intriguing and puzzling experimental results that deserve further attention. Moreover, the issue does not duck criticism, including a paper from renowned water expert José Teixeira of CEA Saclay in France that expresses the sceptic’s viewpoint. Teixeira points out that any explanation based on the behaviour of pure water “is totally incompatible with our present knowledge of liquid water.”

But perhaps the true value of the collection is that it exposes this field as an intellectual shambles. Aware that I might hereby be making enemies of some I have considered friends, I have to say that the cavalier way in which ‘evidence’ is marshalled and hypotheses are proposed with disregard for the conventions of scientific rigour shocked even me – and I have been following this stuff for far too long.

Trying to explain homeopathy through some kind of aqueous ‘memory’ effect has plenty of problems created by the traditions of the field itself, in which ‘remedies’ are prepared by serial dilution and vigorous shaking, called succussion. For example, it is necessary not only that the memory exists but that it is amplified during dilution. In his overview paper, guest editor Martin Chaplin, a chemist at South Bank University in London whose web site on water is a mine of valuable information, points to the surprising recent observation that some molecules form clusters of increasing size as they get more dilute. But this, as he admits, would imply that most homeopathic solutions would be totally inactive, and only a tiny handful would be potent.

Another problem, pointed out by David Anick of the Harvard Medical School and John Ives of the Samueli Institute for Information Biology in Virginia, is that if we are to suppose the ‘memory’ to be somehow encoded in water’s structure, then we must accept that there should be many thousands of such stable structures, each accounting for a specific remedy – for several thousand distinct remedies are marketed by homeopathic companies, each allegedly distinct in its action.

Yet another difficulty, seldom admitted by homeopaths, is that the dilutions of the mother tincture must allegedly be made by factors of ten and not any other amount. This is not mentioned in the papers here, presumably because it is too absurd even for these inventive minds to find an explanation. A related issue that is addressed by Anick is the tradition of using only certain dilution factors, such as 10**6, 10**12, 10**30 and 10**200. He offers a mathematical model for why this should be so that masquerades as an explanation but is in fact tantamount to a refutation: “it would be inconceivable”, he says, “that one number sequence would work in an ideal manner for every mother tincture.” Still, he concludes, the convention might be ‘good enough’. So why not perhaps test if it makes any difference at all?

One of the challenges in assessing these claims is that they tend to play fast and loose with original sources, which obliges you to do a certain amount of detective work. For example, Chaplin states that the ability of enzymes to ‘remember’ the pH of their solvent even when the water is replaced by a non-aqueous solvent implies that the hydrogen ions seem to have an effect in their absence, “contrary to common sense at the simplistic level.” But the paper from 1988 in which this claim is made [5] explains without great ceremony that the ionizable groups in the enzyme simply retain their same ionization state when withdrawn from the aqueous solvent and placed in media that lack the capacity to alter it. There’s no mysterious ‘memory’ here.

Similarly, Chaplin’s comment that “nanoparticles may act in combination with nanobubbles to cause considerable ordering within the solution, thus indicating the possibility of solutions forming large-scale coherent domains [in water]” is supported by a (mis-)citation to a paper that proposes, without evidence, the generally discredited idea of ‘ice-like’ ordering of water around hydrophobic surfaces.

One of the hypotheses for water’s ‘memory’, worked out in some detail by Anick and Ives, invokes the dissolution of silicate anions from the glass walls of the vessel used for dilution and succussion, followed by polymerization of these ions into a robust nanostructured particle around the template of the active ingredient initially present. Certainly, silicate does get added, in minute quantities, to water held in glass (this seemed to be one of the possible explanations for another piece of water pathological science, polywater [6]). But how to progress beyond there, particularly when such a dilute solution favours hydrolysis of polysilicates over their condensation?

Well, say Anick and Ives, there are plenty of examples of silicate solutions being templated by solutes. That’s how ordered mesoporous forms of silica are synthesized in the presence of surfactants, which aggregate into micelles around which the silica condenses [7]. This, then, wraps up that particular part of the problem.

But it does nothing of the sort. This templating has been seen only at high silicate concentrations. It happens when the template is positively charged, complementary to the charge on the silicate ions. The templating gives a crude cast, very different from a biologically active replica of an enzyme or an organic molecule. Indeed, why on earth would a ‘negative’ cast act like the ‘positive’ mold anyway? The template is in general encapsulated by the silica, and so doesn’t act as a catalyst for the formation of many replicas. And for this idea to work, the polysilicate structure has to be capable of reproducing itself once the template has been diluted away – and at just the right level of replicating efficiency to keep its concentration roughly constant on each dilution.

The last of these requirements elicits the greatest degree of fantastical invention from the authors: during the momentary high pressures caused by succussion, the silicate particles act as templates that impose a particular clathrate structure on water, which then itself acts as a template for the formation of identical silicate particles, all in the instant before water returns to atmospheric pressure. (Elsewhere the authors announce that “equilibrium of dissolved [silicate] monomers with a condensed silica phase can take months to establish.”) None of this is meanwhile supported by the slightest experimental evidence; the section labelled ‘Experiments to test the silica hypothesis’ instead describes experiments that could be done.

Another prominent hypothesis for water’s memory draws on work published in 1988 by Italian physicists Giuliano Preparata and Emilio Del Guidice [8]. They claimed that water molecules can form long-ranged ‘quantum coherent domains’ by quantum entanglement, a phenomenon that makes the properties of quantum particles co-dependent over long ranges. Entanglement certainly exists, and it does do some weird stuff – it forms the basis of quantum computing, for example. But can it make water organize itself into microscopic or even macroscopic information-bearing domains? Well, these ‘quantum coherent domains’ have never been observed, and the theory is now widely disregarded. All the same, this idea has become the deus ex machina of pathological water science, a sure sign that the researchers who invoke it have absolutely no idea what is going on in their experiments (although one says such things at one’s peril, since these researchers demonstrated a litigious tendency when their theory was criticized in connection with cold fusion).

Such quantum effects on water’s memory are purportedly discussed in the special issue by Otto Weingärtner of Dr Reckeweg & Co. in Bensheim, Germany – although the paper leaves us none the wiser, for it contains neither experiments nor theory that demonstrate any connection with water. The role of entanglement is made more explicit by Lionel Milgrom of Imperial College in London, who says that “the homeopathic process is regarded as a set of non-commuting complementary observations made by the practitioner… Patient, practitioner, and remedy comprise a three-way entangled therapeutic entity, so that attempting to isolate any of them ‘collapses’ the entangled state.” In other words, this notion is not really about quantum mechanics at all, but quantum mysticism.

Benveniste’s long-term collaborator Yolène Thomas of the Institut Andre Lwoff in Villejuif argues, reasonably enough, that in the end experiment, not theory, should be the arbiter. And at face value, the ‘digital biology’ experiments that she reports are deeply puzzling. She claims that Benveniste and his collaborators accumulated many examples of biological responses being triggered by the digitized radiofrequency ‘fingerprints’ of molecular substances – for example, tumour growth being inhibited by the ‘Taxol signal’, the lac operon genetic switch of bacteria being flipped by the signal from the correct enantiomeric form of arabinose, and vascular dilation in a guinea pig heart being triggered by the signal from the classic vasodilator acetylcholine. What should one make of this? Well, first, it is not clear why it has anything to do with the ‘memory of water’, nor with homeopathy. But second, I can’t help thinking that these experiments, however sincere, have an element of bad faith about them. If you truly believe that you can communicate molecular-recognition information by electromagnetic means, there is no reason whatsoever to study the effect using biological systems as complex as whole cells, let alone whole hearts. Let’s see it work for a simple enzymatic reaction, or better still, an inorganic catalyst, where there is far less scope for experimental artefacts. It is hard to imagine any reason why such experiments have not been attempted, except for the reason that success or failure would be less ambiguous.

What emerges from these papers is an insight into the strategy adopted more or less across the board by those sympathetic to the memory of water. They begin with the truism that it is ‘unscientific’ to simply dismiss an effect a priori because it seems to violate scientific laws. They cite papers which purportedly show effects suggestive of a ‘memory’, but which often on close inspection do nothing of the kind. They weave a web from superficially puzzling but deeply inconclusive experiments and ‘plausibility arguments’ that dissolve the moment you start to think about them, before concluding with the humble suggestion that of course all this doesn’t provide definitive evidence but proves there is something worth further study.

One has to conclude, after reading this special issue, that you can find an ‘explanation’ at this level for water’s memory from just about any physical phenomenon you care to imagine – dissipative non-equilibrium structures, nanobubbles, epitaxial ordering, gel-like thixotropy, oxygen free radical reactions… In each case the argument leaps from vague experiments (if any at all) to sweeping conclusions that typically take no account whatsoever of what is known with confidence about water’s molecular-scale structure, and which rarely address themselves even to any specific aspect of homeopathic practice. The tiresome consequence is that dissecting the idea of the memory of water is like battling the many-headed Hydra, knowing that as soon as you lop off one head, another will sprout.

In his original paper in Nature, Jacques Benveniste offered a hypothesis for how the memory effect works: “specific information must have been transmitted during the dilution/shaking process. Water could act as a template for the [antibody] molecule, for example by an infinite hydrogen-bonded network or electric and magnetic fields.” Read these sentences carefully and you will perhaps decide that Benveniste missed his calling as a post-modernist disciple of his compatriot Jacques Derrida. It has no objective meaning that I can discern. It sounds like science, but only because it copies the contours of scientific prose. This, I would submit, is a fair metaphor for the state of ‘water memory’ studies today.

I once read a book supposedly about the philosophy of religion which was in fact an attempt to make a logical case for God’s existence. Having stepped through all of the traditional arguments – the ontological, the argument from design and so forth – the author admitted that all of them had significant flaws, but concluded that collectively they made a persuasive case. This group of papers is similar, implying that a large enough number of flimsy arguments add up to a single strong one. It leaves me feeling about homeopathy much as I do about religion: those who find it genuinely helpful are right to use it, but they shouldn’t try to use scientific reason to support their decision.


1. E. Davenas et al., Nature 333, 816 (1988).
2. P. Ball, H2O: A Biography of Water (Weidenfeld & Nicolson, 1999).
3. M. Schiff, The Memory of Water (Thorsons, 1995).
4. Homeopathy 96, 141-226 (2007).
5. A. Zaks & A. Klibanov, J. Biol. Chem. 263, 3194 (1988).
6. F. Franks, Polywater (MIT Press, Cambridge, MA, 1981).
7. C. T. Kresge et al., Nature 359, 710 (1992).
8. E. Del Guidice et al. Phys. Rev. Lett. 61, 1085 (1988).

15 comments:

Wavefunction said...

Great article. I skimmed through one or two of the papers, but I think what you said in general is very accurate; most of the learned pronunciations sound deliberately ambiguous to try to deflect serious scientific criticism. A lot of these theories also think that just because something could be possible, no matter how tiny and unsubstantiated the possibility is, it actually is not just possible, but outright true.
However, it would be interesting for modern science to simply examine the substances that these "doctors" use, in concentrated form. Just like I see a considerable difference between homeopathy (which sounds like quackery) and ayurveda or chinese folk medicine (which at least to some extent may have something to them- consider the use of Gold in ayurveda the action of which was investigated and found to be valid and beneficial recently), I also see a considerable difference between this whole dubious concept of dilution, and the possible efficacy of the substances themselves.

martin chaplin said...

I am glad that Philip Ball has read the papers; I hope others will and form their own opinions. I knew when we were putting these papers together that we would be ridiculed for even making the attempt. Of course I am disappointed that Philip is so negative and he harps on so about historical stuff and some old quotes; perhaps his rhetorical flow just carried him along.
It is important to point out some facts concerning this group of papers and Philip’s review of them. We tried to include all of the relevant theories and areas of experimental data. Some may or may not prove important and others less so; as Philip admits, we tried to show the problems with some of the existing theories and did not duck issues. Teixeira does indeed state “The main purpose of this paper is to recall that this hypothesis is totally incompatible with our present knowledge of liquid water”, (a subtly more telling quote than Philip’s abbreviated version, in italics). Philip ignores Teixeira’s key message that he means ‘pure liquid water’ and states “Even in small quantities, some solutes can modify substantially some properties of pure water”; a major theme in several of our papers. Pure liquid H2O simply does not exist anywhere in the Universe except in computer memory.
I disagree with Philip over playing fast and loose with original sources. I do give the example of dry enzymes remembering their last aqueous pH as an example where there clearly is a memory effect and where this was a puzzle when first observed. I agree that there is an acceptable (if circular and unproven) explanation of this ‘memory’ effect given in the paper I cite. In truth, this example of pH memory was not given as some sort of proof that water has a memory but given in line with the theme of my paper that the ‘puzzle’ of a memory effect disappears with an acceptable explanation. Philip does not mention one of my other examples, that of the memory of melted clathrate solutions, where there is still no acceptable explanation.
I am unsure whether Philip believes I deliberately made the mistake in the citation of Katsir et al’ paper (it should be J. Electrochem. Soc not the non-existent J. Am. Electrochem Soc; am I being paranoid or he?); I apologise for that; it was not a devilish plot but simply my error as I was misinformed when sent the proof. However, Philip ignores all the data in that paper that shows a memory effect in water and concentrates his angst on part (and not even an important part) of the explanation given for the experimental findings. As I state in my paper “too often the explanation is examined more closely than the experimental data”.

Philip Ball said...

I hope Martin does not think it was my intention to ridicule this effort. It does not deserve that (although I imagine it might receive it from other quarters). I was pleased initially by how sanely the discussion was being presented, both in the editorial by Peter Fisher and the beginning of Martin’s overview article. My comments reflect my genuine disappointment at how the quality of the contributions deteriorated. Indeed, I think it was something more than disappointment: as someone who genuinely cares in a geeky way about water science, I felt annoyed by some of the nonsensical claims and their disregard of what has been patiently learnt about the way water behaves.

I don’t agree with Martin’s interpretation of José Teixeira’s paper. I don’t think he is saying that ‘water memory’ is incompatible with what we know about the purely hypothetical ‘pure water’ studied in computer simulations. Rather, he seems to be suggesting that any explanation for alleged ‘memory effects’ cannot appeal to the structure of liquid water. He recognizes that solutes can have important effects even at apparently low concentration – but to my reading, he says so as a criticism of the poorly constrained procedures typical of the preparation of homeopathic remedies, which make it hard to know how to interpret the experimental results.

It did not occur to me for a moment to imply that Martin’s mis-citation of Katsir et al. was intentional, and I’m rather saddened to see that he feels I might harbour such suspicions. Partly, I simply wanted to alert readers to that mistake – but I confess that I was also mindful of the fact that, when in a case like this the devil is in the details, one needs to take care to get those details right.

That paper by Katsir et al. reports some very curious results – and one of the authors of the study is a friend whose work I respect very much. But I can’t help feeling that Martin is being a little disingenuous when he complains that I ignore the experiments themselves and focus on a relatively unimportant part of the explanation given for the experimental findings. In his overview, Martin says of this work that it shows how “Nanoparticles may act by themselves or in combination with the nanobubbles to cause considerable ordering within the solution, thus indicating the possibility of solutions forming large-scale coherent domains.” Now, I may be misinterpreting what he means, but I understood this to refer to ‘considerable ordering’ of water structure – that, after all, is what is usually implied by talk of ‘ordering’ within aqueous solutions, and the reference to ‘large-scale coherent domains’ seems to echo the terminology of Del Guidice’s hypothesis of quantum-mechanically induced ‘coherent domains’ of water. So I looked through Katsir et al. in search of some evidence of ordering of water structure. And the only reference to this is the one I mention, where the authors talk speculatively about ‘ice-like’ ordering of water round nanobubbles – an idea that draws on the hypothesis of Franks and Evans regarding hydrophobic solutes, which is now over 50 years old and generally discredited. So it is not clear to me that the criticism expressed in my discussion was misplaced.

I hope Martin will take my comments in the friendly way that they are intended. I think we will disagree on some of these issues. But I think we agree on the notion that the collection of papers at least has the value of laying out the arguments so that others can make up their own minds.

Wavefunction said...
This comment has been removed by the author.
Wavefunction said...

I think I agree with Mr. Chaplin's views in his article that the whole issue of water having memory must be independent from whether such an effect could possibly explain the action of homeopathic remedies. In fact I think the theory should be divorced from trying to recruit it to explain homepathy. Because I think that one would instantly run into trouble if he or she tries to apply the principle of water memory to homeopathy. If we believe that homeopathic remedies would also work like modern drugs by modulating proteins, DNA, etc. at least in some way or the other, then a lot of questions present themselves if one tries to explain homeopathy based on the water memory theory. For example, what is it exactly in the water that persists after so much dilution, and produces a reaction from a protein or antibody? Based on our knowledge of protein-ligand interactions, how can this entity representing the memory of the earlier substance interact with the protein? Does it form hydrogen bonds in the active site? How does it induce the protein to change its conformation? Does it bind to enzymes and then become part of the catalysed reaction by the accepted mechanism of the enzyme stablizing the transition state of this entity's reaction? Another set of questions; how long does this memory persist? How does it not get affected by the presence of so many thousands of small molecules in which the body is awash? Wouldn't these molecules likely disrupt the memory of the earlier molecule and leave their own imprint in the water? Wouldn't this entity likely get broken up and dispersed in the bulk aqueous environment of the body?
I am afraid that at this point, applying the memory of water theory to homeopathy raises many more questions in my mind compared to the general phenomenon it tries to explain.

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