THE SIMILIA PRINCIPLE AS A THERAPEUTICSTRATEGY: A RESEARCH PROGRAM

ON STIMULATION OF SELF-DEFENSE IN DISORDERED MAMMALIAN CELLS

Roeland Van Wijk, PhD and Fred AC Wiegant, PhD

The Similia Principle as a Therapeutic Strategy

original paper

Roeland Van Wijk and Fred AC Wiegant are from theDepartment of Molecular Cell Biology, Faculty of Biology,Utrecht University, Utrecht, the Netherlands.

The similia principle is considered to be the essence of homeopa-thy. This article describes a research program for study of the similiaprinciple in cultured mammalian cells. This systematic program withits rather simple research model was set up ultimately to contribute tothe design of studies of the similia principle with more complex organ-isms such as humans. With respect to application of the similia prin-ciple, the concepts of self-defense and self-recovery are central. At thecellular level, self-defense and recovery largely depend on the avail-ability of proteins with a cell-protective function, most notably, stressor heat shock proteins.

To study the similia principle, we use four lines of research toexamine the processes of self-defense. First, stimulation of self-defensein disturbed and disordered cells is studied by using low doses of anagent homologous or identical to the disturbing agent. The second lineof research deals with the specificity of this stimulation: Is cellular self-defense after exposure to toxicant A also effectively stimulated in ananalogous or heterologous way by low doses of other toxicants such asB or C? The third line of research involves the duration of low-dose sen-sitivity of disordered cells for homologous stimulations, in particular,the desensitization of cells toward these homologous stimulations. Thefourth line of research deals with whether—according to the similiaprinciple—the state of desensitization can be overruled by heterologouscondition(s) that induce an analogous pattern of protector proteins(ie, a pattern closely resembling the damage-induced pattern) andthus effectively stimulate cellular defense and recovery. (AlternativeTherapies in Health and Medicine. 1997;3(2):33-38)

The essence of homeopathy is the stimulation of bio-logical defense and recovery mechanisms by the useof compounds according to the similia principle.The similia principle suggests that any state of dis-turbance that is not corrected spontaneously (and

leads to a state of “disease”) can be corrected by minute doses ofcompounds that at a higher dose can produce effects closelyresembling the symptoms of the disease being treated or byminute amounts of the compounds that actually caused the dis-ease.

When cells are damaged, a mechanism is switched on towithstand the disturbing effects and to stimulate recovery.Increased understanding of such a mechanism would strengthenthe foundation of the similia principle.1,2 The basis of this mecha-nism that regulates the transition between life and death hasbeen the subject of much research for many decades. As a tenta-tive approach to characterizing the essence of the living state, itwas proposed that life is a process of being an “organizing enti-ty,” which means an open system that (re)structures and(re)organizes itself. Defense and recovery are biological phenom-ena that encompass the way in which components of the systemare temporally, spatially, and hierarchically rearranged. To studythe similia principle, one must understand how to intervene in,adjust, or stimulate these recovery processes. This approachrequires quantitative experimentation and evaluation methods(eg, mathematical modeling) and thus requires parameters tostudy the damage-induced recovery mechanisms experimentally.This article describes the phases of a research program to studythe similia principle in cultured mammalian cells.

Understanding of the mechanisms of cellular protectionand recovery from damage in non–lethally injured cells at themolecular level has increased greatly in recent years. Theseprocesses appear to be largely dependent on the availability ofproteins with a cell-protective function, most notably stress orheat shock proteins.3-5 When working with cells as a model sys-tem, it is crucial to determine what actually occurs in cases ofdisorder and especially the way the defense and recovery mecha-nisms are regulated to prevent further infliction of injury or cell

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ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 33

death. This article thus focuses on the research strategies fordetermining which cellular components play a role in defenseand on the integration of this information. The chosen researchstrategy is on complex systems, which requires the analysis ofnonlinear interactions in a network. The task of discovering thenature of the defense process during interventions according tothe similia principle is the next topic of research. Next, the pos-tulated, precise kinetic and interactive behavior of defense pro-teins must be tested and it must be shown that the results of thevarious experiments, when fitted into a quantitative model, arein accord with the observed changes.

DAMAGE AND DEFENSEProteotoxicity

The so-called stress response, which started as a molecularcuriosity in fruit flies in the early 1960s, now constitutes anactive area of research in molecular cell biology.3 The heat shockproteins, one of the most highly conserved group of proteinscharacterized so far, are implicated as being essential compo-nents in a number of diverse biological processes, in particularcellular protection. Following the nomenclature first used forfruit flies, the various heat shock proteins in animal cells arenamed on the basis of their mode of induction and apparentmolecular mass. Hence their designation as hsp70 or grp78, forexample, refers to heat shock proteins of 70 kD and glucose-reg-ulated proteins of 78 kD, respectively. A survey of these proteinsis presented in the Table.

Earlier work was perplexing in that many different agentswere able to lead to similar changes in gene expression.However, in the past 15 years, a variety of observations have pro-vided support for the so-called abnormal protein hypothesis sug-gested to explain the induction of the heat shock response.6 Thisaspect of toxicity at the level of proteins has been termed pro-teotoxicity.7 When cells have been exposed to heat shock or totoxic substances such as cadmium and arsenite, or to oxidativestresses, many proteins exhibit deleterious changes in structure.These changes then interfere with the functional interactivecapabilities of these proteins. The risk is also high that theseabnormal protein molecules aggregate not only with other dam-aged proteins but also with still functional proteinaceous cellularstructures. The damage at the level of proteins lies at the basis ofcellular damage and eventually cellular death.

Stress Proteins in Cell ProtectionTo understand cellular recovery, one must study the mecha-

nisms that are activated when proteins are damaged and deter-mine how the cell copes with these damaged, life-threateningmolecules.

Some work on in vitro refolding of a small number of pro-teins led to the long-lasting impression that folding of newly syn-thesized polypeptides is an intrinsic feature of their primarystructure, independent of other factors. However, the relativelyhigh protein concentration in the cytosol gives rise to misfoldingfollowed by aggregation. To deal with this kind of problem, a set

of stress proteins, collectively called chaperones, ensure thatpolypeptides fold and assemble properly in the cell. The stressproteins are also named according to their function. Examplesinclude chaperone proteins (which form complexes with proteina-ceous and other, more intricate, cellular structures in order toprevent premature or deleterious interactions between pro-teins), binding proteins (which form complexes with receptor pro-teins to regulate their activity, ie, a receptor function), orprotector proteins (which have crucial functions in the mechanismof cell defense and recovery). In this respect, the protector pro-teins seem crucial in many ways in the normal functioning ofproteins under adverse conditions and in the refolding of struc-turally damaged proteins.4

34 ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 The Similia Principle as a Therapeutic Strategy

Functions in cell metabolismand cellular stress defense

Heat and ethanol tolerance

Stabilization of proteins;maintenance of the inactiveprotein form during trans-port

Essential for cell viability

Role in protein folding?

Molecular chaperone;required for protein assem-bly, protein translocation,secretion and import intoorganelles

(Thermo)tolerance

Promotes survival in extremetemperatures

Maturation of proteins forexcretion protein transloca-tion in mitochondria

Molecular chaperone thatfacilitates folding ofmonomeric proteins andassembly of oligomeric pro-tein complexes; mainly inmitochondrial matrix

Metabolism of haem

Contributes to thermotoler-ance and cytoskeletal stabi-lization

Protein denuration

Hspfamily

hsp100

hsp90

hsp70

hsp60

small hsps

Stress protein

hsp100

hsp90 (hsp84)

grp94 (grp95)

hsp70 (hsp73/hsc70)

hsp68(hsp72/hspi70)

grp78 (BiP)

hsp60

hsp32(haem oxygenase)

hsp27

ubiquitin

Major stress protein families and their functions

Adapted from Parsell and Lindquist4 (1993)

Pattern of Protector Proteins is Damage SpecificA variety of different protector proteins have been found.

Interestingly, the pattern of protector proteins that is inducedappears to be damage specific.8-10 Under different deleteriousconditions, qualitatively different patterns of protector proteinsseem to be induced. Although an explanation for such a complexregulation is lacking, the patterns do suggest some differentia-tion in the induction of the type of damage-induced protectionmechanisms.

Because these protector proteins are essential to survivethreatening conditions and because their induction occurs atconcentrations of various toxic compounds that are not yetlethal for the cells, the damage-specific pattern of induction maybe considered as the cellular equivalent of the homeopathic rem-edy picture.

The Problem of Regulation of Availability of Protector Proteins

A simple model for the regulation of protector proteins indefense after cell damage is depicted in Figure 1. The quantity offree protector proteins available in the cell decreases after celldamage. As long as these protector proteins are available, dam-age is reduced to a minimum. However, when a shortage of pro-tector proteins arises in the case of an overload of damage, theabnormal protein molecules can complex with other cell struc-tures. Cell damage and death can then be avoided only by pro-duction of increasing amounts of new protector proteins. The

replenishment of these protector proteins starts with activationof associated protector protein gene promoters on the cell’sDNA. This highly specific activation occurs by binding of specif-ic DNA-binding factors, called heat shock transcription factors(HSFs), on these DNA sites.11 The binding of the HSF to the pro-moter on the cell’s DNA is the signal that triggers transfer ofinformation from DNA into messenger RNA (mRNA), leadingeventually to synthesis of new protector proteins. Whether ornot these DNA-binding factors interact with the DNA dependson the existing quantity of protector proteins in the cell. Thegenome is specifically activated to trigger this synthesis of addi-tional protector proteins only when the quantity of protectorproteins falls below a certain threshold. Normally, at least onetype of protective protein, hsp70, and a DNA-binding factor,HSF, form a complex that provides the basis for this regulation.If protector proteins are required to neutralize abnormal pro-teins, this complex then dissociates, releasing HSF, which thenbinds to the promoters and induces production of mRNA, withthe ensuing synthesis of new protector proteins. When sufficientnew protector proteins have been produced, that is, when thelevel of these proteins is raised above the threshold value, hsp70will again form a complex with HSF molecules, uncoupling theHSF from DNA, with a concomitant halt in production ofmRNA. In terms of systems theory, one might say that this is theautoregulation loop that forms the basis of damage-inducedrecovery processes.

Mathematical Modeling as a Future Step in Understanding the Regulation of Defense

Defense and recovery are not simple and singular phenom-ena but are determined by the kinetic parameters of the autoreg-ulation loop as illustrated in Figure 2. Insight into theeffectiveness of this loop for cellular defense can therefore beobtained only from studies involving the parameters mentionedin this mathematical model. This mathematical model of defenseand recovery processes has only recently started with the devel-opment of a model of hsp70 regulation in the cell.12 So far, fivemain blocks, each describing one or more processes involved inthe functions of hsp70 and its synthesis, have been developed.1,12

These blocks constitute the basic structure of a mathematicalmodel for the regulation of hsp70 in cells. The major processesincluded in the model so far are (1) denaturation of proteinsafter an increase in temperature and the binding of hsp70 todenatured or nascent proteins; (2) interaction of hsp70 with HSFand the activation of HSF not bound to hsp70; (3) interaction ofactivated HSF with a specific HSF binding sequence (heat shockelement, HSE) on DNA; (4) the relationship between HSE andtranscriptionally active HSF and the level of hsp70mRNA active-ly engaged in synthesis of hsp70; and (5) translation of viablehsp70mRNA into its protein.

In the model constructed so far, the output of this regula-tion is the level of free, that is, unbound, hsp70 in the cell. Futuresteps in developing this mathematical model concern the inclu-sion of lethality in order to predict stress-dependent survival and

The Similia Principle as a Therapeutic Strategy ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 35

FIGURE 1 Basic processes of damage and defense at the cellularlevel. Proteotoxicity is illustrated as a change in protein conforma-

tion. Protector proteins interact with these abnormal proteins.After depletion of the pool of free HSPs, supplementation of these

protector proteins occurs by way of the compensation cycle.

Proteotoxicity Compensation cycle

Pool of freeHSPs

Denaturedprotein

Stress

HSF (inactive)

Protector protein

HSF (active)

DNA

HSPmRNA

HSP

changes in cellular sensitivity to stressors.To sum up, the integrity of the cellular systems, their

defense and recovery, depends not only on the available protec-tive proteins but also on the speed of activation of the total res-cue mechanism. Future developments in this research aredirected at the damage dependency and differentiation of thementioned production process. A quantitative experimentalanalysis and a mathematical evaluation are considered essentialfor this study and for understanding any interventions in thisproduction process, particularly interventions according to thesimilia principle.

SIMILIA PRINCIPLEAccording to homeopathic insights, recovery can be stimu-

lated by all kinds of substances, provided that they are applied ina specific way. Of all substances, the one most suitable for stimu-lation of recovery is the one that can produce the artificial situa-tion of disorder that most closely resembles the disordered state.In other words, this concept hinges on the resemblance betweensymptoms of the disturbed system and the symptoms caused bythe applied substance in a healthy system.

Application of Low Doses of Homologous Damaging Conditions

The similia principle in its most elementary form can easilybe tested at the cellular level by determination of the extent towhich recovery is stimulated by a small dose of a substance thatin the first instance—at a higher dose—is responsible for dereg-ulating the system or leading to sickness. The relevant questionfor this overview is whether this stimulation will be translatedinto increased synthesis of protector proteins and increased sur-vival of cells.

This hypothesis, representing homologous sensitization,has been studied by a step-down heating protocol in which theinitial treatment with high heat is immediately followed by a sec-ond treatment at lower doses. When these step-down heatingconditions were used, an enhanced synthesis of protector pro-teins was indeed seen.13-15 Other studies show an enhanced occur-rence of thermotolerance when mild step-down heatings wereused.16

The next relevant question is whether this response is a gen-eral occurrence and can thus also be observed after stressor con-ditions other than heat shocks. To this end, a damage-inducingtreatment of cells with arsenite or cadmium was followed by lowdoses of arsenite or cadmium, respectively. When this step-downtreatment with arsenite or cadmium was used, cells exhibited anenhanced synthesis of various protector proteins and develop-ment of tolerance.17,18 The lower doses had no effect on synthesisof protector proteins or development of tolerance in cells thatwere not pretreated (ie, healthy cells).

Figure 2 shows, schematically, the transient induction ofhsp70. The synthesis of this protein is further enhanced when alow stressor dose is applied during the so-called posttreatmentperiod. The level of tolerance that is achieved is also higher whenthe low dose is applied after treatment as compared to cells thatreceived a pretreatment only.

The Specificity of the Low-Dose EffectWith respect to the specificity of the defense-enhancing

effect of low doses of an analogous stressor, some recent studiesexamined induction of protector proteins in sensitized cells bylow doses of analogous but potentially damaging conditions. Sofar, experiments have examined the effects of pretreatmentsgiven with either a heat shock, sodium arsenite, or cadmiumchloride. After these pretreatments, the cultures were exposed tolow doses of heat, arsenite, or cadmium or to control conditions.

36 ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 The Similia Principle as a Therapeutic Strategy

FIGURE 2 Schematic presentation of the effect of a low dose of ahomologous stressor on the synthesis of hsp70 (A) and on devel-opment of tolerance (B). When the stress condition is followed

by a low dose of the same stressor, an enhancement of hsp70 syn-thesis (filled triangles) and of tolerance development is observedin comparison with the effect of the stress condition alone (opencircles). A low dose of the stressor does not influence the controlcells (open triangles). C=control, x=low-dose stressor, X=stres-

sor, X-x=stressor followed by low-dose stressor.

Rela

tive

synt

hesi

s of h

sp70

2.0

1.5

1.0

0.5

0.00 2 4 6 8

Time (hours)

ARe

lativ

e su

rviv

al (%

)

60

40

20

0

B

C x X X-x

The Similia Principle as a Therapeutic Strategy ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 37

The stimulating effect on the synthesis of various protector pro-teins was then studied. This application of either heat shock,arsenite, or cadmium at subliminal conditions to already disor-dered cells early in their recovery yielded a different degree ofsynthesis of protector proteins. Only incubation of damagedcells with low doses of homologous conditions resulted in thisextra synthesis of protector proteins.1 Additionally, the degree ofstimulation by low doses of stressors depended on the degree ofsimilarity between the two stressors (Figure 3): The more similarthe induced pattern of protector proteins by two stressors, thelarger the stimulatory action. These observations confirm thespecificity of the low-dose effect and are now extended by incor-poration of a broader range of stress conditions in the experi-mental protocol.

Specific DesensitizationA particular aspect of the cellular response to stressors is

that the cells show a biphasic change in their sensitivity to astressor. An initially enhanced sensitivity (sensitization) towarda second application of the same stressor is followed by areduced sensitivity (desensitization or tolerance). This phenome-non is represented schematically in Figure 4. This biphasicchange in sensitivity is observed after heat treatments and aftertreatments with cadmium18 or arsenite.19 In particular, thechange in sensitivity can be seen after the period of stressor-induced synthesis of protector proteins. This state of refractori-

ness (or tolerance) is also seen in the induction of synthesis ofprotector proteins by a second heat shock20-22 and by fractionatedarsenite17,23 or cadmium treatments.18 The consequence of thistemporal refractoriness is that homologous sensitization is onlytransient. These observations led to the conclusion that lowdoses of homologous substances are effective only during theearly period of recovery. The next questions in the research pro-gram are whether this desensitization later in cellular recovery isa stressor-specific phenomenon and to what extent a heterolo-gous reinduction remains possible.

Heterologous ReinductionRecently, the specificity of desensitization of protector pro-

tein induction was tested with heat shock, sodium arsenite, andcadmium chloride used as primary and secondary inducers ofprotector proteins.23 The data suggest that the degree, but notthe pattern, of reinduction of protector proteins is influenced bythe type of stressor used in the pretreatments. Thus, stimulationof synthesis of protector proteins after cadmium as the sec-ondary stressor is severely inhibited in cadmium-pretreatedcells, whereas reinductions after arsenite and heat shock arespecifically inhibited in cells pretreated with arsenite and heatshock, respectively.

In summary, homologous sensitization is transient, andhomologous desensitization develops specifically. Apparently, acommon denominator regulates the coordinate expression of agroup of protector proteins. Heterologous reinduction can stilloccur but, in that case, the pattern of protector proteins inducedby the secondarily applied stressor shows a stressor specificitythat is dependent only on the second treatment and is indepen-dent of any pretreatment.

FIGURE 3 Schematic presentation of the specificity in stimula-tion of HSP synthesis by low doses of stressors. A high dose

induces a certain level of HSPs, which is further enhanced whensubsequently incubated with a low dose of the same stressor, butnot with a low dose of stressor conditions that were not similar.A low dose exerts no effects on the level of hsp70 found in con-

trol conditions (black bars).

Rela

tive

synt

hesi

s of h

sp70

2.0

1.0

0

After

Before

0 as cd 0 as cd

As Cd

FIGURE 4 Schematic presentation of the change in sensitivity(filled squares) and HSP inducibility (open squares) at varioustimes after stressor application. Closed circles=control level.

LD50

(arb

itrar

y un

its)

Time (hours)

6

5

4

3

2

1

0

6

5

4

3

2

1

0

HSP

indu

cibi

lity

(arb

itrar

y un

its)

0 1 2 3 4 5 6

Future Research Aimed at Further Understanding of the Similia Principle

The possible implication of the results mentioned so far isthat the increased production of protector proteins at a latertime after an injury, that is, during the period of homologous tol-erance, occurs only after application of a heterologous damagingcompound. When we consider the pattern of synthesized protec-tor proteins as the molecular symptoms of recovery, the speci-ficity of the similia principle reveals itself in the degree ofrelatedness between the effects of the disturbing compound onthe pattern of synthesis of these protector proteins. We mustsearch for analogous damaging conditions that induce patternsof protector proteins similar to those generated by the primarystressor without being identical to this primary stressor. For thisstep, different compounds must be tested at the cellular level.

Another possibility is to look for conditions that induce thewhole range of protector proteins, such as, for instance, the useof a mixture of stressors in low doses (Figure 5). Then, as a resultof a concerted action, the synthesis of all protector proteins willbe enhanced by an overruling or circumvention of the lack ofinduction of some protector proteins due to stressor specificity.

In fact, from this perspective, nature seems to use fever (lowhyperthermic temperatures) to provide organisms with a meansof stimulating protection and recovery mechanisms after dam-age, as suggested by preliminary data.1

Significance of Fundamental StudiesStudies on the similia principle at the cellular level are with-

out doubt significant for our understanding of the stimulation ofrecovery processes at the cellular level. It is apparent that theregulation of recovery can be stimulated in a specific way by

application of low doses of damaging conditions. The selectionof condition can be based on the molecular symptoms of the cel-lular defense process. In this respect, the application of lowdoses according to the similia principle warrants further study.

It should now also be easier to understand the role of thesecellular recovery processes in an organ’s functionality after expo-sure of an intact organism to stressful conditions. Therefore, thesimilia principle can be expected to manifest itself as a generalbiological phenomenon. This offers exciting opportunities fordeveloping new avenues for therapeutic interventions in bio-medicine.

AcknowledgmentsC A van der Mast, PhD, is gratefully acknowledged for critical reading of the manuscript. This workwas supported by the HomInt organization, Karlsruhe, Germany.

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16. Van Wijk R, Ovelgönne JH, de Koning E, Jaarsveld Van Rijn I, Wiegant FAC. Mild step-down heating causes increased transcription levels of hsp68 and hsp84 mRNA andenhances thermotolerance development in Reuber H35 hepatoma cells. Int JHyperthermia. 1994;10:115-125.

17. Ovelgönne JH, Wiegant FAC, Souren IEM, Van Rijn I, Van Wijk R. Enhancement of thestress response by low concentrations of arsenite in arsenite-pretreated H35 hepatomacells. Toxicol Appl Pharmacol. 1995;132:146-155.

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38 ALTERNATIVE THERAPIES, MARCH 1997, VOL. 3, NO. 2 The Similia Principle as a Therapeutic Strategy

FIGURE 5 Stimulation of recovery of damaged cells by threetypes of treatment. Upon damage by stressor X, a specific patternof HSPs (indicated by the solid bars) is observed. In the time after

damage, the cells show a differential sensitivity in time towardthese treatments. These treatments include a homologous condi-tion (isopathy, X followed by x); a singular heterologous but simi-lar condition (X followed by y), and a composite of heterologous

conditions (X followed by z1 through z3).

Time (hours)

StimulatingconditionsDamage z

yx

X x y

z1

z2

z3

z1-3