methodology of receptor research–-a philosophical perspective

J . OF RECEPTOR & SIIGNAL TRANSDUCTION RESEARCH, 19(1-4). 1-14 (1999)

INTKODIJCTORY LECTURE

METHODOLOG'Y OF RECEPTOR RESEAFtCH-A PHIILOSOPHICAL PERSPECTIVE

Peter Janich

Institut fur Philosophic, Philipps-Universitat, D-35032 Marburg, G.F.R.

ABSTRACT

Two examples taken from the philosophy of physics (!measurement and experiment) show the dependence of quantitative data and of causal judgements on technical aims that are invested into both laboratory research and the concept for- mation of a successful science. Accordingly, methodology is defined as the theory of methods, i.e. of the rules governing actions constitutive of research and the phrasing of its results. Judgement on methods is a matter of means-and-ends rationality. The objects and relations under consideration are not natural but technical ones.

With respect to analytical chemistry, a problem concerning the application of mathematics to quantitative data is described in order to argue for the irreducibil- ity of measurement of macroscopic quantities (like volume) to the counting of numbers of micro-objects (like molecules): the basic concepts of microbiology, analytic chemistry and toxicology remain related to certain iheoretical (and corresponding experimental) contexts.

Starting from the perspective that receptor research is dealing with the effects of chemical substances on organisms, a few constraints on receptor research are characterised. The idealisation of causes and effects by describing them in terms of chemistry (on a molecular level) hinges on a problematic presupposition. It is objected that there is neither a way down from levels mow complex to simpler ones nor a way up from simple to complex levels in so far as the criteria for medical diagnoses are not causally linked with chemical descriptions.

As a result, the significance of the traditional connection bletween the medical treatment of persons and the manageableness of health effects Iby pharmaceutical means is stressed. Whether molecular models, theories and t:xplanations are help-

1

Copyright c 1999 hy Pvlarc:I IkLLer, liic

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2 JANICH

ful for a phenomenological description has to be tested. accordingly but cannot generally be presupposed.

INTRODUCTION: "METHODOLOGY"?

The literal meaning of "methodology" derived from the Ancient Greek logos

(doctrine, theory) and methodos (way towards) clearly suggests that we are deal-

ing with a philosophical subject. It does not concern pharmaceuticals or chemical

substances and their effect on organs, cells or molecules in living beings, but

methods, i.e. ways humans act. "To act" is a verb covering purposeful actions sci-

entists perform while doing research and communicating its results. "Methodol-

ogy" means theory (or better: knowledge) of "methods", i.e. ways of acting as to

be successfbl, as to realize ends by following an appropriate type of rationality.

Methodologies cannot be spelled out without using terms such as Itmeans,"

"ends," "success," "failure" and others which do not usually form part of scientific

terminologies of chemistry, or physiology. For short, they are not terms belonging

to theories in the natural sciences.

Being a philosopher, it thereforecame as a surprise to be invited to speak to a

community of scientists who are meeting under a philosophical conference title

and yet do straightforward science. So I decided to follow Socratian footprints and

to ask whether what seems to be acknowledged opinion (doxa) in methodology of

receptor research truly is knowledge (episteme).

1. PHYSICS AS PARADIGM: MEASUREMENT AND EXPERIMENT

To begin with, let me discuss two examples of methodological means of phys-

ics. Firstly, because this is the field best known to me in science and, secondly,

because these means are highly appreciated in your field of research too: meas-

urement and experiment. Certainly, quantitative experimental control is indispen-

sable for receptor research - but what makes measurement and experiment appro-

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METHODOLOGY OF RECEPTOR RESEARCH 3

priate means, and it0 which ends? Or, as Immanuel Kant would have phrased this

question, in which1 sense are measurements and experiments "conditions of the

possibility" of pharmacological knowledge?

The term "mear;urement" means the producticm of results which are stated in

mathematical terms and fillfill certain demands -- demands which are "methodo-

logical" in character: measurements have to be independent of the person per-

forming them, and of the particular measuring tool in order to be empirical and

informative about the measured object. This demand is usually called "transsub-

jectivity. 'I

The term "experiment" means a technical installation running from a starting

situation which is artificially produced, over an event (which is not a human ac-

tion) to a result whic,h may be termed the "effec:t" of the artificial "cause." Ex-

periments have to fWill the methodological claim to reproducibility. This means

that the repetition of the same action patterns of the scientist producing the start-

ing situation leads to an equal running of the experiment and produces equal ef-

fects. General conriections between causes and effects are established or produced

this way. Experimlents are the basis of so-called causal explanations and render

them universally valid. I call this methodological claim "univlersality," for short

Apparently, "tra.nssubjectivity" and "universality" are two forms of claims to

generality, on the part of the acting persons and on the part of the subjects under

consideration, respectnvely. These descriptions may represent what experimental

scientists in fact do - and no point of controversial understanding - besides the

fact that methodology of measurement and experiment is not itself natural science

but obeys metascientific criteria.

Different philosophical or even metaphysical backgrounds of understanding of

science, however, rnay come in where a successful methodoll2g.y is looked for. Of

course, researchers are keen to act successfully in ithe same sense in which we aim

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4 JANICH

at success with actions in every-day life - and in the same sense in which philoso-

phers prefer success to failure. Therefore, success of methods in receptor research

should not be mistaken for success of methodology, i.e. knowledge on what it is

that renders scientific methods successful. What, then - my question now reads -

makes methods successfbl in reaching transsubjective and universal results - say,

in receptor research? Again, "success" is not a technical term belonging to or oc-

curring in any quantitative experimental theory in science.

2. FROM PHYSICS TO ANALYTICAL CHEMISTRY

As things are simpler in physics than in chemistry, and as chemistry applies

physical methods, I start out with the question: What renders measurement suc-

cessful in physics? Let me regard time measurement as a simple physical exam-

ple. "Time" is, for physicists, but what is measured by clocks. However, what is a

clock? Textbook answers usually explain the function of clocks by natural laws,

again - say, by the law of pendulum oscillations or of electronic quartz-stabilised

circuits. This is a "naturalistic" answer, because it suggests that clocks, as any

other measuring tools, are submitted to the same natural regularities as any object

or event in the universe, although nobody denies that clocks are technically pro-

duced by man. Textbooks treat them like natural objects, not like artificial ones -

therefore, this understanding is called "naturalistic."

However, this naturalistic understanding of measurement cannot be correct. As

everybody knows, clocks (like any other technical device used for research or in

every-day life) can be imperfect, disturbed, broken or whatsoever - which means

that they do not function as they are supposed to: they produce useless data. Use-

less measuring tools succumb, of course, to the so-called natural laws in the very

same way as well-functioning tools do. From this it follows that "natural laws," or

any other result of empirical science, cannot define or govern the distinction be-

tween disturbed and undisturbed measuring tools and consequently cannot tell

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correct from incorrect data. A clock that does not run at all does not contradict or

falsify any natural law. But the disturbed measurement misses the purposes of the

person performing the measurement (and of the person conistructing, building or

selling the tool). Any measurement in science produces valild results only relative

to the ends of the instrument's user - and therefore can meet its methodological

claim to transsubjectivity only relative to a set of those ends .which are made ex-

plicit in order to methlodologically control the success of research.

Now you may sense how uncomfortable my philosophical role has become:

While you are talking about substances and their effects am organisms, I am

forced to address you, your actions and their success. Still, let me put that delicate

task on the backbuirner for a while and first take a look at experiments which serve

as my second example.

Causes and ef ixts are said to be at work irre,spective of human control or at-

tention, i.e. in matters where there is no human observer. Entire evolutionary biol-

ogy, for instance, is held to be a field where causes and effects are at work, and

the human biologi,st only can hope to gain a glimpse of the story. Concerning cau-

sality, we are not restricted to David Hume's solution that it is only by being ac-

customed to certain sequences of states or events ithat we come to believe that they

are causally connected. Neither are we thrown back on the Kantian solution that

causality is a transcendental principle. The way out is shown by the methodologi-

cal role of experiments: Whatever people may say when they confess their belief

about nature, we produce effects by technical means through performing experi-

ments. I propose that the situation produced by the experimenter be baptised

"cause" and its running and final state, "effect." We human beings cause effects

by technical mean!;, by technical interventions into the situations found or at hand.

"Natural" events, however, which are not at all piroduced by man (such as certain

astronomical cases or in natural metabolism), causally can be described and ex-

plained by investing causal knowledge gained in experiments -. "as if'' nature were

a person performing our experiments. In philosophy, this understanding is called

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6 JANICH

the interventionist theory of causality. Any knowledge about causal connections

between events or states of affairs is accessible and validated only by means of

active intervening into '*natural" situations. This, by the way, is the basic idea also

of the Aristotelean distinction between nature and technics (or art): the artificial is

made, provoked or produced by man, the natural, however, carries the origin of its

change in itself. And very helpful for modern science: "by chancel' (kata symbe-

bekos) is (first), what might have been purposefully realized by a person, but was

only caused as a side effect to another purposeful action, and (second), the analo-

gous case in "natural" change.

Now, once again, I am asking the question as to what makes our experiments

successful in the sense of leading to universally valid empirical results? And,

again, naturalistic answers prevail in the current discussion: It is often said that

nature, the natural causal regularities make experiments possible. However a

closer look at the conditions of successful experiments shows a situation very

similar to the one we met earlier in the case of measurements: If one holds nature

responsible for the possibility of experiments, one is obliged to hold it responsible

for both successfbl and failing experiments. But "failure," again, can be charac-

terized only as the missing of human ends or purposes. Clearly, experience comes

in where the experimenter has to accept that some events cannot be effected even

if they seemed probable in the light of previous knowledge. Obviously, any ex-

perimental experience is relative; it is related to the ends the acting experimenter

pursues. The universality of experimental results is only based on the experi-

menter's skill to sufficiently reproduce the experimental starting situation - inde-

pendently of the observation that equal runnings of experiments happen repeat-

edly. In other words, the experimenter is like an engineer who constructs, builds

and runs a machine - and only if this job is done successfully, the client comes

and pays for the machine, e.g., in the form of empirical results. Methodologically

speaking, any scientist must set out his plans and technical purposes by planning

the function of his machinery.

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METHODOLOGY OF RECEPTOR RESEARCH

So-called "chance" discovery - even though this is said to be important in the

development of new Idrugs - can be a discovery only relative to available, clearly

defined and recognizable effects. Such discoveries "by chance" occur only to peo-

ple who already know which effects are to be reached or avoided.

These philosophical results, developed in so-c.alled "prototheories" of methodi-

cal philosophy, hold for all measurements and experiments, be they physical,

chemical or biological. Additional problems arise, however, if quantitative ex-

periments are carried out in analytical chemistry with respect of "very small" con-

centrations. The mathematical means to establish that the relation of two sub-

stances is, e.g., 1: 10'' with respect to volume or weight are very simple. But the

meaning of such a measure with respect to the technical re,alisation of the corre-

sponding measuring device and procedure is highly problematic.

I have suggested before that the success of measurement is not a matter of un-

derstanding natural laws but one of realizing human ends. Mathematically it is

very easy to postulate a certain level of data precision but, from a certain level

onward, it becomes more and more difficult - and sometimes impossible - to

technically realize this precision. To mention thlese probleims that confront ana-

lytical chemistry in its progression to ever incre,asing ratios shall launch the dis-

cussion of a remedy in common understanding: Ithe switch From the macroscopic

level of measuring tools to the micro-level of atoms and molecules. In fact, the

methodological probllems of measurement and experiment seem to disappear if

one talks about stiruclures of and reactions between single molecules - as if these

companions of the receptor researcher could be handled the same way as our

measuring tools, handled in the literal sense of taking and moving them with our

hands. However, all micro-objects are defined, recognised and managed only in

the context of certain theories and of their testing by measurement and experiment

by means of laboratory equipment which, in turn, fbnctions according to sophisti-

cated theories. In short, the molecular level is not at all the proverbial "Island of

the Blissful" where the problems outlined above have vanished. As to be valid,

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8 JANICH

any statement about reactions between molecules (be they imported through a

drug into an organism and acting on it) depends on the embedding theory, on the

context which, step by step, leads from the macro-objects to the hypothetical ob-

jects on the micro-level, and on all the theories needed to "interpret" readings of

high-tech devices.

3. PHILOSOPHICAL CONCLUSIONS FOR SUCCESSFUL RECEPTOR RE-

SEARCH?

It is carrying coals to Newcastle to mention that, of course, current receptor re-

search is done entirely on the micro-level of chemical models for molecules and

types of reaction. Using the phrase "model for" (instead of "model of') has a lot

to do with methodology: It marks the difference between a naturalistic idea of

mapping properties of natural entities and an instrumentalist idea of restricting

models to the role of being useful for certain effects.

Philosophically speaking, I would count an interest in making pictures of real-

ity among quasi-religious orientations. Counting this realistic interest in mapping

reality among belief systems rather than among successful methodologies has a

simple reason: It has no function whatsoever in telling true from false descriptions

or matching from inappropriate pictures. The quality of "pictures" can be judged

only in cases where the two domains of reality can be compared, the pictured and

the picturing domains - just as the quality of a photograph is compared, say, with

respect to colour, to the object the photo depicts. Such a comparison, however, is

impossible in the case of atoms, molecules, and the behaviour of single particles.

All we have got is "pictures" in the form of models and theories as opposed to

laboratory practice.

The instrumentalist idea, however, that models should be suited for evaluation

with respect to the use for certain demands dispenses with all metaphysical as-

pects or terms such as "reality," "existence," "nature," "mapping,"etc. "Truth,"

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"corroboration" or ''use'' of "models for," howewer, are just terms related to the

purposes of, say, receptor research to produce results useful for medical treatment

by drugs.

The instrumeritalist view, however, does no1 exempt the researcher from an-

other phi1osophic:al problem that is usually discussed under the heading of "re-

ductionism " Can, briefly speaking, phenomena of health care and human decease

be reduced to molecular models for the substances applied i o a human patient and

to models for the organism as a whole, its organs, cells or sutlstances produced by

the human body, with and without certain doses of drugs? Of course, the two par-

ties on the battle field stay for and against reduction (its possibility, use ect ) of

macro-phenomena to the micro-level

I am afraid that, again, this debate rests on a metaphysical rather than prag-

matic background, because it depends on a desc:riptivistic, or even realistic, bias:

Ektities on both Ilevels, thle micro-level of chemical models and the macro-level of

health phenomena, are considered somehow "given" - like natural objects.

Both ways, the reductionist "top-down way" leading from descriptions of the

patient's reaction on drugs to causal explanations of a receptor mechanism, and

the "bottom-up vvay" from descriptions of in-vitro reactions to phenomena de-

scribed in clinical tests, do not explain the criteria of success or lack of success of

the respective methods of' research at work The irealistic back,ground of both ways

obscures the fact that the entities on the top and at the bottolm of these explana-

tions are defined and produced in different contexts and, above all, for different

purposes They belong, as it were, to different "kits" the pieces of which are un-

doubtedly useful for the purpose of the particular kit but may be completely use-

less or of restrictedly usehllness when transfered into anotlher kit. Anyway, what

is called here "the kits" (for chemistry and medicine) are brought about by very

different traditions ol'hunlan practices.

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10 JANICH

In terms of human actions and their means-and-ends rationality, the "kits" be-

long to different practices which serve different master goals: Chemistry is ori-

ented towards a universal management of substances and their change whereas medicine deals with human beings, the state of their health and a whole bunch of

cultural and historical factors. My argument, however, is not based on an ontology

of matter and human beings but shall remain completely restricted to methodo-

logical aspects. I do not impose on you to share types of ontological or meta-

physical believes or axioms. I choose as a starting point what I assume to be your

own conviction about your scientific work in receptor research.

You may choose any example you like for a drug, its effects, its mechanism of

addressing certain targets in the organism, of drug designing or casual detection of

unexpected indication etc. As receptor research is supposed to be scientific control

of drugs and their effects, I quote from the result of my methodological reflection

on quantitative experiments: Any successfbl experiment which consists in the

repeatable, reproducible production of a drug and corresponding clinically tested

effects (and side effects) shows the structure of an if-then-judgement: If certain

chemical compounds are produced, dosed, given to persons with explicitly de-

scribed states of health and symptoms who may even be instructed the same way

(all fbrther precautions of clinical tests being granted), then certain effects can be

observed, be it in the case of an individual or in a statistic description of a group

of persons. (My point does not at all concern the aspect of statistical vs. nonstatis-

tical, say, deterministic experiments which can well be classified in terms of

physics.) My question, then, is: What makes experiments successful in the sense

that you gain empirical knowledge about causes and effects? To avoid the well-

known problems of validation of statistical propositions, let me confine myself to

a somewhat hypothetical situation where you explore the effects that a certain

drug has on an individual person - an example which is not irrelevant insofar as

statistical results on groups of persons must presuppose that there is at least some

description of the effect on the individual.

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My point is that the experiment on effects o f a drug depends on the autonomy

of a person to judge how he or she feels. Of course, there are important cases

avoiding diagnostica I communication between patient and medical doctor where

one is simply interested in certain parameters measurable without recourse to an-

swers to diagnostic questions. But the restriction of patients to a description of

internistic values, i.e. to measureable physiologiical parameters, is not solving but

begging the question as to which role those internistic parameters play for the

"Befindlichkeit" (self-described health, condition, mood) of the patient or the per-

son tested.

To be sure, I am not discussing moral problems here, only epistemic ones. I

presuppose that I am discussing the case of a well-informed test person who com-

pletely agrees to be submitted to a clinical test. Ehen if, say, a researcher performs

an experiment on hi!; own body, there remains tlhe same methodological problem:

The very idea of experiments as means to empirically establish causes and effects

is to purposefidly perform certain actions on subject matterls which themselves are

no actions, no intentions, no specific aspects of' those human activities of which

researching itself consists. Metaphorically speaking, a clash happens between two

worlds, one of human actions and one of natural laws - and these worlds are not

isolated areas ind,ependent of each other. Rather, they are imavoidably connected

in so far as only human actions lead to knowledge of natural laws. No scientist

can escape that clash by holding that what he does as a scientist itself is no more

than a very complex natural event based on highly complex forms of natural laws

according to which his body and his brain are working. If scientific knowledge of

receptor research is considered only a kind of eflfect of natural causes, it could not

be valid, true or, to avoid those dangerous philosophical words, successful.

In other words, claiming that receptor research produces results is assuming

that you would not call something "results of research" if lit were allowed just to

insert a few "NOS", a few negations into the linguistic representations of these

results. "Results" are claimed to be valid - and distinguishable fiom their nega-

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12 JANICH

tion, for instance. Results are products of rational acting. They are inextricably

bound up with reaching or realizing ends, purposes, and are therefore based on the

autonomy of the researcher to choose his questions, problems, and methods, and

to judge whether he or she succeeded or failed. The researcher is autonomous to

put forward ends. Pursuing ends is indispensable for any claim to scientific results

- quite apart fiom any moral considerations.

I do not deny the possibility of describing human beings and their behaviour or

state of health in terms of scientific theories. Also, I do not deny that those de-

scriptions are necessary and usekl for certains ends. Even descriptions of humans

phrased exclusively in the terms of physics (weight, temperature, volume and

other parameters) are possible and often make sense - say, for the constructor of

an aeroplane or even for the medical doctor. But receptor research fails to be the

fundamental science for pharmaceutical health care if it sticks to the scientific

restriction - because, then, it reaches only people "in so far" as they can be con-

fined to those parameters, to models for organisms, for machines incapable of

acting.

There is no way out in the sense of an objective scientific description of the test

persons' or patients' health state as an alternative to an appropriate medical diag-

nosis. If the medical doctor is not able to communicate his medical knowledge in

such a way that the patient can transform the doctor's questions or descriptions

into his or her own finding, then there is no diagnosis. Even in the ideal situation

that both doctor and patient agree (and report that they feel well understood by

each other), there still persists a principle difference between - logically speaking

- the propositions (Behauptungen) of medical descriptions and the patient's decla-

rations (Bekundungen). In terms of logic, the doctor's descriptions can be right or

wrong, true or false. The patient's declarations can not. They are authentic. The

patient can choose to lie or to be honest. He or she is able to purposefblly deceive

the doctor, and it may be that the doctor has good reasons for detecting the decep-

tion and for disbelieving patient's declarations. But there is no way whatsoever

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METHODOLOGY OF RE:CEPTOR RESEARCH 13

that could possibly overcome the gap between a. descriptioin .which, through meth-

odological means of science, can be subjected to control, and the declarations of

"inner" states a person authenticates.

Back to receptor research and quantitative experiments: It appears that only ig-

norance of the long-range methodical coherence of chemical knowledge about

drugs and the problem of judging the effects i n medical dliagnoses allows the as-

sumption that there are natural causes and effects in the u:se of drugs. But experi-

ments in the strong sense, as they can be performed in physics and chemistry,

seem impossible. Receptor research even suffers from more problems in this re-

spect than does, for example, psychology. In psychologic,al experiments, persons

even may act in accordance with the instructions of the experimenter, and they

may be submitted to an endeavour into their behaviour which then occurs to the

test person. But the distinction between actions and behaviour on the part oi'the

test persons and the actions of the experimenter is maintained.

4. OPEN PROBLEMS

To be sure. I use Aspirin if headache bothers me. And there is a wide range of

reliable knowledge ,about the causation of certain effects through drugs. 1 do not

doubt the cases of development of new drugs or occasional discoveries of unex-

pected indications I have read about in preparation of this paper. There are im-

pressive success stories in scientific receptor research.

But, still, there are problems open to a discussion of methods of receptor

research: The level of chemical concepts and models is not to be regarded as the

given natural anld fundamental level forming thte ever-lasting permanently reliable

basis of the business. Chly embedding pharmacological questions into the entire

field, including criteria for validity and empiricity on the siide of the experimenter,

and relating them to the declarations of the test persons, will promise results

instead of belief. Tiere is no molecular headache and no machine-type organism,

neither on the sirle of researcher nor on ha t of the patient.

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14 JANICH

Appreciation of both the autonomy of the scientist and the authenticity of the

test person is the motif of my philosophical warning against restricting methodol-

ogy to the means of physics, chemistry and biology.

REFERENCES

Janich, P. Protophysics of Time, Dordrecht, Boston, Lancaster 1985 (Boston Studies in the Philosophy of Science, Vol. 30).

Janich, P. Grenzen der Naturwissenschaft. Erkennen als Handeln, Munchen 1992.

Janich, P. Konstruktivismus und Naturerkenntnis. Auf dem Weg zum Kulturalis- mus, Frankfbrt 1996.

Janich, P. Das MaB der Dinge. Protophysik von Raum, Zeit und Materie, Frank- fbrt 1997.

Janich, P.; Psarros, N. (eds.) Die Sprache der Chemie, Wurzburg 1996.

Janich, P.; Psarros, N. (eds.) The Autonomy of Chemistry, Wurzburg 1998.

Janich, P. Der wahre MeRwert, in Janich, P.; Psarros, N.; Thieme, P. C. (eds.) Chemische Grenzwerte, Heidelberg 1998.

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methodology of receptor research–-a philosophical perspective

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