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How is an optimum environment defined?
ENVIHONAIENTAL
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How
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Is an Optimum VAN
Environment R.
Defined?
POTTER
Any discussion of the future in the context of physiologic hazards in man’s environment will inevitably have to be broad enough, it seems to me, to consider leisure as a possible health hazard, and at the other extreme, information overload (15) or future shock (25) as hazards which society will have to consider. A full-page advertisement that appeared in 1958 illustrates what I mean by the hazards of leisure. It is entitled, “Power companies build for your future electric living,” and subtitled, “Electricity may do your yard work.” I think it was this that first aroused my interest in thr physiologic hazards of leisure, a commodit!that you and I have not suffered from particularly, if we define “leisure” as time that provides relief from responsibilities. The major message that I wish to deliver is that an optimum enviromnent is OIJ~ that delivers what I would like to call an “optimum stress;” but I have come to realize that the word “stress” produces stress in many physiologists, and therefore I will not again refer to “optimum stress.” Instead, I will follow the definitive “Perspectives of Adaptation” presented by Prosser and by Adolph in Sect. 4 of the Handbook of Physiology: “Adaptation to the Environment” (7). Prosser defines as an environmental circmnstance which induces adaptations, and a “stressor” what I shall be talking about is the concept of deliberately promoting an optimum stressor level (Fig. 1). Indeed, I wish to promote the idea of a merger bctweerl physiology, genetics, and molecular biology on the one hand, with anthropology, psychology, and philosophy on the other. Our goal for the future should bc to adapt our evolving culture to the fact that adaptation is a normal feature of life and that we need to know much more about the process than WC do now. Rut it is not enough to consider adaptation as an esoteric topic dealt with by physiologists. It is a topic that is fundamental to all the specialties mentioned above, and moreover it is a topic that needs to be incorporated into our educational system and into our cultural milieu. CULTURE
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Prof. Clifford Gecrtz (10) of the Anthropology Department of the Universie of Chicago has contributed an excellent chapter to the book entitled “New Views on the Nature of Man,” edited by John R. Platt. It is entitled “The Impact of the Concept of Culture on the Concept of Man,” and its thesis is that (1) culture is a set of control mechanisms for controlling or programming human behavior, and (2) man is precisely the animal most desperately dependent upon such extragenetic, outside-the-skin control mechanism for ordering his behavior. He says: “One of the most significant facts about us may finally bc that we all begin with 476
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the natural equipment to lead a thousand lives but end in the end having lived only one.” The question is whether we, as physiologists, molecular biologists, and genoticists, are prepared to tell society how to move toward a cultural tradition that can help each individual find an optimum stressor level and steer successfully between the Charybdis of too much leisure and the Scylla of information overload. The question I am raising is whether our 2Oth-centurv culture is providing the proper kind of “extragenetic, outside-the-skin control mechanisms” that the human animal is so “desperately dependent upon.” Do prospective parents know that every individual is genetically different from every other individual, that only those genetic capabilities that are possessed can ever be expressed, and that every genetic capabiIity can be fully expressed only in the presence of an optimum stressor level, applied at the right time-and then not continuously? Do we, as scientists and humanists, have any idea \vhat to tell these hypothetical prospective parents if they ask us for practical answers to these questions? There are historical precedents for these questions. In 1890, we find William James saying, “Keep the faculty of effort alive in you by a little gratuitous exercise cvcry day, That is, be systematically ascetic or heroic in little unnecessar)’ points, do every day or t\tTo something for no other reason than that you would rather not do it; so that when the hour of dirt riced draws nigh, it may find you not unnerved and untrained to stand the test.” (2, p. 715). And in 1919, we hear the 2Oth-century cynicism replyin g, in the words of Somerset hlaugham: “I forget who it was that recommended men for their soul’s good to do each da) two things they disliked: . . . it is a precept that I have followed scrupulously; for every day I have got up and I have gone to bed” (2, p. 875). In the same vein, I belicbve it was Robert Maynard Hutchins who spoke for academicians in gcnernl, when hc said: ‘Whenever I fc,el the urge to exercise coming on, I lip dowwl lentil the fcseling got’s away.”
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ADAPTATION
What Maugham and Hutchins do not seam to realize is that adaptation is not something that is just a physiologic response to some abnormal or novel situation, some hypoxic condition at a mountain top where average people never go. The living animal is adapting during every moment of life. Adaptation is not merely a mechanism “for the adjustment of organisms to the action of unfavorable (sic) factors in the environment” (Barbashova in Ref. 7, p. 49). Adaptations are part of the everyday life mechanism, and they arc noted as adaptations by the physiologist only when they differ from “ordinary responses” sufficiently to be “increments or decrements in the ordinary response” that “require time to develop” (Adolph in Ref. 7, p. 34). The word “adaptation” is frequently misunderstood because it has come to have two meanings. Some people think of evolutionary adaptation, which involves natural selection of mutants that fit a particular environment. This kind of adaptation occurs in populations over a large number of generations. The other kind of adaptation is physiologic adaptation, which applies to the individual members of a population. In the present discussion, I am concerned only with physiologic adaptation and follow Prosser (in Ref. 7, p. ll), who defines it as “any property of an organism which favors survival in a specific environment,” although Prosser adds the words that narrow the meaning when he says “particularly a stressful one.” Prosser states that “an adaptation permits maintenance of physiological activitv and survival when the environment alters with respect to one or more parameters.” As a biochemist and molecular biologist, I have the thesis that, if we esaminc the organism at the molecular level, the environment is changing on a minute-tominute basis and the “ordinary responses” at the enzyme or nucleic acid level constantly are undergoing adaptive increments or decrements in enzyme activity or amount in a complex feedback system that is designed to maintain certain features of the internal milieu within limits that will promote survival. \1’e can either cultivate this adaptive capacity or we can let it atrophy. The key point is that, “if an organism can adapt, by the same token it will ‘deadapt.’ When we carry a heavy load, our ability to carry loads increases, but the corollary is that, when we have no loads to carry, our ability to carry loads decreases. Just how big a load should we be able to carry, and what kind of loadcarrying program will be best for each individual?” In this contest, a load can. of course, be physical, intellectual, or emotional (7). The idea that an effort should be made to dcfinc “health” as more than the absence of disease was emphasized by Rene Dubos in “Man Adapting“ (8), when he said (p. 391) : “A medical philosophy which assumes a priori that the ideal is to make human life absolutely safe and effortless may paradoxically create a state of affairs in which mankind will progressively lose the ability to meet the real experience of life and to overcome the stresses and risks that this expcricnce inevitably entails.” I think that Dubos would be willing to include individual men, as well as mankind in the above statement. Elsewhere, Dubos comments (pp. 362-363) that “in the United States, the emphasis is on controlling disease rather than on living more wisely.” “The public
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health services themselves, despite their misleading name, are concerned less m,ith hmlth than with the control of the specific diseases considered important in the communities they serve. They do little to define, rrcognizc, or measure the healthy state, let alone the hypothetical condition designated ‘positive health.’ ” I sllspect that most of 11s feel that the name of the, public health service is not 50 misleading, and that the evolution of concepts will naturally move toward the, conwpt of positive health as infectious diseases and malnutrition are conyuerd and degewrntive diseaws continue to increase. In this went, \vc’ must not only eliminate dangerous chemicals from our wvironmcnt ;IS m11ch as possihk. lxlt also karn Irow to liw inure wisely. ENZYhlE
AD.~1’TATIOK
TO
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I’Il!.siol()gic adaptation at the enzyme level is a subjwt that is close to the cow of this yntirc conference, as nell as to the core of this session. Should WV aim for an c~nvironm~nt that is completely frw from toxic hazards. ,p \Vrl can answer that question very quickly \,y rwognizing that such an achievement is not only improlxll~le, it is impossil,lc! Then what is the effect of a low dew of a to\-ic s111)stance, a close that does not product death or obvious pathology in a time that is short csnough to suggest an obvious ~ausc,-rind-cff~ct relationship? The answer is that. for many toxic substances at dosages that prodncc no rapid overt s)mptoms itI the illtact animal, there is a rapid increaw in activity of a variety of cnzynws within 2-C hours, which appexs to 1~ a result of synthesis of new enzyme, first indicated by the experiments of Comwy, Alillrr. and Ilillcr ( 6). Numerous esatnplc3 xe now available (9). So the nest question is whrther the animal is any worse off or any hettcxr off for having an increased level of certain wzymes in li\w (6, 9), or intestine (26). In the study of ~Vattenberg and Lcong (26), it was shown that 6 mg of phenothinzine increased the activity of benzpyrene hydrosylasc in rat liver from 13 to -311 units/mg, and in intestinal mucosa from 16 to 55 ntlits/nq Chlorpromazine, a phcnothiazinc derivative that is a well-known tranquilizer, had almost identical wsnlts for IivcBr, and increased the value in intestine to 114 units. At a dew of onl! 1 mg per rat given 48 hours prior to exposure to 30 mg of dimethylbenzanthraccwc, phcnothiazine protected ninct of ten rats against adrenal necrosis. This study has as its over-all objective the determination of “optimum methods for achievin,q protection from the effects of chemical carcinogens in tqc~rimental animals and, possibly, c~ventually in man.” Further stI&es on the protective effects of smalI(ar daily dews, such as arc’ used over long periods of time as tranquilizers, will be of ititercst. Xleanwhilc. a clinical application of the induction of enzyme activity in a human 11:~sc~)me to oltr attention. Gaffe, Levy, and Matsnznnra (27) have reported the rise of phenobarbital ( 15 mg daily) to enhance glucitronide conjugation capacity in a congenitally hyperbiliruhinemic infant. The authors claim that theirs is tll(‘ first demonstration of the apparent induction of the glucuronide conjugating systcam by phenohnrhitnl in man, and the first therapeutic application of enzyme induction. There is no reason to doul)t that phenob;lrbital did callse increased
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synthesis of the enzyme, since enzyme induction by phenobarbital is well known (9). At the present moment, it appears impossible to answer the question as to whether amounts of toxic substances that will induce certain enzymes are intrinsically helpful or harmful. Of course, we have been made aware during this conference that even noninducing doses of some compounds may be capable of producing irreversible damage to DNA, and hence capable of acting as carcinogens. Recently, Siperstein (23) has reported deletion of the negative feedback system for cholcstrrol biosynthesis in liver hy &toxin at a level of 10 parts per billion in the diet of trout and in the liver of rats after only 2 days of a diet containing &toxin at a level of 10 ppn~. In this case, it is not yet established whether the change is irreversiblcs or reversible, but it is clear that the phenomenon could give the appearance of enzyme activation or induction. It should be noted that trout receiving aflatosin at 10 parts per billion from birth develop hepatomas to the extent of SO,%lOO%.Thus, we are in the position of having to make considerable efforts to find any virtue in the ingestion of any foreign compound if it can be avoided, unless there is clear indication that the benefits outweigh the possible or known risk. Further discussionson animals in toxic environments are available in the Handbook rcferrrd to earlier ( 7). No beneficial effects seem to be mentioned in the section on polluted air (by E. H. Morrow, on pp. 795-808 in Ref. 7) or in the section on man and industrial chemicals (by II. W. Gerarde, on pp. 829-834 in Ref. 7). although in both chapters there are snggcstions of adaptation in various instances. Tahlcs showing Iev~ls to which workers can be exposed day after day without adverse effect do not appear to havesbeen based on criteria other than the ability to work efficiently and the absc,ncc of claims of pathology. Thus, at the moment, WC can suggest that, although there is evidence that humans can adapt to some extent to a variety of toxic chemicals there is still no basis for assuming that there are no disadvantages to the adapting individual, and no basis for complacency about the increasing levels of ambient toxicity. Meanwhile, let us examine the type of adaptive changes that might be considered in examining the lift of a completely healthy man or animal.
Changes in enzyme amount resulting from changing rates of synthesis and degradation of enzyme protein occur not only in physiologic adaptation to toxic hazards in the environment. Such changes can also be observed in the course of each 2Chour cycle, as a result of feeding habits and as a result of changes in dietary composition. In 1961, Ono and I (21) reported enzyme changes in liver rats fed at1 Iibitzrln under controlled lighting conditions, in which food was eaten in the dark hours. The liver glycogen decreased in the light hours and increased in the dark hours, and glucose 6-phosphate dehydrogenasc showed mild oscillations in opposite phase. More recently, WV (20) studied a number of enzymes in livers and hepatomas of rats fed diets containing O%,1%, 30%, 6070,and 9OZ protein only during 12 hours of darkness with no food during 12 hours of light in each 24. We noted oscillations in liver glycogen with both peak and minimum levels that were inversely related to protein and directly proportional to carbo-
]lydrate in the diet, In this study, there was a marked oscillation in tyrosine transaminase in rat liver, with maximum values proportional to protein intake at midnight, 6 hours after the onset of feeding, with declines to resting levels thereafter, even while the glycogcn values were still risin,. 0 Recently, this phenomenon has ~~ee~~studied in more detaiI by or. Minro Watanabe in our laboratory, and thr detailed data confirm the discontinuity between liver glycogcn and liver tyrosinc transaminasc, and in addition show that the plasma corticostcrone decrcnses while lthc rise in tyrosine tmnsaminase occlux The induction of this enzyme by injc>ctions of adrenal steroids was well kno\vn, bllt the rapid increases during food ingrastion have not been previously reported, possibly bccausc~ in the rat the peak i< at midnight and tends to reach daytime levc~ls by 6 AM ( B-:31 ). These examples show that metabolic transitions occur throughout the daily rolrtinc of sleep and waking, eating and not eating, and that these transitions are a<,companicd by marked changes in several enzyme activities. liKZY\IE
ADAPTATIOX
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In the 1961 study (21), we also carried out the procedure of fasting rats for :i days and then refeeding various diets, as has been carried out by Tepperman ;u~l l’c~pprrman (24). In this situation, the glucose 6-phosphate dehydrogenase aotivity in the liver responds by rising to unusually high levels, compared with t11c daily cycle owing to ;t changed feedback rclntionship, and greatly overshoots tl~cbnormal range. The enzyme level rises to about 20 times the usual l~vcl during al,out 72 hours, and then slowlv returns to normal levels over a period of about IO days. It is clear that thck opt&m stressor IcveI for the s>Tnthesis of this enzyme i, not attained in the ad lihitrrnz feeding regimen. In a recent symposium on feeding patterns and their consequences, Mayer (14 ) c~mphasizcdthat the pattern of metabolism may be influenced by the distribution (lf the food intake iu one, two, three or a number of mc&. Tcpperman and Tel,pcrman (24) and others have carried out many experiments on rats that havci huw fasted for 21 or 22 hours in each 24, and correspondingly f(xd for only 2 OI 3 hours per day. Suc11animals slio~vecl a striking incrcnsc in fat production from l)oth acetate and glucose, and they stored liver glycogcn to higher kvels than :~rlirnnls fed crtl libittlm. hIorc~ovcr, the fat pads shouwl an increased level of fxt deposition. From these studies, there has been ;I tcndcw!y to conclrlde that frequent snacks are better than one meal a day for the human, as well as the rat w IIW~IW, and there is a widespread lwlicf that frequ(Bnt small meals reprcserlt ;I regimen that can bc%rcwxnmendcd as 011~f(%ltllrc* of ;m ()ptimllJ~l tm~~ironment. It is III!. ~UI~>OSC~ hew to question this point of \,iex\. and in fact to t&e th(, oplx)sitcl position. Incidentally, it is reported that the custom of three fIllI meals ;I day ~KLS been cstahlished only since 1890: that in hnglo-Sas(m tradition there \vtlre chill\t\VO IllCtllS il da\,. l)rc~akf%t ant1 dinner; ;wd in tlN3 16th ccnturv dillner \s-;ls clt&1 at 11 AA\I (4). \t’e start from the assrlmption that the animal or 1~1lmanis not eqlGpp(ad },) instinct to do what is best for him in circnmstancc,s other than those lln&>r xvhich his species evolved to its present state. Particularly for rats in small c:l
provision of food on an ad Zil~itrm basis has no instinctive support to provide information on “living more wisely,” a goal emphasized by Dubos ( 8), as mclntioned earlier. True. our society has come to value the slim figure. achieved by a low-calorie diet, but this has been coupled with the idea of frqucmt snacks and never, to my knowledge, with the idea of one‘ good meal once a day. Secondly, WV start from the assumption that fasting is normal, bcncficinl, and not unnatural. This vics\v is prol)ably contrary to popular and medical opinion, both of which arc probablv influenced by the knowledge th;~t stomach ulcers arc‘ given palliative treatment by frcqiicnt small meals of milk. My assumption is that physiologic functions are meant to be used, and that atrophy of disuse is not limited to skeletal muscle. It is also assumed that brain function, both intellectual and characterwise, is influenced by bodily function. Animals possess metabolic machinery for storing fncl far in excess of what CRY bc stored in the form of liver glycogen. According to Cahill (5), the liver glycogen in man is able to maintain blood glucose for only about 14 hours, and, of course, muscle glycogen is not directly available as a source of glucose. Thus, in the absence of food intake, the human must initiate the process of gluconcogenesis from protein within 12 hours, and the evidence suggests that in rodents the situation is not greatly different. Cahill shows the relative sizes of the various glucose r(Ascrvcls in comparison with the total potential reserves, and the total glucose pool is only about 290 molts, or a little less than 1%’ of the total of about 30,000 moles, based on the fact that men can snrvivc a total fast of 60-90 days. It has commonly been assumed from studies on laboratory rats that fasting lcads to a rather prompt adrenal cortical stimulation, which in turn leads to increased gluconeogenesis from protein (1, 22). However, in a recent study wo men Lverc fasted 4 days and three tncn 6 days, lvith by Kollar et (11 ( 13), t ITowever, an ;\s yet iinino evidence of adrenal activation in any of them. normally absent from the iirinc, dcntified “stress rcsponsivc indolc substance.” was maintained at high levels in all six subjects after the second day of starvation. What lencls intcrvst to this observation is thr finding by Rosen and Nichol (22) that two tryl>tophan metabolitcs, 5-OH-tryptoplian and scrotonill. arc: effective inducers of tyrosine transaminasc in rat liver. It appears that the stress of fasting may lead to adaptive changes mc&atcd both by indole-conand that the two classes of inducers are taining substances and by cortisone mcrelv separate stages in a seq~nce of adaptivcy changers, which vary in cliff erent species. The interest in my laboratory has not betm in the effect of fasting per SC; but rather in the effect of prolonging the intervals between food intake as an approach to an optimum stressor level. The typical laboratory rat lives at a constant temperature, with food constantly available, and with little opportunity or incentive to exercise. In rats that have been trained to eat their daily allotselection, ment of food in 2 or 3 hours the result is obesity (24 ) Under natural rats have been selected to desire food every night and to sleep in the daylight hours, but they have also been selected for the ability to survive if they ~10not ohtain food every night. We decided to explore the consequences of training
rats to un&.qo cycles of feeding and fastin, o \\rith durations of 43 hours, rather than 2-l hours. From the experience \vith url libitrtrll feeding regimens, with food limited to 12 l~ol~rs in c:tcll “4, and \vitll f00c1 u~Z Zibitrrt~~ after ;I 3-day fast, \vc \Vcllt (~1) to &V&P r~@mc~t~s that have attem@d to attain the hypth~tie~~l optimw~ that might lx* optitnnm for strcwor levels correspondin, (r to :,I, environmmt Starting \vith rats that \vcrc t’cd 12 h011rs the grchatcst nmnbcr of parameters. ill (,a~11 23, \xThicll is not lllucll different from crtl fibitrrtn fecsding, \I;(* adoptcAd tljc simple cspcdient of feeding every other night, instead of every night. Thus these :~nimals ;trc fly1 12 lmurs in ever!? 48, and arc fasting for 36 honrs. \IVcBrefer fusting-adapted rats” ( 19). Some espcriments ha\e \WC~ to them as “36-hour don61 lvith a &-hour cycle in \vhich food is available for onlv S hours in 35. ,uld thcx, are called “N-hour fasting adaptc’d rats” (S-31). . It was soon noticed that the fastilifi-adapted rats are hyperactive. \\‘e thercforc installed activitv cages and rccordcd milcagc for each animal. It can be reportc~tl that M-hour fa&ing-adapted rats will survive in small cages of the usnal type, but if allowed access to activity cages they nil1 all run themselves to death in S-10 days, ilhlstrating the breakdown of instinctive “wisdom.” In contrast. the 36-hour fasting-adapted rats arc able to snrvivt and adapt to the rcgimtsn with or without exercise. The :36-honr fastinS-ndaptcd animals run an avcragc of 15 km dnring the lZhours of darkness \\hcn no food is available ( 19). and on the following day. still hungry. they sleep much of the time and run much INS. The cltl liDitur,t controls csercisc and cat at night and s1cc.p most of the day, with almost no day activity rc~corclcd. \\‘cs lla\~~ studied ;I number of cnzymcs and have, also studied nuclc+ acid mc~taholism, but data for only one enzyme Lvill bc mentioned hcrc. CClucose 6. phosphate dehydrogcnase shon~s great fluctuations and avcragcs much highcsi vahles than the ((~7 libif~n~ controls (19). \T’e feel that thc,se data adequately dcxmonstrate the fact that adaptive tlnzymc changes arc part of nor~nal physiology and that tlicsc changes can \W exaggerated by increasing the time lWwcc~11 nwals. ‘l‘llc~ animals on this regimen have not l)crbn studied for longevity, but it is csl(Lar that obesity dots not result dnrillg 30 days, and that the growth cur\.(’ during this period does not develop a steeper slope than the control cllrvc. :LS ill the case of rats fed 2 hours pc’r dav (12). The gro\vth rate is qrlite similal to that of malt rats stnclied by Rcrg (3) at the lc\.els of :3X and 46% restrictioll of food intake, and falls michwy lx~t\vcw~ the rates for his groups. I3erfi’s stlldies dernonstratcd incrcuscd longevity and general health without evidcncc of immaturity. In the ?&hour fasted rats, it is as yet lmknown \%,hether the food intake \~ould increase to the lc,vel of the crd lil~jtllrn feeding in time, or whcthcr in the long run restricted feeding on a once-per-day basis wollld be preferable. It can be suggested, however, that the usual restricted food intake always results in fasting periods of 22-23 hours, and that fasting may lx) partly responsiblr for the beneficial effect of the caloric restriction. At this timr, we can only specnlatc that the fasting-adapted animals derive
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benefit from the active use of their abilities to produce large shifts in intracellular enzyme patterns, and leave it to the future to determine whether mental powers, motivations, and character would be helped or hindered in humans on similar regimens.
Turning now to the actual task of defining an optimum environment, I think I have tried to make the point that the culture in which \ve live is an important part of our environment. What WC recommend as physiologists may become a part of our culture or it may be ignored, depending on the force of our logic and the force of counterpressures. A cogent example is the relationship between cigarettes and lung cancer? where the experts are pretty much agreed but the counterforces still prevail. In the case of defining an optimum environment, I think that it is essential to go beyond a mere consideration of toxic hazards and to recommend positive steps that could raise men above mere absence of disease to the concept of “positive health” mentioned by Dubos (8). My basic concern is that physiologists should be in the forefront of describing and analyzing the mechanisms of physiologic adaptation, not only in physiologic terms, but in behavioristic and molecular terms-not only in the academic sense, but also with the aim of guiding mankind during the next 20 or 30 years of rapid change to wc know not what. If affluence is not conducive to an optimum environment, then what can we say to those who seek it? What are the minimum requirements for a world that physiologists could recommend and work toward? I have made a list of seven points, not as a physiologist but as a scientist and a humanist. I present them as the whole package, recognizing that, as I am a physiologist, my main concern is the fourth point. which has to do with physiologic adaptation. However, I might emphasize that, until we know more about the nature of adaptation and the molecular targets of toxic hazards, we can say very little about the problems of threshold and potentiation, which are the crux of the pollution problem. My seven points are as follows: 1. I would begin with basic needs that can bc satisfied by effort. Thcsc include food, shelter, clothing, space, privacy, leisure, and education, both moral and intellectual. (Regarding the ethical basis of science, see Glass (11). 2. I would insist on freedom from toxic chemicals, unnecessary trauma (primarily war and traffic injuries), and preventable cliseasc. 3. I would demand a culture that had a rcsspcct for sound ecologic principles with a long-range point of view. The aim must be to live with nature as in a about th(, ability of future science balanced aquarium, with no assumptions to rescue a sick planet. 4. The point that is the most personal with me, as it is based on my research experience over many years, is that the culture should prepare us for and expect of each individual adaptive responses, continually from birth to death, as a result of systematic challenges by physical and mental tasks which come at appropriate times, and are within individual capabilities, which are known to
increase rapidly at certain periods in life and decline later. This proposition is based on molecular genetics, which shows that our genetic capacity does not automatically express its&, and that each capability is called forth maximally only in response to an optimum stressor level. ,5. The nest point calls for individual happiness that involves oscillation betlveen satisfaction and dissatisfaction, with a sustained sense of identity, &spite
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a rapidly changing world show ~13in our private information centers. 6. The nc,st point calls for productivity that involves commitment to other members of society, directI\, to our family, our church, our community, or indirectly to mankind. 7. Finally, each of ~7s can contribl&b to the further cvotution of our clrltnrc, to our present society. and to our own satisfaction b!* a continual war& for beauty and order that does not drny that role of individuality and disorder (16, 17). 11~connection \vith the subject of adaptive responses, which is my main concern under my assigned topic of how to define an optimum environment, I feel it is \vithin the scope of erlvironmcntal physiolog, (0 ) to postulate that individual organisms shoal a w,idc variation in their tc&enc)- to seek out such challenges unaided, and that most individuals in fact arc equipped by instinct and natural selection to satisfy only their basic physiologic nerds by the easiest possible route and no more; (b ) to inquire what counwl to give a society that is basically ui~informed as to the nature of mnn as nrll as to the goals. attitudes, and pcrsonnl values which should be inculcated into preschool and in-school individuals in order to build a free society worth!; of mankind; and (c ) to inquire whether individuals are in gcncral unwilling to challenge systematically their own adaptive capabilities and whether society should attempt to inf!fucncc the attitude of the swung in favor of systematic cscrcisr, periodic fasting, and continual development of new mental and motor skills, and, if so, how these adaptive challcwges can be initiated 1~17so&t!, but maintained h! free individuals, perhaps reinforced by somekind of voluntary grouping. The first step in any program that might hopefully assist in the evolution of our culture toward better concepts of positive health is to secure more knowledge. I wish to advocate that the study of the individualistic aspects, as well as the principles, of physiologic adaptation is an especially important sector of environmental phvsiology and that much more research \vbich cornbines both organismic and molecular biology should be our first objective. Such studies should in particular be cognizant of the biologic rhythms stressed b! Astthoff and the individual variations stressedby Sxgcnt at these sessions.
1. ASHMORE,
J., W~GLE.
ct7J/me BP,& 2. BAI&ETT, J. Massachusetts 3. BERG, R. N. to size, health
S. H.,
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TTFTE,
T.
( 196-I).
Studies On gluconcogenesis.
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2, 101-111. Qllotations.” 18th and Centennial Edition. LittIc. Brown. Boston, ( 1955). ( 1960). Nutrition and longrvity in the rat. I. I:ood intake in elation and fertility. J. Ntrfr. 71. %2-%-t.
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4. BRASCH, R. “How Did It Begin?” hlcKay (1966). ( 1964). Some observations on hypoglycemia in man, A&an. Enqme ij. CAHILL, G. F;., JH. Reg. 2, 137-148. 6. CONNEY, A. H., GRILLER, E. C., AND ~,IILLER, J. A. (1956). The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res. 16, 450459. 7. DILL, D. B. “IIandhook of Physiology.” Sect. 4. Am. Physiol. Sot. Williams & Wilkins. Baltimore, ,\laryIand ( 1963 ). 8. Du~~os, R. “hIan Adapting.” Yale Univ. Press, New Haven, Connecticut ( 1965). 9. ERNSTER. I,., ANI) OHRENIUS, S. (1965). Slll,stlate-inducec synthesis of the hydroxylating enzyme system of rat liver microsomes. Fcderatim Proc. 24, 1190-l 199. 10. (ZEEKTZ, C. The impact of the concept of cnlture on the concept of man. In “New Views on the Nature of Man” (John R. Platt, ed. ), IT mv. of Chicago Press, Chicago, Illinois (1965). 11. CLASS, B. (1965). The ethics of science. Sciwtcc 150, 1254-1261. 12. HOLLIFIELI), C., A>L) PARSON. M’. (1962). hletabolic adaptations to a “stuff and starve” feeding program. II. Obesity and the persistence of adaptive changes in adipose tissue and li\,cr occiirring in rats limitrcl to a short daily feeding period. J. Clin. Itwest. 41 250-253. 13. K<~LLAR, E. J., SLXIXR, (:. H., PALMER , J. O., DOCTEII, R. F., AXD ;L~ANDEL, A. J. ( 1963). hleasurcment of stress in fasting man. Aroll. Car. P.s!/chiat. 11, 113-125. Introductory rrniarks. Symposium on Feeding Patterns and their 13. &xxn, J. (1966). Biochemical Consequences. Fetlvratioll Proc. 23, rj9. 15. ~IILLER, J. G. Psychological aspects of commnnication overloads, pp. 201-204. Intern, Psych. Clinics: Commnnication in Clinical Practice (R. W. Waggoner and D. J. Carek, eds. ). Little, Brown, Boston Massachnsctts ( 1964). Other reports by hliller include: Adjusting to Overloads of Information, pp. 87-100. In “Disorders of Commnnication.” NLII: Rrsearch Pnhlications, Assoc. Res. in Nervous & Mental Disease, 1964; and The individual as an information processing system. pp. l-28, 111 “Information Storage and Neural Control” ( W. S. Fields and \V. Abbott, eds. ). Thomas, Springfield, Illinois ( 1963). 16. NEUTRA, R. S. “Survival Through Design.” Oxford IJniv. Press, New York ( 1954). 17. POTTER, V. R. (1964). Society and science. S&we 146, 1018. 18. POTTEH, V. R., AND AUEH~A~H, V. H. ( 1959). Adaptive enzymes and feedback mechanisms. Lob. Innest. 8, 395-509. 19. POTTER, V. R., &BERT, R. A., AND Prror, II. C. (19%). Enzyme levels in rats adapted to 36-how fasting. Adran. E~yme Rvg. 4, 247-265. 20. POTTER, 17. R., &BERT, R. A., PITOT, H. C., PERAINO, C., LAMAR, C., JH., LESHEH, S., Systematic oscillations in metabolic activity in rat liver AND MORRIS, H. P. (1966). and in hepatomas. I. hlorris hepatoma 7793. Cancer Z&P. 26, 1547-1560. 21. POTTER, \'. R., AND 0x0. T. ( 1961). Enzyme patterns in rat liver and Morris hepatoma 512:3 tliirinp mrtaholic transitions. C&Z Slrrirl~ Harbor Symp. Qrrmt. Bid. 26, 33.5362. 22. ROSEN, F., AKD NICHOL, C. A. (1964). Studies on the nature and specificity of the induction of several adaptive enzymes responsive to cortisol. A&an. Enzyme Reg. 2, 115-135. 23. SIFERSTEIS, hf. D. ( 1966 ). Deletion of the cholesterol negative feedback system in precancerous li\er. Abst. J. Clin. Invest. 45, 107.3. 24. TEPPERMAN, H. hl., AND TEPPERXU, J. ( 1964). Adaptive hyperlipogenesis, Federation Proc. 23, 70-75. 25. TOFFLER, A. ( 1965). The future as a way of life. Horizon 7, No. 3, 108-115. 26. WATTEP\‘BER~, I,. W., AND LEOK, J. L. (1965). Effects of phenothiazines on protective systems against polycyclic hydrocarbons. Cancer Res. 25, 365-370. 27. YAFFE, S. J,, LEVY. C:., hlAmuzAwA, T., AND BALIAH, T. ( 1966). Enhancement of glucuronide-conjugating capacity in a hyperbilinemic infant due to apparent enzyme induction hy phenobarbital. izTcto Eng. J. Med. 275, 1461-1466.
DEFINING
AN
ADDITIONAL The
Ol’TIhIUM
ENVIRONMEKT
187
REFERENCES
following references were recei\-rd after the manuscript was prepared: 28. BAIUL, E. F., AND POTTER, V. R. (1968). Systematic oscillations of amino acid transport in liver from rats adapted to controlled feeding schedules. j. Nut?. 95, 228-237. (1968). Systematic 29. POTTER, V. R., BARIL, E. F.? WATANAHE, M., AND WHITTLE, E. D. oscillations in liver from rats adapted to controlled feeding schedules. Federation PTOC. 27, 1238-1245. 30. WATANABE, M., POTTER. V. R., AND PITOT, H. C. ( 1968). Systematic oscillations in tyrosine transaminase and other metabolic functions in liver of normal and adrenalrctomized rats on controlled feeding schedules. J. Nutr. 95, 207-227. ( 1968). Systematic oscillations in the metabolism .31. WHITTLE, E. D., AND POTTER, V. R. of erotic acid in thr rat adapted to a rontrolled feeding schedllle. ]. Nutr. 95, 238-246.
I
How
2, 476487
( 1969)
Is an Optimum VAN
Environment R.
Defined?
POTTER
Any discussion of the future in the context of physiologic hazards in man’s environment will inevitably have to be broad enough, it seems to me, to consider leisure as a possible health hazard, and at the other extreme, information overload (15) or future shock (25) as hazards which society will have to consider. A full-page advertisement that appeared in 1958 illustrates what I mean by the hazards of leisure. It is entitled, “Power companies build for your future electric living,” and subtitled, “Electricity may do your yard work.” I think it was this that first aroused my interest in thr physiologic hazards of leisure, a commodit!that you and I have not suffered from particularly, if we define “leisure” as time that provides relief from responsibilities. The major message that I wish to deliver is that an optimum enviromnent is OIJ~ that delivers what I would like to call an “optimum stress;” but I have come to realize that the word “stress” produces stress in many physiologists, and therefore I will not again refer to “optimum stress.” Instead, I will follow the definitive “Perspectives of Adaptation” presented by Prosser and by Adolph in Sect. 4 of the Handbook of Physiology: “Adaptation to the Environment” (7). Prosser defines as an environmental circmnstance which induces adaptations, and a “stressor” what I shall be talking about is the concept of deliberately promoting an optimum stressor level (Fig. 1). Indeed, I wish to promote the idea of a merger bctweerl physiology, genetics, and molecular biology on the one hand, with anthropology, psychology, and philosophy on the other. Our goal for the future should bc to adapt our evolving culture to the fact that adaptation is a normal feature of life and that we need to know much more about the process than WC do now. Rut it is not enough to consider adaptation as an esoteric topic dealt with by physiologists. It is a topic that is fundamental to all the specialties mentioned above, and moreover it is a topic that needs to be incorporated into our educational system and into our cultural milieu. CULTURE
AS
EN\‘IRONhlENT
Prof. Clifford Gecrtz (10) of the Anthropology Department of the Universie of Chicago has contributed an excellent chapter to the book entitled “New Views on the Nature of Man,” edited by John R. Platt. It is entitled “The Impact of the Concept of Culture on the Concept of Man,” and its thesis is that (1) culture is a set of control mechanisms for controlling or programming human behavior, and (2) man is precisely the animal most desperately dependent upon such extragenetic, outside-the-skin control mechanism for ordering his behavior. He says: “One of the most significant facts about us may finally bc that we all begin with 476
177
“FUTURE INCREASING
STRESSOR
SHOCK”
LEVEL
the natural equipment to lead a thousand lives but end in the end having lived only one.” The question is whether we, as physiologists, molecular biologists, and genoticists, are prepared to tell society how to move toward a cultural tradition that can help each individual find an optimum stressor level and steer successfully between the Charybdis of too much leisure and the Scylla of information overload. The question I am raising is whether our 2Oth-centurv culture is providing the proper kind of “extragenetic, outside-the-skin control mechanisms” that the human animal is so “desperately dependent upon.” Do prospective parents know that every individual is genetically different from every other individual, that only those genetic capabilities that are possessed can ever be expressed, and that every genetic capabiIity can be fully expressed only in the presence of an optimum stressor level, applied at the right time-and then not continuously? Do we, as scientists and humanists, have any idea \vhat to tell these hypothetical prospective parents if they ask us for practical answers to these questions? There are historical precedents for these questions. In 1890, we find William James saying, “Keep the faculty of effort alive in you by a little gratuitous exercise cvcry day, That is, be systematically ascetic or heroic in little unnecessar)’ points, do every day or t\tTo something for no other reason than that you would rather not do it; so that when the hour of dirt riced draws nigh, it may find you not unnerved and untrained to stand the test.” (2, p. 715). And in 1919, we hear the 2Oth-century cynicism replyin g, in the words of Somerset hlaugham: “I forget who it was that recommended men for their soul’s good to do each da) two things they disliked: . . . it is a precept that I have followed scrupulously; for every day I have got up and I have gone to bed” (2, p. 875). In the same vein, I belicbve it was Robert Maynard Hutchins who spoke for academicians in gcnernl, when hc said: ‘Whenever I fc,el the urge to exercise coming on, I lip dowwl lentil the fcseling got’s away.”
478
VAS
PHYSIOLOGIC
R.
POTTER
ADAPTATION
What Maugham and Hutchins do not seam to realize is that adaptation is not something that is just a physiologic response to some abnormal or novel situation, some hypoxic condition at a mountain top where average people never go. The living animal is adapting during every moment of life. Adaptation is not merely a mechanism “for the adjustment of organisms to the action of unfavorable (sic) factors in the environment” (Barbashova in Ref. 7, p. 49). Adaptations are part of the everyday life mechanism, and they arc noted as adaptations by the physiologist only when they differ from “ordinary responses” sufficiently to be “increments or decrements in the ordinary response” that “require time to develop” (Adolph in Ref. 7, p. 34). The word “adaptation” is frequently misunderstood because it has come to have two meanings. Some people think of evolutionary adaptation, which involves natural selection of mutants that fit a particular environment. This kind of adaptation occurs in populations over a large number of generations. The other kind of adaptation is physiologic adaptation, which applies to the individual members of a population. In the present discussion, I am concerned only with physiologic adaptation and follow Prosser (in Ref. 7, p. ll), who defines it as “any property of an organism which favors survival in a specific environment,” although Prosser adds the words that narrow the meaning when he says “particularly a stressful one.” Prosser states that “an adaptation permits maintenance of physiological activitv and survival when the environment alters with respect to one or more parameters.” As a biochemist and molecular biologist, I have the thesis that, if we esaminc the organism at the molecular level, the environment is changing on a minute-tominute basis and the “ordinary responses” at the enzyme or nucleic acid level constantly are undergoing adaptive increments or decrements in enzyme activity or amount in a complex feedback system that is designed to maintain certain features of the internal milieu within limits that will promote survival. \1’e can either cultivate this adaptive capacity or we can let it atrophy. The key point is that, “if an organism can adapt, by the same token it will ‘deadapt.’ When we carry a heavy load, our ability to carry loads increases, but the corollary is that, when we have no loads to carry, our ability to carry loads decreases. Just how big a load should we be able to carry, and what kind of loadcarrying program will be best for each individual?” In this contest, a load can. of course, be physical, intellectual, or emotional (7). The idea that an effort should be made to dcfinc “health” as more than the absence of disease was emphasized by Rene Dubos in “Man Adapting“ (8), when he said (p. 391) : “A medical philosophy which assumes a priori that the ideal is to make human life absolutely safe and effortless may paradoxically create a state of affairs in which mankind will progressively lose the ability to meet the real experience of life and to overcome the stresses and risks that this expcricnce inevitably entails.” I think that Dubos would be willing to include individual men, as well as mankind in the above statement. Elsewhere, Dubos comments (pp. 362-363) that “in the United States, the emphasis is on controlling disease rather than on living more wisely.” “The public
DEFIXIN(:
AN
OI’TI~lUI\I
479
ESVIROShIENT
health services themselves, despite their misleading name, are concerned less m,ith hmlth than with the control of the specific diseases considered important in the communities they serve. They do little to define, rrcognizc, or measure the healthy state, let alone the hypothetical condition designated ‘positive health.’ ” I sllspect that most of 11s feel that the name of the, public health service is not 50 misleading, and that the evolution of concepts will naturally move toward the, conwpt of positive health as infectious diseases and malnutrition are conyuerd and degewrntive diseaws continue to increase. In this went, \vc’ must not only eliminate dangerous chemicals from our wvironmcnt ;IS m11ch as possihk. lxlt also karn Irow to liw inure wisely. ENZYhlE
AD.~1’TATIOK
TO
TOXIC
IIAZhKDS
I’Il!.siol()gic adaptation at the enzyme level is a subjwt that is close to the cow of this yntirc conference, as nell as to the core of this session. Should WV aim for an c~nvironm~nt that is completely frw from toxic hazards. ,p \Vrl can answer that question very quickly \,y rwognizing that such an achievement is not only improlxll~le, it is impossil,lc! Then what is the effect of a low dew of a to\-ic s111)stance, a close that does not product death or obvious pathology in a time that is short csnough to suggest an obvious ~ausc,-rind-cff~ct relationship? The answer is that. for many toxic substances at dosages that prodncc no rapid overt s)mptoms itI the illtact animal, there is a rapid increaw in activity of a variety of cnzynws within 2-C hours, which appexs to 1~ a result of synthesis of new enzyme, first indicated by the experiments of Comwy, Alillrr. and Ilillcr ( 6). Numerous esatnplc3 xe now available (9). So the nest question is whrther the animal is any worse off or any hettcxr off for having an increased level of certain wzymes in li\w (6, 9), or intestine (26). In the study of ~Vattenberg and Lcong (26), it was shown that 6 mg of phenothinzine increased the activity of benzpyrene hydrosylasc in rat liver from 13 to -311 units/mg, and in intestinal mucosa from 16 to 55 ntlits/nq Chlorpromazine, a phcnothiazinc derivative that is a well-known tranquilizer, had almost identical wsnlts for IivcBr, and increased the value in intestine to 114 units. At a dew of onl! 1 mg per rat given 48 hours prior to exposure to 30 mg of dimethylbenzanthraccwc, phcnothiazine protected ninct of ten rats against adrenal necrosis. This study has as its over-all objective the determination of “optimum methods for achievin,q protection from the effects of chemical carcinogens in tqc~rimental animals and, possibly, c~ventually in man.” Further stI&es on the protective effects of smalI(ar daily dews, such as arc’ used over long periods of time as tranquilizers, will be of ititercst. Xleanwhilc. a clinical application of the induction of enzyme activity in a human 11:~sc~)me to oltr attention. Gaffe, Levy, and Matsnznnra (27) have reported the rise of phenobarbital ( 15 mg daily) to enhance glucitronide conjugation capacity in a congenitally hyperbiliruhinemic infant. The authors claim that theirs is tll(‘ first demonstration of the apparent induction of the glucuronide conjugating systcam by phenohnrhitnl in man, and the first therapeutic application of enzyme induction. There is no reason to doul)t that phenob;lrbital did callse increased
480
VAN
R.
POTTER
synthesis of the enzyme, since enzyme induction by phenobarbital is well known (9). At the present moment, it appears impossible to answer the question as to whether amounts of toxic substances that will induce certain enzymes are intrinsically helpful or harmful. Of course, we have been made aware during this conference that even noninducing doses of some compounds may be capable of producing irreversible damage to DNA, and hence capable of acting as carcinogens. Recently, Siperstein (23) has reported deletion of the negative feedback system for cholcstrrol biosynthesis in liver hy &toxin at a level of 10 parts per billion in the diet of trout and in the liver of rats after only 2 days of a diet containing &toxin at a level of 10 ppn~. In this case, it is not yet established whether the change is irreversiblcs or reversible, but it is clear that the phenomenon could give the appearance of enzyme activation or induction. It should be noted that trout receiving aflatosin at 10 parts per billion from birth develop hepatomas to the extent of SO,%lOO%.Thus, we are in the position of having to make considerable efforts to find any virtue in the ingestion of any foreign compound if it can be avoided, unless there is clear indication that the benefits outweigh the possible or known risk. Further discussionson animals in toxic environments are available in the Handbook rcferrrd to earlier ( 7). No beneficial effects seem to be mentioned in the section on polluted air (by E. H. Morrow, on pp. 795-808 in Ref. 7) or in the section on man and industrial chemicals (by II. W. Gerarde, on pp. 829-834 in Ref. 7). although in both chapters there are snggcstions of adaptation in various instances. Tahlcs showing Iev~ls to which workers can be exposed day after day without adverse effect do not appear to havesbeen based on criteria other than the ability to work efficiently and the absc,ncc of claims of pathology. Thus, at the moment, WC can suggest that, although there is evidence that humans can adapt to some extent to a variety of toxic chemicals there is still no basis for assuming that there are no disadvantages to the adapting individual, and no basis for complacency about the increasing levels of ambient toxicity. Meanwhile, let us examine the type of adaptive changes that might be considered in examining the lift of a completely healthy man or animal.
Changes in enzyme amount resulting from changing rates of synthesis and degradation of enzyme protein occur not only in physiologic adaptation to toxic hazards in the environment. Such changes can also be observed in the course of each 2Chour cycle, as a result of feeding habits and as a result of changes in dietary composition. In 1961, Ono and I (21) reported enzyme changes in liver rats fed at1 Iibitzrln under controlled lighting conditions, in which food was eaten in the dark hours. The liver glycogen decreased in the light hours and increased in the dark hours, and glucose 6-phosphate dehydrogenasc showed mild oscillations in opposite phase. More recently, WV (20) studied a number of enzymes in livers and hepatomas of rats fed diets containing O%,1%, 30%, 6070,and 9OZ protein only during 12 hours of darkness with no food during 12 hours of light in each 24. We noted oscillations in liver glycogen with both peak and minimum levels that were inversely related to protein and directly proportional to carbo-
]lydrate in the diet, In this study, there was a marked oscillation in tyrosine transaminase in rat liver, with maximum values proportional to protein intake at midnight, 6 hours after the onset of feeding, with declines to resting levels thereafter, even while the glycogcn values were still risin,. 0 Recently, this phenomenon has ~~ee~~studied in more detaiI by or. Minro Watanabe in our laboratory, and thr detailed data confirm the discontinuity between liver glycogcn and liver tyrosinc transaminasc, and in addition show that the plasma corticostcrone decrcnses while lthc rise in tyrosine tmnsaminase occlux The induction of this enzyme by injc>ctions of adrenal steroids was well kno\vn, bllt the rapid increases during food ingrastion have not been previously reported, possibly bccausc~ in the rat the peak i< at midnight and tends to reach daytime levc~ls by 6 AM ( B-:31 ). These examples show that metabolic transitions occur throughout the daily rolrtinc of sleep and waking, eating and not eating, and that these transitions are a<,companicd by marked changes in several enzyme activities. liKZY\IE
ADAPTATIOX
TO
FASTIS<:
In the 1961 study (21), we also carried out the procedure of fasting rats for :i days and then refeeding various diets, as has been carried out by Tepperman ;u~l l’c~pprrman (24). In this situation, the glucose 6-phosphate dehydrogenase aotivity in the liver responds by rising to unusually high levels, compared with t11c daily cycle owing to ;t changed feedback rclntionship, and greatly overshoots tl~cbnormal range. The enzyme level rises to about 20 times the usual l~vcl during al,out 72 hours, and then slowlv returns to normal levels over a period of about IO days. It is clear that thck opt&m stressor IcveI for the s>Tnthesis of this enzyme i, not attained in the ad lihitrrnz feeding regimen. In a recent symposium on feeding patterns and their consequences, Mayer (14 ) c~mphasizcdthat the pattern of metabolism may be influenced by the distribution (lf the food intake iu one, two, three or a number of mc&. Tcpperman and Tel,pcrman (24) and others have carried out many experiments on rats that havci huw fasted for 21 or 22 hours in each 24, and correspondingly f(xd for only 2 OI 3 hours per day. Suc11animals slio~vecl a striking incrcnsc in fat production from l)oth acetate and glucose, and they stored liver glycogcn to higher kvels than :~rlirnnls fed crtl libittlm. hIorc~ovcr, the fat pads shouwl an increased level of fxt deposition. From these studies, there has been ;I tcndcw!y to conclrlde that frequent snacks are better than one meal a day for the human, as well as the rat w IIW~IW, and there is a widespread lwlicf that frequ(Bnt small meals reprcserlt ;I regimen that can bc%rcwxnmendcd as 011~f(%ltllrc* of ;m ()ptimllJ~l tm~~ironment. It is III!. ~UI~>OSC~ hew to question this point of \,iex\. and in fact to t&e th(, oplx)sitcl position. Incidentally, it is reported that the custom of three fIllI meals ;I day ~KLS been cstahlished only since 1890: that in hnglo-Sas(m tradition there \vtlre chill\t\VO IllCtllS il da\,. l)rc~akf%t ant1 dinner; ;wd in tlN3 16th ccnturv dillner \s-;ls clt&1 at 11 AA\I (4). \t’e start from the assrlmption that the animal or 1~1lmanis not eqlGpp(ad },) instinct to do what is best for him in circnmstancc,s other than those lln&>r xvhich his species evolved to its present state. Particularly for rats in small c:l
provision of food on an ad Zil~itrm basis has no instinctive support to provide information on “living more wisely,” a goal emphasized by Dubos ( 8), as mclntioned earlier. True. our society has come to value the slim figure. achieved by a low-calorie diet, but this has been coupled with the idea of frqucmt snacks and never, to my knowledge, with the idea of one‘ good meal once a day. Secondly, WV start from the assumption that fasting is normal, bcncficinl, and not unnatural. This vics\v is prol)ably contrary to popular and medical opinion, both of which arc probablv influenced by the knowledge th;~t stomach ulcers arc‘ given palliative treatment by frcqiicnt small meals of milk. My assumption is that physiologic functions are meant to be used, and that atrophy of disuse is not limited to skeletal muscle. It is also assumed that brain function, both intellectual and characterwise, is influenced by bodily function. Animals possess metabolic machinery for storing fncl far in excess of what CRY bc stored in the form of liver glycogen. According to Cahill (5), the liver glycogen in man is able to maintain blood glucose for only about 14 hours, and, of course, muscle glycogen is not directly available as a source of glucose. Thus, in the absence of food intake, the human must initiate the process of gluconcogenesis from protein within 12 hours, and the evidence suggests that in rodents the situation is not greatly different. Cahill shows the relative sizes of the various glucose r(Ascrvcls in comparison with the total potential reserves, and the total glucose pool is only about 290 molts, or a little less than 1%’ of the total of about 30,000 moles, based on the fact that men can snrvivc a total fast of 60-90 days. It has commonly been assumed from studies on laboratory rats that fasting lcads to a rather prompt adrenal cortical stimulation, which in turn leads to increased gluconeogenesis from protein (1, 22). However, in a recent study wo men Lverc fasted 4 days and three tncn 6 days, lvith by Kollar et (11 ( 13), t ITowever, an ;\s yet iinino evidence of adrenal activation in any of them. normally absent from the iirinc, dcntified “stress rcsponsivc indolc substance.” was maintained at high levels in all six subjects after the second day of starvation. What lencls intcrvst to this observation is thr finding by Rosen and Nichol (22) that two tryl>tophan metabolitcs, 5-OH-tryptoplian and scrotonill. arc: effective inducers of tyrosine transaminasc in rat liver. It appears that the stress of fasting may lead to adaptive changes mc&atcd both by indole-conand that the two classes of inducers are taining substances and by cortisone mcrelv separate stages in a seq~nce of adaptivcy changers, which vary in cliff erent species. The interest in my laboratory has not betm in the effect of fasting per SC; but rather in the effect of prolonging the intervals between food intake as an approach to an optimum stressor level. The typical laboratory rat lives at a constant temperature, with food constantly available, and with little opportunity or incentive to exercise. In rats that have been trained to eat their daily allotselection, ment of food in 2 or 3 hours the result is obesity (24 ) Under natural rats have been selected to desire food every night and to sleep in the daylight hours, but they have also been selected for the ability to survive if they ~10not ohtain food every night. We decided to explore the consequences of training
rats to un&.qo cycles of feeding and fastin, o \\rith durations of 43 hours, rather than 2-l hours. From the experience \vith url libitrtrll feeding regimens, with food limited to 12 l~ol~rs in c:tcll “4, and \vitll f00c1 u~Z Zibitrrt~~ after ;I 3-day fast, \vc \Vcllt (~1) to &V&P r~@mc~t~s that have attem@d to attain the hypth~tie~~l optimw~ that might lx* optitnnm for strcwor levels correspondin, (r to :,I, environmmt Starting \vith rats that \vcrc t’cd 12 h011rs the grchatcst nmnbcr of parameters. ill (,a~11 23, \xThicll is not lllucll different from crtl fibitrrtn fecsding, \I;(* adoptcAd tljc simple cspcdient of feeding every other night, instead of every night. Thus these :~nimals ;trc fly1 12 lmurs in ever!? 48, and arc fasting for 36 honrs. \IVcBrefer fusting-adapted rats” ( 19). Some espcriments ha\e \WC~ to them as “36-hour don61 lvith a &-hour cycle in \vhich food is available for onlv S hours in 35. ,uld thcx, are called “N-hour fasting adaptc’d rats” (S-31). . It was soon noticed that the fastilifi-adapted rats are hyperactive. \\‘e thercforc installed activitv cages and rccordcd milcagc for each animal. It can be reportc~tl that M-hour fa&ing-adapted rats will survive in small cages of the usnal type, but if allowed access to activity cages they nil1 all run themselves to death in S-10 days, ilhlstrating the breakdown of instinctive “wisdom.” In contrast. the 36-hour fasting-adapted rats arc able to snrvivt and adapt to the rcgimtsn with or without exercise. The :36-honr fastinS-ndaptcd animals run an avcragc of 15 km dnring the lZhours of darkness \\hcn no food is available ( 19). and on the following day. still hungry. they sleep much of the time and run much INS. The cltl liDitur,t controls csercisc and cat at night and s1cc.p most of the day, with almost no day activity rc~corclcd. \\‘cs lla\~~ studied ;I number of cnzymcs and have, also studied nuclc+ acid mc~taholism, but data for only one enzyme Lvill bc mentioned hcrc. CClucose 6. phosphate dehydrogcnase shon~s great fluctuations and avcragcs much highcsi vahles than the ((~7 libif~n~ controls (19). \T’e feel that thc,se data adequately dcxmonstrate the fact that adaptive tlnzymc changes arc part of nor~nal physiology and that tlicsc changes can \W exaggerated by increasing the time lWwcc~11 nwals. ‘l‘llc~ animals on this regimen have not l)crbn studied for longevity, but it is csl(Lar that obesity dots not result dnrillg 30 days, and that the growth cur\.(’ during this period does not develop a steeper slope than the control cllrvc. :LS ill the case of rats fed 2 hours pc’r dav (12). The gro\vth rate is qrlite similal to that of malt rats stnclied by Rcrg (3) at the lc\.els of :3X and 46% restrictioll of food intake, and falls michwy lx~t\vcw~ the rates for his groups. I3erfi’s stlldies dernonstratcd incrcuscd longevity and general health without evidcncc of immaturity. In the ?&hour fasted rats, it is as yet lmknown \%,hether the food intake \~ould increase to the lc,vel of the crd lil~jtllrn feeding in time, or whcthcr in the long run restricted feeding on a once-per-day basis wollld be preferable. It can be suggested, however, that the usual restricted food intake always results in fasting periods of 22-23 hours, and that fasting may lx) partly responsiblr for the beneficial effect of the caloric restriction. At this timr, we can only specnlatc that the fasting-adapted animals derive
484
VAN
R.
POTTER
benefit from the active use of their abilities to produce large shifts in intracellular enzyme patterns, and leave it to the future to determine whether mental powers, motivations, and character would be helped or hindered in humans on similar regimens.
Turning now to the actual task of defining an optimum environment, I think I have tried to make the point that the culture in which \ve live is an important part of our environment. What WC recommend as physiologists may become a part of our culture or it may be ignored, depending on the force of our logic and the force of counterpressures. A cogent example is the relationship between cigarettes and lung cancer? where the experts are pretty much agreed but the counterforces still prevail. In the case of defining an optimum environment, I think that it is essential to go beyond a mere consideration of toxic hazards and to recommend positive steps that could raise men above mere absence of disease to the concept of “positive health” mentioned by Dubos (8). My basic concern is that physiologists should be in the forefront of describing and analyzing the mechanisms of physiologic adaptation, not only in physiologic terms, but in behavioristic and molecular terms-not only in the academic sense, but also with the aim of guiding mankind during the next 20 or 30 years of rapid change to wc know not what. If affluence is not conducive to an optimum environment, then what can we say to those who seek it? What are the minimum requirements for a world that physiologists could recommend and work toward? I have made a list of seven points, not as a physiologist but as a scientist and a humanist. I present them as the whole package, recognizing that, as I am a physiologist, my main concern is the fourth point. which has to do with physiologic adaptation. However, I might emphasize that, until we know more about the nature of adaptation and the molecular targets of toxic hazards, we can say very little about the problems of threshold and potentiation, which are the crux of the pollution problem. My seven points are as follows: 1. I would begin with basic needs that can bc satisfied by effort. Thcsc include food, shelter, clothing, space, privacy, leisure, and education, both moral and intellectual. (Regarding the ethical basis of science, see Glass (11). 2. I would insist on freedom from toxic chemicals, unnecessary trauma (primarily war and traffic injuries), and preventable cliseasc. 3. I would demand a culture that had a rcsspcct for sound ecologic principles with a long-range point of view. The aim must be to live with nature as in a about th(, ability of future science balanced aquarium, with no assumptions to rescue a sick planet. 4. The point that is the most personal with me, as it is based on my research experience over many years, is that the culture should prepare us for and expect of each individual adaptive responses, continually from birth to death, as a result of systematic challenges by physical and mental tasks which come at appropriate times, and are within individual capabilities, which are known to
increase rapidly at certain periods in life and decline later. This proposition is based on molecular genetics, which shows that our genetic capacity does not automatically express its&, and that each capability is called forth maximally only in response to an optimum stressor level. ,5. The nest point calls for individual happiness that involves oscillation betlveen satisfaction and dissatisfaction, with a sustained sense of identity, &spite
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a rapidly changing world show ~13in our private information centers. 6. The nc,st point calls for productivity that involves commitment to other members of society, directI\, to our family, our church, our community, or indirectly to mankind. 7. Finally, each of ~7s can contribl&b to the further cvotution of our clrltnrc, to our present society. and to our own satisfaction b!* a continual war& for beauty and order that does not drny that role of individuality and disorder (16, 17). 11~connection \vith the subject of adaptive responses, which is my main concern under my assigned topic of how to define an optimum environment, I feel it is \vithin the scope of erlvironmcntal physiolog, (0 ) to postulate that individual organisms shoal a w,idc variation in their tc&enc)- to seek out such challenges unaided, and that most individuals in fact arc equipped by instinct and natural selection to satisfy only their basic physiologic nerds by the easiest possible route and no more; (b ) to inquire what counwl to give a society that is basically ui~informed as to the nature of mnn as nrll as to the goals. attitudes, and pcrsonnl values which should be inculcated into preschool and in-school individuals in order to build a free society worth!; of mankind; and (c ) to inquire whether individuals are in gcncral unwilling to challenge systematically their own adaptive capabilities and whether society should attempt to inf!fucncc the attitude of the swung in favor of systematic cscrcisr, periodic fasting, and continual development of new mental and motor skills, and, if so, how these adaptive challcwges can be initiated 1~17so&t!, but maintained h! free individuals, perhaps reinforced by somekind of voluntary grouping. The first step in any program that might hopefully assist in the evolution of our culture toward better concepts of positive health is to secure more knowledge. I wish to advocate that the study of the individualistic aspects, as well as the principles, of physiologic adaptation is an especially important sector of environmental phvsiology and that much more research \vbich cornbines both organismic and molecular biology should be our first objective. Such studies should in particular be cognizant of the biologic rhythms stressed b! Astthoff and the individual variations stressedby Sxgcnt at these sessions.
1. ASHMORE,
J., W~GLE.
ct7J/me BP,& 2. BAI&ETT, J. Massachusetts 3. BERG, R. N. to size, health
S. H.,
AM
TTFTE,
T.
( 196-I).
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Admn.
2, 101-111. Qllotations.” 18th and Centennial Edition. LittIc. Brown. Boston, ( 1955). ( 1960). Nutrition and longrvity in the rat. I. I:ood intake in elation and fertility. J. Ntrfr. 71. %2-%-t.
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4. BRASCH, R. “How Did It Begin?” hlcKay (1966). ( 1964). Some observations on hypoglycemia in man, A&an. Enqme ij. CAHILL, G. F;., JH. Reg. 2, 137-148. 6. CONNEY, A. H., GRILLER, E. C., AND ~,IILLER, J. A. (1956). The metabolism of methylated aminoazo dyes. V. Evidence for induction of enzyme synthesis in the rat by 3-methylcholanthrene. Cancer Res. 16, 450459. 7. DILL, D. B. “IIandhook of Physiology.” Sect. 4. Am. Physiol. Sot. Williams & Wilkins. Baltimore, ,\laryIand ( 1963 ). 8. Du~~os, R. “hIan Adapting.” Yale Univ. Press, New Haven, Connecticut ( 1965). 9. ERNSTER. I,., ANI) OHRENIUS, S. (1965). Slll,stlate-inducec synthesis of the hydroxylating enzyme system of rat liver microsomes. Fcderatim Proc. 24, 1190-l 199. 10. (ZEEKTZ, C. The impact of the concept of cnlture on the concept of man. In “New Views on the Nature of Man” (John R. Platt, ed. ), IT mv. of Chicago Press, Chicago, Illinois (1965). 11. CLASS, B. (1965). The ethics of science. Sciwtcc 150, 1254-1261. 12. HOLLIFIELI), C., A>L) PARSON. M’. (1962). hletabolic adaptations to a “stuff and starve” feeding program. II. Obesity and the persistence of adaptive changes in adipose tissue and li\,cr occiirring in rats limitrcl to a short daily feeding period. J. Clin. Itwest. 41 250-253. 13. K<~LLAR, E. J., SLXIXR, (:. H., PALMER , J. O., DOCTEII, R. F., AXD ;L~ANDEL, A. J. ( 1963). hleasurcment of stress in fasting man. Aroll. Car. P.s!/chiat. 11, 113-125. Introductory rrniarks. Symposium on Feeding Patterns and their 13. &xxn, J. (1966). Biochemical Consequences. Fetlvratioll Proc. 23, rj9. 15. ~IILLER, J. G. Psychological aspects of commnnication overloads, pp. 201-204. Intern, Psych. Clinics: Commnnication in Clinical Practice (R. W. Waggoner and D. J. Carek, eds. ). Little, Brown, Boston Massachnsctts ( 1964). Other reports by hliller include: Adjusting to Overloads of Information, pp. 87-100. In “Disorders of Commnnication.” NLII: Rrsearch Pnhlications, Assoc. Res. in Nervous & Mental Disease, 1964; and The individual as an information processing system. pp. l-28, 111 “Information Storage and Neural Control” ( W. S. Fields and \V. Abbott, eds. ). Thomas, Springfield, Illinois ( 1963). 16. NEUTRA, R. S. “Survival Through Design.” Oxford IJniv. Press, New York ( 1954). 17. POTTER, V. R. (1964). Society and science. S&we 146, 1018. 18. POTTEH, V. R., AND AUEH~A~H, V. H. ( 1959). Adaptive enzymes and feedback mechanisms. Lob. Innest. 8, 395-509. 19. POTTER, V. R., &BERT, R. A., AND Prror, II. C. (19%). Enzyme levels in rats adapted to 36-how fasting. Adran. E~yme Rvg. 4, 247-265. 20. POTTER, 17. R., &BERT, R. A., PITOT, H. C., PERAINO, C., LAMAR, C., JH., LESHEH, S., Systematic oscillations in metabolic activity in rat liver AND MORRIS, H. P. (1966). and in hepatomas. I. hlorris hepatoma 7793. Cancer Z&P. 26, 1547-1560. 21. POTTER, \'. R., AND 0x0. T. ( 1961). Enzyme patterns in rat liver and Morris hepatoma 512:3 tliirinp mrtaholic transitions. C&Z Slrrirl~ Harbor Symp. Qrrmt. Bid. 26, 33.5362. 22. ROSEN, F., AKD NICHOL, C. A. (1964). Studies on the nature and specificity of the induction of several adaptive enzymes responsive to cortisol. A&an. Enzyme Reg. 2, 115-135. 23. SIFERSTEIS, hf. D. ( 1966 ). Deletion of the cholesterol negative feedback system in precancerous li\er. Abst. J. Clin. Invest. 45, 107.3. 24. TEPPERMAN, H. hl., AND TEPPERXU, J. ( 1964). Adaptive hyperlipogenesis, Federation Proc. 23, 70-75. 25. TOFFLER, A. ( 1965). The future as a way of life. Horizon 7, No. 3, 108-115. 26. WATTEP\‘BER~, I,. W., AND LEOK, J. L. (1965). Effects of phenothiazines on protective systems against polycyclic hydrocarbons. Cancer Res. 25, 365-370. 27. YAFFE, S. J,, LEVY. C:., hlAmuzAwA, T., AND BALIAH, T. ( 1966). Enhancement of glucuronide-conjugating capacity in a hyperbilinemic infant due to apparent enzyme induction hy phenobarbital. izTcto Eng. J. Med. 275, 1461-1466.
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REFERENCES
following references were recei\-rd after the manuscript was prepared: 28. BAIUL, E. F., AND POTTER, V. R. (1968). Systematic oscillations of amino acid transport in liver from rats adapted to controlled feeding schedules. j. Nut?. 95, 228-237. (1968). Systematic 29. POTTER, V. R., BARIL, E. F.? WATANAHE, M., AND WHITTLE, E. D. oscillations in liver from rats adapted to controlled feeding schedules. Federation PTOC. 27, 1238-1245. 30. WATANABE, M., POTTER. V. R., AND PITOT, H. C. ( 1968). Systematic oscillations in tyrosine transaminase and other metabolic functions in liver of normal and adrenalrctomized rats on controlled feeding schedules. J. Nutr. 95, 207-227. ( 1968). Systematic oscillations in the metabolism .31. WHITTLE, E. D., AND POTTER, V. R. of erotic acid in thr rat adapted to a rontrolled feeding schedllle. ]. Nutr. 95, 238-246.