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k California Association of Chemistry Teachers J. Yule Bogue
405 Minoco Road Portola Volley, California 94025
Drugs of the Future
The range of ethical prescription drugs at any given time is a reflection of the state of medicine at that time. I n discussing drugs of the future, therefore, we must bear in mind the possible areas of advance in medicine and biology. A detailed knowledge of the disease process and of normal physiology is a prerequisite for the rational approach to synthesis of new chemical compounds which will cure, alleviate, or prevent malfunctions within the body or diseases resulting from the invasion by micro-organisms. The real difficulty in research aimed at the discovery of new drugs is the limited knowledge of the relationship between chemical structure and biological activity. I n other words, the chemist concerned with speculative synthesis in the pharmaceutical field cannot, as yet, use scientifically derived criteria in his selection of molecular structures which will possess the desired pharmacodynamic actions and be resistant to premature metabolic inactivation by the body. Environment from Which Drugs Arise
I n the last 20 years, 90% of the new basic drugs have come from industrial laboratories, 9% from universities and other academic institutions, and 1% from government research establishments. While these figures are factual, they are not a measure of the relative significance of the contributions to our understanding, prevention, and control of the disease process. The academic and industrial laboratories are interdependent in their efforts to discover truly worthwhile and more effectivenew drugs. The industry could not have made contributions of such magnitude had it not been for the truly remarkable advances in fundamental knowledge of living processes that have come from the university laboratories. Both groups are equally important and there is little to choose in the quality of the research staffs. While the facilities in many industrial laboratories may surpass those of the university, it is the environment together with the intellectual qualities of the research workers that determines success in either case. That this is recognized by both groups is demonstrated increasingly by the closeness of the collaboration apparent today. Consultants drawn from the very top ranks of the academic world are a potent force in improving relations and understanding between universities and industry. The industrial research staff look forward to their visits Lecture presented at the Terlt,h Armual Summer Conference of CACT at. Asilnmar, California, Augnst 1968.
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and welcome the opportunity to discuss their problems and findings with these experienced and erudite minds. The visiting is not one-way traffic, however, for the consultants are often visited on their home ground to discuss particular problems which may arise between visits, or to display some aspects of research policy. Many consultants operate on a world-wide basis, visiting pharmaceutical research laboratories abroad as well as at home. They have, of course, their international academic contacts, and are often helpful in introducing industrial scientists to academic investigators and their current work before its publication. Considering the long delay in publication, this knowledge can accelerate progress in research by avoiding unnecessary work or altering the course of the investigations. Incidentally, if the research side of industry is as bad as its detractors claim, would it really be able to attract these first class men of such high standing? The exchange of ideas is also fostered to a greater extent than previously by frequent visits to each others' laboratories, by industrial scientists serving on committees and editorial boards of scientific societies, and contributing to them by reading communications and also publishing in the scientific journals. Another factor leading to a better understanding is the secondment of research workers from industry to university laboratories and other research institutes at home and abroad. The resultant knowledge is made available to the whole world, sponsors and competitors alike. I n the field of toxicity, which is one of the most important problem areas of drug research, there is complete and frank interchange of both methods and findings of structure/toxicity relationships by competing firms. Financing of Drug Research
We will complete this brief outline of the environment from which new drugs arise with a few words on the financing of research. I n industry, the money to support research comes from the profits of commercially successful drugs. The successful drugs must bear the cost of the research which fails to produce a new drug to meet medical needs. Research expenditure in the ethical sector of the industry is conveniently expressed as a percentage of sales or profits. It ranges, according to company, from less than 5% to greater than 15%, and averages around 10% of sales income throughout the world. The average for all other industries is just over 3%.
Academic institutions draw their funds from endowments, gifts by individuals and industry, and from the state, i.e., a central government and its agencies. This latter, in many cases, is the major source of funds and is not without serious disadvantages. I n accepting such grants, a university loses some of its independence. Money given for basic ~esearchshould not be earmarked for a particular type of research. I n basic research the scientist must be free to select his subject, method of approach and technique. It is difficult to raise funds for research projects not favored by fashion and of no immediate or apparent practical use, particularly in the biological field. Yet nearly all the great advances in drug research have their origin in observations of biological phenomena (1). Financial aid given to academic departments to support medical and biological research should be given in a manner similar to that pertaining to the funding of the Medical Research Council in England. Once the M.R.C. has obtained a grant, i t can, within very broad limits, spend it as it deems fit in the light of its own scientific assessment. The procedure, in the manner of Maecenas, for supporting basic research removes the danger of interference which is an inhibitor of good research. Maecenas (died 8 B.c.) was a patron of Horace and Virgil; his sponsorship was characterized by being generous, unrestrictive, and disinterested. The Maecenas approach also avoids dishonesty on the part of the scientist when asking for funds, a common consequence if strings are attached to a grant (2). Support of academic research by industry is either in the attitude of Maecenas, or for research related directly to the iudustrial effort. I n a talk before the Pharmaceutical Society of Great Britain in 1962 ( 4 ) I said It frequently hzppens that a drug which is considered at one time to be a. notable therapeutic advance and the most effective for a. given purpose, is imexpectedly eclipsed by a superior drug produced by a competitor. Because t,he pnblieation of a patent of a new drug brings down the whole weight of world research on the product, it may then he superseded. This eclipse may wipe oot three to five years or more of heavy investment in research and development and even in expensive plant to manufacture the drug before the firm hss had adequate opportunity of recouping its outlay. What was an asset is now converted into a liability.
I n spite of this, research and development expenditure in the pharmaceutical industry is unlikely to decrease. Which ever way we express it, be it in terms of the actual amount of money spent or as a percentage of turnover, it will go up; only the rate of increase is liable to fluctuate. It is reasonable to assume that the outlay will continue to average between 8 and 10% of sales. The annual research and development expenditure will be doubled by the late 70's and on a world basis could reach the $1 billion mark in the 1980's. Sixty to sixty-five per cent of this will be accounted for by the USA. The number of new compounds will not increase in the same proportion. There will be a smaller total number of compounds per unit of time and these will, in addition, take longer to reach the range. The varied mandatory controls, the increase in the duration and scope of animal toxicity trials followed by proving trials, more human pharmacology and, finally, extensive development trials of sufficient magnitude to produce
evidence of therapeutic efficacy, will all cost more money and slow down the rate of appearance of new drugs. Properly developed and planned controls can only do good; they will weed out those drugs of doubtful value as well as the firms who either do not have, or are unwilling or unable to have access to appropriate technical facilities. Current regulations will prevent the appearance of dubious preparations, including proprietaries; and ultimately, they will result in the removal of a clutter of useless drugs out of which no one should be making a profit. The Yield from Research
Many of the traditional and so-called "standard" drugs are ineffective and poorly tolerated due to unpleasant side reactions, particularly when the dose is pushed to produce the desired effect. Their displacement by truly effective, easily administered and welltolerated drugs benefits the patient. A good example of this is found in the diuretic field where mercurials and ammonium chloride were displaced by chlorthiazide and hydrochlorothiazide, and now ethacrynic acid. What do we get in the way of new drugs for this enormous expenditure? By new drugs, I mean new chemical substances-not new products which include new mixtures of known drugs, duplicates of single known drugs and new dosage forms of known drugs. Since 1948 the average number of new chemical entities has been about 40 per year in the USA. Taking the total international research expenditure, the cost of a new drug which attains FDA acceptance standard is of the order of $25-828 million. This is a 7 to 8-fold rise in cost in 10 years. Scientific achievement cannot really be measured in terms of the money spent on research; the money spent gives only some indication of the magnitude of the effort. The greater portion of new drugs should come from the USA, as the U.S. expenditure is greater and there are more firms in the business. This may not always be so if we consider new chemical entities only. Over a recent three year period, the USA produced 96 and the UII 101. The UII expenditure on drug research is about one tenth that of the USA. However, it seems that the number of new drugs produced is directly related to the amount of money spent in looking for them. It is a fallacy to assume that if you spend enough money, new wonder drugs are bound to appear. No one company has resources vast enough to cover every possible field. Choices have to be made and the judgment required for making them is based on an assessment of present knowledge combined with an insight into the significance of new knowledge. The choice will be conditioned by technical feasibility, medical need, the particular skills available within the research department, and the relationship to the company's overall research pattern. The number of projects varies; highly specialized firms may concentrate on a very limited field such as eye preparations, whereas a larger organization may work on ten or a dozen major fields, with a similar number of supporting projects. The latter effort is primarily to add to knowledge with a view to progressing towards an all-out effort involving chemical synthesis; for example, studying a disease process and the development of a biological assay. Volume 46, Number 8, August 1969
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Prognosis on Drug Discovery
How are drugs discovered today, and will there be any change in the way in which they are discovered in the future? I n answering this, we can conveniently divide the approach into four main methods: Firstfundamental research. This rational approach is based on a study of the disease process in biological and biochemical terms with a complete understanding of its aetiology and a replication of the disease in an experimental animal. Similarities and dissimilarities between the experimentally induced and the naturally occurring disease would need to be thoroughly understood. The experimental condition is necessary for screening or assay. The assay must be not only reproducible, but capable of detecting shades of difference in degree of activity of the speculative compounds under test. Under ideal conditions, the biochemical information should be able to define the drug to be synthesized. However, this state of affairshas not yet been achieved. Second-synthesis around known drugs or natural products in the body, such as hormones, or substances playing an important role in the physiological or pathological mechanisms of the body. This, of course, is analogy synthesis and many of the discoveries have come from this approach. Third-natural product screening. This is really a random screening of the products of fungi and plants; and the method has resulted in a variety of important and useful antibiotics. It was started by Fleming's chance observation of penicillium contamination of a culture plate and later developed into a practical and very useful product by Howard Florey. Fourth-random screening of chemicals. This is a poor and inefficient way of looking for new drugs, since useful medicinal activity is not a common characteristic of organic chemical substances. Injected into the above methods is the Empirical Accident. Even today it is a significant source of discovery. Here the essential points to bear in mind are (a) acute observation and (b) an organization capable of taking immediate advantage of such observations. The incidence of hit by any of these methods is not high. I n the case of random screening, it is of the order of 500,000: 1against finding for example, a potent anticonvulsant. But the odds against finding something like an anti-cancer activity are probably several millions to one (4). It is perhaps salutary to realize that a t best the incidence of hit is about 3000: 1. Out of the 14,600 compounds tested in 1958, only 44 new chemicals reached the prescription pad in the USA; and in 1964, over 150,000 were tested with only 17 being marketedor aratio of 8500: 1. About a third of these compounds originated in laboratories outside the USA; and of the total, it is probable that only 2530% were really worthwhile. The incidence of hit now becomes 12,000: 1 for 1955 and 40,000:l for 1964. Part of this latter figure is accounted for by the increase in stringency on the part of the F.D.A. following the Thalidomide tragedy. But it also reflects a decline in the rate of discovery, for the targets are becoming more complex. I n the past 30 years the progress of the pharmacentical industry has been characterized by a series of discovery explosions. Before World War I1 it was the vitamins; these were followed by the sulphonamides and 470
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anti-malarials during the war. The control of bacterial infections by the sulphonamides stimulated the search for chemical substances with this and otter types of biological activity. The antibiotic era came in with the end of the war. From then on there were significant new discoveries at about three-year intervals. 'I'hty came in the following order: tranquilhzers, diuretics witah the partial control of high blood pressure, antidepressants, oral contraceptives, and today, the dawn of effective cardiovascular drugs; namely, hypocholesterolaemics and @-blockerswhich act directly on the heart. What of the future? While the upward trend of the research effort will continue, the number of effective drugs produced i n a unit of time will be less in proportion to the increase in cost for the reasons already mentioned; namely, the intricacies of the disease process, stricter controls, and longer clinical development time. It is disturbing to find that from time to time a chemist may be tempted to measure his productivity in terms of the number of compounds he produces in a year. This is no measure of research efficiency; it is, in fact, the reverse. The churning out of numerous variants on a basic structure, while necessary in some cases such as patent work, may be wasteful of his time and that of the biologist who is testing the compounds. What matters is the ingenuity of his chemistry and the novelty of the compounds in relation to the biological mechanisms involved. Since future drugs will be more complex and sophisticated, there will be a reduction in the number of new compounds per man year. Drugs of the Future
The drugs of the future will depend upon biological and biochemical originality backed up by sophisticated chemical manipulation. The investigation will probably begin with a team of three biologists and two biochemists who would elucidate the physiological and pathological processes under study. They then might be able to explain how an existing drug, if any, acted and how an ideal new drug should act. It is to he hoped that in the more distant future there will be sufficient understanding for the team to suggest the structure that should be synthesized. At this stage, the team would include perhaps five chemists making a group of 10 working on the project. The supporting disciplines such as physical chemistry, analysis, and toxicology would, of course, be additional. Toxicity. Toxicity is the main barrier to the continued development of promising substances. Any biologically active substance must, by its very nature, possess toxic properties under appropriate conditions; it is unlikely that any completely non-toxic substance will have therapeutic activity. Toxicity may be manifested in a variety of ways, such as excess of the desired therapeutic effect, allergic reactions, and dangerous actions on any organ or system of the body which is completely dissociated from therapeutic activity; in other words, unpredictable on any basis whether it be chemical or biological. Toxicity assessment involves acute, sub-acute, and chronic experiments a t different dose levels for weeks, months, or years, as in the case of possible carcinogenesis. Frequent measurements of the effects on a suitable animal species spectrum while under dosing, and the subsequent microscopic examination of a wide variety of tissues and organs is essential.
This is time consuming and expensive; it accounts for from 5 to 10% of the annual research budget and for a capital investment of about three times this figure. Unfortunately, some toxic manifestations are speciesspecific, occurring perhaps in only one animal species while absent in others. Nevertheless, in our present state of knowledge, prudence requires that man should be considered equivalent to the least favored species. When this occurs, the potential drug cannot be recommended for brial in man. The casualty rate of promising compounds a t this stage may he as high as 5 out of every 6 tested-this after many tens of thousands of dollars and man-years have already been expended on the project. Currently, there is a real danger of controlling agencies demanding arbitrary tests of drug safety which are not only a waste of time, but give a false sense of security. Mandatory tests must he meaningful. There is no doubt that due to our lack of knowledge, we are carrying out a large number of useless experiments which shed no additional light on the likelihood of the occurrence of toxic reactions in man. We are all agreed, however, that more fundamental biological and biochemical knowledge is required; it is equally true that there are new experiments to be done which cannot be designed until this knowledge is available. The degree of safety of a drug is a consequence of this knowledge which embraces the understanding of drug action, drug metabolism, and chemical structure, in relation to living processes. S o far, n o laboratovy or animal test can guarantee a n effect, or lack of effect, desirable or undesirable in man. This all means that there is a definite element of risk when a drug has to be given to "somebody who has to he first." As Dowling (5) has pointed out Investigating t,he action of dntgs in h~lmansis an honored and respected calling-a calling that has been followed by some of medicine's greatest names . . . Thestudy of drugs by clinicians is a part of clinical invest,igation. The testing of drugs on man is as old ax medicine itself. The sohsianbiation of drug-related side effects is not as easy as it would appear a t first sight, for even douhle-blind clinical trials have shown the nlaeebo. a hioloeicallv
Within the next decade we will see the development of an internationally acceptable coding system and the development of machine compatible systems of recording detailed descriptions of patient clinical response to adverse toxic reactions. The biggest difficulty is likely to be the development of a n internationally agreed terminology to he linked to the code. The system of coding and storing will be highly flexible and capable of accepting programs and data both planned and different from those envisaged a t the time; and it must have the ability to feed back information and derived instruction to modify the experiments or trials in being. Finney defines the monitoring of drugs as any systematic collection and analysis of information pertaining to adverse effects or other idiosyncratic phenomena associated with the normal use of drugs. He emphasizes the necessity of the computer giving an early warning when the accumulating evidence suggests that the drug has adverse side effects, and not waiting until the evidence is overwhelming. A properly planned computer would screen a large number of records in respect of a wide range of variables, thereby enabling medical as-
sessors to exert their expertise in interpreting the medical data processed by the computer. There is one thing that the computer will not do and that is reduce the biological time constants of man or experimental animals. Such a system has already been started in the States and will when developed, be linked with Europe. With such aids, human pharmacology will develop more rapidly than a t present. By human pharmacology, we mean the study of the effect of drugs on man in health and disease. It is suspected that in some cases the body's reaction to a drug may be different in the diseased state when compared with the normal. The advent of more powerful and sophisticated drugs with a remarkable degree of specificity in modifying organ functions in a profound manner (essential for the treatment of diseases of organic dysfunction or deep-seated degenerative disease) has increased the emphasis on the mode of action of drugs and toxicity studies in depth. An essential part of this is human pharmacology without subjecting the individual to undue hazard. Such studies should not be carried out on the under-privileged or on people of under-developed countries, for active participation and understanding can be very important. An example of this is to be seen in the prolonged study over several years to discover the effects of lowering the blood cholesterol aud other serum lipids on morbidity and mortality in atherosclerotic disease. Fovmulation. The dosage form of a drug is of great importance. The patient response to a single therapeutic agent may vary between patient discomfort and reversal or total lack of therapeutic effect, according to the form in which the drug is administered. The examples of this are legion; the availability, absorption, and blood levels are profoundly influenced by the formulation. For example, in the case of tetracycline, calcium diphosphate used as a filler will decrease absorption, while citric acid and glucosamine enhance it. Increase in pressure in making a tablet may increase the disintegration time. I n the case of suspensions, the choice of dispersing agents such as carboxymethylcellulose, lecithin, polyvinylpyrrolidine, etc., will influence suspension stability, thickness, foaming, and the likelihood of needle blockage. Particle size can be of major significance; very small particles of erythromycin esters are subject to acid attack, large particles are slowly absorbed, while a mid-way size is satisfactory. I n other cases, very small particles produced by micronizing thereby increasing the surface area will result in a smaller dose to produce the necessary blood levels. Levy and Nelson summarize the position; they say Formulation of drugs into various dosage forms may modify profoundly the onset, intensity and duration of physiological response, the correct dosage for the patient, the incidence and intensity of side effects and the stability of drugs.. .. I t is dear that in some cases choice of dosage form and manufacturer's brand may be as important as choice of the actual therapeutic agent.
Currently, as yon know, drugs are given as tablets, capsules, solutions, injections, ointments, and so on. But the future will see quite new types and ways of administering drugs. You may have read the recent announcement that a new company has been formed to discover such methods. Drugs which can be obtained without prescription, Volume 46, Number 8, August 1969
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often called o-t-c (over-the-counter) drugs or proprietaries are legion. Many are useless, possibly dangerous, or fraudulent. The future will see stricter controls which will result in an expansion of those based on genuine sound research and developed and proved safe in professional use; i.e., drugs that have been ethically distributed for a considerahle time only to hospitals and clinicians. This will result in a worthwhile range of truly effective and useful products, and a t the same time see the elimination of useless formulations like flu powders, cold cures, and the like. New formulations of known drugs and entirely new compounds for o-t-c distribution will be subject to stricter F.D.A. and similar controls, including proof of eflcacy. Probable Breakthrough Areas
Let us now discuss the fields in which we are likely to find new drugs both in the near and more distant future. I n our present state of knowledge, the hreakthroughs we should like to see and those we will see, will not necessarily he the same. I n my opinion, the fields in which new break-throughs are most likely to occur might he as follows; however, the order of listing has littalesignificance. They are Cordiovasculor Disease Including Atherosclerosis
We are already in the midst of this. For example, drugs known as &blockers, which can control the force of the heart heat, are under extensive trial in man. There are many possibilities here including a high degree of specificity for the heart alone. Another drug is also under intensive human investigation for the control of blood lipids. I t is Atromid-S or Clofihrate, which could be of importance in the treatment and prevention of coronary heart disease. I t is believed, with good reason, that high levels of blood cholesterol are associated with a high incidence of coronary heart disease. Infiammotion, Arthritis, and Allergy
Prolonged administration of corticosteroids is not the answer because of the unwanted side effects. A non-steroid anti-inflammatory drug which can he given for a long time is likely to he discovered. Gastrointestinal lnflammotion Leading to Ulcer Formofion
The current work on gastrin, a stomach hormone, is likely to lead to drugs which will control secretion and prevent ulcer formation. Centrol Nervous System ond Psychophormocology
This includes drugs which may depress or stimulate or affect the CNS in different ways, thereby opening up a therapeutic approach to the treatment of mental illness. We shall probably see the introduction of drugs which will improve mental activity in the retarded and also improve memory and concentration. Mild CNS stimulants of a caffeine-like nature might well come out of these studies. Wound Heoling
I believe it may he possible to improve the rate of healing or a t least the quality without excessive scar formation. 472
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Oddly enough, advances here are most likely to come from investigations in the animal husbandry field. The control of fat deposition is important in both the human and animal fields; in the latter, bacon raisers find excess fat in pigs to he a problem. Methods of controlling fat metabolism, with a preference towards protein synthesis, is obviously desirable. Apart from those cases involving metabolic disorder, the simplest answer in man is to eat less and balance the diet. The agents used should he non-hormonal. Non-Additive Analgesics
A boon to both patient and physician would he a drug approaching the power of morphine without addiction, and without the irritant properties of large doses of aspirin which can cause gastrointestinal bleeding and other undesirable toxic effects. I think such a drug or evena series of them is likely t o be found. Senescence
The number of people in advanced countries living beyond 70 will increase considerably as therapeutks improve. However, geriatrics has a long way to go in understanding the aging process and it is unlikely that there will be any useful drugs in the near future which will modify the aging process as a whole. But there are indications that we may be able to inhibit the process of senescence in individual organs such as the kidney. While older people are more susceptible to chronic troubles such as bronchitis, cancer, rheumatism, heart disease, and mental deterioration, discoveries in these disease fields will do much to make old age more comfortable. For example, the slowing or prevention of arterial degeneration could be a major factor in preventing mental deterioration. A better understanding of the etiology of many diseases such as cancer, will come from a more detailed understanding of the role of DNA (deoxyribonucleic acid) in the maintenance of type in cells and in higher forms of life. I n an address in 1963 Todd (6) said One phenomenon which is of very general interest and which may shortly find an explanation from work in this field ia that of aging. The stages of growth, maturity, aging and death are universal in living creatures. And yet if an animal is just an assemblage of individual cells undergoing continuous growth and reproduction by division according to a known pattern, aging is not easy to understand since cells would be expected to be virtually immortal. The phenomenon has been attributed by some to random mutations but in a complex organism like man I find this explanation rather unsatisfactory. More attractive is the possibility suggested to me recently by my colleague, Dr. 13. E. Orgel. As he points out, we know that in the synthesis of enzyme proteins through the agency of nocleic acids there is a small but finite chance of error in the selection of amino acids. Where the enzyme protein prodoced is simply involved in some process of intermediary metabolism an error can have no serious consequences since it will be confined to very few molecules of transient importance. But if the error is in an enzyme protein involved in the series of reactions leading to new genetic materid the situation is very different; for the error will he passed on, the mistakes will multiply and gradually the cell will change and ultimately its capacity to grow and divide will come to a halt. This, it seems to me, is an attractive hypothesis for the process of aging and one which offers scope for considerahle experimental develop ment.
Cancer and Virus Diseases
Apart from the possibility of an early break-through in leukemia, it would seem that the enormous effort which has been put into the search for a cancer arresting, curing, or preventing agent has met with little success. Many thousands of compounds are screened each year against a wide variety of experimentally induced tumors in animals. The animal screen ranges through transplanted tumors, virus induced tumors, and chemically induced tumors. The significance of inhibition of these experimentally induced growths by chemical means to the naturally occurring malignant growths in man has not yet been elucidated. There is considerable doubt, however, that the screening of compounds against transplanted tumors in the lahoratory animal is of sufficient significance to justify extrapolation of the findings to man. It does not lead to any understanding of the human disease process nor has its inhibition ever been shown to have any relevance to natural malignancy in man. It is by a better understanding of the mechanism of human malignancy that a solution is likely to come. A more meaningful experimental model could then be developed. Cancer is a condition in which normal cells become abnormal and develop, multiply and invade normal tissue. Normal cells do not invade other normal tissues. What are the factors which bring about this difference? At one time it was thought that cancer cells multiplied more rapidly than normal cells. A great deal of potential therapy was, in consequence, directed towards killing rapidly multiplying cells preferentially, i.e., those cells multiplying more rapidly than the normal cells necessary to maintain life. However, it is now realized that cancer cells do not multiply more rapidly than all normal cells. Drugs, therefore, which do kill rapidly dividing cells if given in sufficient dosage to kill cancer cells could he lethal to the patient, for there are many cells essential to life which multiply a t a prodigious rate. This has been dramatically pointed out by Solomon Garb and John Pfeiffer. There are on the average, 5,000,000 red blood cells in a cubic millimeter of hlood which means 5 hillion/cm3 or 5 trillion (U.S.)/l. Since we have 5 1 of blood in our bodies, we have 25 trillion-25,000,000,000,000 red cells in our hlood. Now the red cells have a limited life and are replaced every 120 days or in 10,368,000 seconds. The number of new red cells produced per second is, therefore, 2,400,000! No cancer grows at this rate; if it did, it would weigh well over 20 lb in one year. You will understand now why some anti-cancer drugs based on killing rapidly dividing cells cause severe or lethal blood abnormalities. The red cells are not the only rapidly multiplying cells of the body; for example, the lining of the intestinal tract is replaced every 24 hr. The skin is also constantly replaced while the nerve cells sse not. Cancer Drugs
As mentioned previously, a characteristic of cancerous growth is the invasion of normal tissues by growing in between normal cells. Normal growing tissues and non-malignant growths are unable to do this. Elucidation of this mechanism could result in the synthesis of an agent which might hlock it and thereby contain the growth, even though it did not effect a true cure.
Molecular biology is the most probable source of a break-through, particularly with a greater understanding of protein synthesis and the roles of DNA and RRA. The first glimmer has appeared; adenovirus tumors have been inhibited by 5-iodo-2-deoxyuridine which also prevents DNA virus replication. Currently, the getting of an adequate dose of a cytotoxic drug to a cancerous tumor is difficult without swamping the patient. Cancerous growths have a poor circulation in terms of through-put, although they have a relatively large blood volume within them. These facts might offer possibilities. A possible solution is indicated by the existence of an immunological factor which suggests that immune globulin might be uscd to carry cytotoxic drugs specifically to the tumor.
This is a very interesting substance produced within a cell, for it prevents the replication of viruses. It was discovered in the Medical Research Council Laboratories in England by Dr. Alex Isaccs and Jean Lindeman in 1957. Essentially it is a cellular reaction to a virus, modified by chemical or physical means such as ultra-violet irradiation. When such a virus is injected into an animal, it passes into the cells and causes them to produce a harmless substance which prevents these cells from manufacturing virus particles when a virulent strain is subsequently injected. This protecting substance has been dubbed interferon. A virus cannot multiply by itself. I t must enter a cell-leaving its protein overcoat behind-and convert the interior of the cell into a virus manufacturing unit of the virus type carrying out the invasion. Hence the significance of RiYA which is the carrier of the required genetic information to make the cell do this. I n this manner, some 200 new viruses are produced by a cell in about half an hour. Obviously, anything which can hlock or prevent this replication process will prevent the establishment of a virus disease such as influenza. Unfortunately, interferon prepared from animal cell cultures is capable of giving protection for only 24-48 hr after injection. Furthermore-a particular interferon produced in this way is not universally anti-viral. I t tends to be restricted to specific groups. Therefore, foreknowledge is required of the strain of virus about to attack. I t is evident that the best thing to do is to induce interferon formation in a potential victim of infection by synthetic chemical or biochemical means. This will avoid the contamination of the product by unwanted impurities such as protein, allergenic substances (inevitable when natural protein sources are used), or animal antigens. The first crucial step in the direction of a synthetic interferon inducer has, in fact, been accomplished by that remarkable pioneering company Merck. Using elegant methods and reasoning, they found that helenine from a penicillium mold induced resistance to two viruses in mice. They reasoned that the active principle was probably a nucleotide. Purification showed it to be double-stranded RNA, confirming their previous idea that RNA was the key to interferon production. It was inactivated by protein impurities while singlestrand RNA and Dh'A were inactive. Pure doublestrand RNA was extracted f ~ o ma virus and was found to he an interferon inducer. With this knowledge, they Volume 46, Number 8, August 1969
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set about attempting to make a synthetic inducer from nncleic acid analogs, polymers of cytosine, adenine, etc. Their most active substance was a complex of polyinosinic and polycytidylic acids which was effective in microgram quantities. I n the not too distant future, perhaps within the next decade, such substances will be available to combat virus diseases for which there are no vaccines, and as a prophylaxis for respiratory viral infections like the common cold and influenza. I n the case of flu prophylaxis for example, i t will not be necessary to prepare new specific vaccines to keep up with and match the ever changing genetic make-up of influenza viruses. There are innumerable possibilities of different nucleotide combinations, and it is not unreasonable to expect that synthetic interferon inducers of varied specificities will be powerful enough to give protection for a month or possibly longer. Let us hope that these interferon inducers will be shown to have a low toxicity. This is essential, as they will be administered to normal healthy individuals. Family Planning and Fertility Control
While the current hormonal progesterone/oestrogen method (the pill) will continue for some time, increase in our knowledge of the extremely complex physiology of human reproduction will eventually lead to a nonhormonal interference without otherwise modifying the physiological mechanisms of the maternal organism. This has already been accomplished in animals. An anti-zygotic agent would come under this heading, for it is known that the recently fertilized egg is extremely vulnerable to spontaneous and induced influences. Interference at this stage has also been attained chemically in animals. An anti-zygotic agent has the advantage in that a single dose can be given two or three days after mating and the development of the egg is inhibited if fertilization has occurred. For the male partner, a single dose regime with antispermatogenic effect is also possible. The period of infertility lasts for four weeks in rats. The state of infertility can be maintained indefinitely by monthly doses and it is completely reversible when the treatment is withdrawn. By about the year 2000, we should have non-hormonal family planning with chemical control of both the male and the female and it will be completely reversible a t will. This rather long period ahead is due to the prolonged control trials that will be necessary. It is agreed that there are thirteen well recognized major steps or stages at which physiological reproductive mechanisms are subject to control. Blocking of any one of these steps will effectivelyprevent reproduction, since each step is essential. The choice of the step to be blocked is determined in part by the possible consequences and hazards to normal physiology. However, the possibility of being able to choose the site of action, together with the very wide range of chemical types which may he tailored to our requirements, leads one to expect a safe, acceptable and cheap solution within the next 25 years. Biosynthesis
It is quite clear that laboratories all over the world are investigating the potentialities of suspended animal 474 / Journal o f Chemical Educotion
cell cultures, plant tissue cultures, and microbiological fermentation as a means of producing complex biologically active substances. These efforts will follow two broad courses (1) the production of natural products and of biologically active compounds both known and new (2) food products, chemicalls and intermediates for the chemical and other industries
Under (I), which concerns us today, there are many exciting prospects such as the chemical modification of hormones secreted by cell cultures and the modification of alkaloids in plant cell cultures by the introduction of novel intermediates into the substrate. With the development of an adequate degree of sophistication, we could obtain products tailored to our specific requirements. Cell cultures could he valuable sources of physiologically active polypeptides of unique types. Except in those cases where a reaction is unique to a particular mammalian tissue, there is no real evidence that mammalian cells have advantages over microorganisms as metabolic agents. The inspired investigations of Bloch, Lynen, and Cornforth cited by Todd (6) have established in detail the mechanism by which micro-organisms synthesize terpenoids, rubber, and the steroids from acetic acid-a mechanism which makes use of the organic phosphates to make carbon-carbon linkages. The efficient production of human and veterinary virus vaccines using continuous cell lines will be a reality in thc '70's. There is already evidence that under appropriate conditions, continuous cell lines need not constitute a carcinogenic hazard. The operation of a continuous culture plant or a 1000 gal stainless steel vessel of suspended cells with versatility of control is a more attractive proposition than running a farm of vaccine and sera-producing horses. The former would have a much higher output and require less space than the latter. The overheads, too, would he lower, particularly when production was stopped. Under (2) the field is also wide. For example, hydrocarbon substrates from crude oil or refinery fractions are freely available and of definable quality; here the products range from amino acids and other nitrogenous products to alcohols and dibasic acids. Success in establishing continuous fermentation and culture methods-as opposed to batch methods-and continuous cell lines, combined with the development of useful organisms, enzymes, and substrates, will benefit both medicine and the chemical industry. Growing cells in a controlled environment different from that occurring in an animal, and the addition of unnatural precursors to the substrate, would produce entirely new substances which might defy synthesis by other means. I do not foresee the early synthesis of enzymes possessing the high degree of specificity of natural enzymes for use in biosynthesis or other purposes. This is not surprising, for they are usually proteins. Biosynthesis could, however, he a useful source of enzymes. The new drugs produced by this means would be highly specific, possessing virtually only the action required to combat a particular disease. While they will not be devoid of toxicity, they may well be devoid of some of the undesirable side effects found in current drugs and hormones when used therapeutically.
Instead of extracting hormones from animal glands which, so far, have eluded synthesis, we shall be able to produce these from animal cell cultures, including man. They could, of course, be modified by alterations of, or by additions to the substrate. The technique of grafting and transplanting organs is facilitated by means of steroids and other drugs capable of blocking the inductive phase of antibody formation. It is not beyond the bounds of possibility that animal organ transplantation into man-perhaps from higher apes-may be successfully achieved using similar techniques or by breeding animals with entirely new tissue antibody producing characteristics to serve as living organ banks. Our improved knowledge of physiology and hiochemistry in both health and disease will require the development of diagnostic aids as yet undefined. These may take the form of enzymes or co-enzymes through which alterations in cellular metabolism could he traced. We are about to see routine studies a t the cellular level in man. Incipient mal-function would be detected earlier than now, perhaps in some cases before the disease process had started at all. Knowledge of this type would result in specification of the drug characteristics required. Prophylaxis through drugs will soon he a reality and advanced human pharmacology will be medically and socially acceptable. The hazards of extrapolation from the laboratory animal to man can never be removed, but they would be considerably decreased in the light of these developments.
Estrone Figure 1.
Testosterone
The mole and female sex hormones.
eclectic range of therapeutic usefulness. It is obvious that the biological effects of the female and male sex hormones are somewhat different. Figure 1 shows the two structures. I n criticizing the pharmaceutical in-. dustry for indulging in trivial molecular manipulation, a member of the British parliament actually used the addition or removal of the groups shown in these two molecules as an example for his argument. Woodward (71, in comparing quinine with its dstereoisomer quinidine, shows that the same chemical composition with a difference in the spatial arrangement of identical groupings of atoms produces different forms of matter with different biological properties. Quinine is useful in the treatment of malaria while quinidine is used in the control of auricular fibrillation and flutter-an action not possessed by quinine. Figure 2, after Woodward, illustrates the two structures. The difference in the arrangement in space of OMe
Molecular Manipulation
The pharmaceutical industry is often accused of directing too much of its research effort to minor molecular change, sometimes called molecular roulette. This criticism arises from a complete lack of understanding of the relationship of chemical structure to biological activity. Slight variations in structure may not only improve the desired properties of the original compound, but also result in a completely different therapeutic effect. A few examples demonstrate this: Sulphonamides make a classic case; chemical modifications not only resulted in improved anti-bacterial action and better tolerance, but in derivatives with entirely new effects. Following the clinical observation of the diuretic effect of sulphanilamide and the elucidation of the mechanism of its action at Cambridge University, extremely powerful and useful derivatives such as diamox and chlorothiadde were developed by industry. Not only were they an improvement over the older mercurial type of diuretic in effectiveness,but they were safer and more consistent in action. Other substituted sulphonamides were found to possess blood-sugar lowering activity which led to the oral anti-diabetic drugs such as tolbutarnide used in milder forms of diabetes mellitus which cannot be controlled by diet alone. The steroids are yet another example of the profound differences in biological action as the result of molecular manipulation. It is probable that some 25,000 steroids have been synthesized. The medical applications are many; they vary from fertility control to inflammation and arthritis alleviation, a truly
Quinine
Quinidine
Fieure 2. TWO rtrvctvrer which are very similar but have different and very useful phonnacalogicol properties ore quinine and its D-stereoisomer quinidine.
the identical group of atoms occurs a t the sites numbered 8 and 9. The above examples clearly demonstrate how uninformed are those critics who denigrate molecular manipulation. Literature Cited (1) CHAIN, ERNEST B., J . ROY.SOC.Arts, 111,856 (1963). (2) YON MURALT,A. i ' P r ~ h l e min~ the Encouragement of the Advance of Science" i n "Pointers and Pathways in liesewch," Ciha of India, Bombay, 1963. I . YULI:,Pham. J., 188,27 (1962). (b) BOGUIT, (3) (a) Bocuc, . J. YULE, "Science, Industry and the State," (Editor: SMITH.G. T ~ L I N. G Peraamon )Press. London. 1965,. PP. .. 53-70.' (4) SPINKS,A,, "Ev~hmtionof New Drugs in Man," in "Proceeding~of 2nd International Pharmacological Meeting," Prague, 1963. (5) DOWLINC, HENRYF., J. Amer. Med. Assoe., 187, 212 (1964). ( 6 ) TODD, LORD, "New Horizons in Organic Chemistry," in "Pointers and Pathwavs in Research." Ciba of India. Bomhay, 1963. (7) WOODWARD, A. R., "Synthesis of Organic Compounds" in "Pointers and Pathways in Research," Ciha, of India, Bombay, 1963.
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