00:00:00 The following program is produced by KQED and the American Chemical Society.

00:00:11 The alchemist had it easy. Try anything until it worked, and sometimes it did.

00:00:18 Paul Ehrlich's magic bullet against syphilis made medicinal chemistry a little more certain.

00:00:24 Then came the antibiotics, the sulfur drugs that saved so many lives in World War II.

00:00:29 Now there are drugs to calm or literally explode the mind, cure a headache or say of a dying heart,

00:00:37 make you sleep or keep you awake, stop pain and thwart malaria.

00:00:43 And the biochemical revolution discussed on the previous program in this series

00:00:47 is providing enough data to keep medicinal chemists content for years.

00:00:52 But the drug makers have been made sharply aware of new hazards,

00:00:56 a new understanding of what misused drugs can do both to the body and the mind.

00:01:02 Thalidomide and LSD are two extreme illustrations.

00:01:06 Now they're no longer content to approach drug design on a hit-and-miss basis.

00:01:11 They become architects of molecules, drawing and constructing the ideal shapes for drugs best suited to an illness.

00:01:19 Today we examine the hopes and achievements of this new medicine as it applies to the biochemical revolution,

00:01:26 drugs such as LSD, and population control.

00:01:30 Here is the moderator, David Perlin, science editor of the San Francisco Chronicle.

00:01:49 Our guests this evening are Dr. Aaron Bendick, who is head of the organic biochemistry section

00:01:56 and professor of biochemistry at the Sloan-Kettering Institute for Cancer Research in New York City.

00:02:02 Dr. John H. Beal, vice president for research and development of the Aldrich Chemical Company in Milwaukee.

00:02:09 And Dr. Ralph I. Dorfman, senior vice president at Syntex Research in Palo Alto, California,

00:02:16 and director of the Institute of Hormone Biology there.

00:02:20 These three men have widely varying interests in hormones and fertility control,

00:02:27 in drugs that act in many ways on the mind, in cancer research,

00:02:34 and the strange molecule that we were talking about in our previous program, DNA.

00:02:41 So I'll talk to Dr. Bendick first and ask you, Dr. Bendick,

00:02:47 DNA, in a sense synthesized, actively synthesized, carries information.

00:02:56 Can it carry information from one cell to another,

00:02:59 and can the ability of transmitting information this way possibly lead to something useful in controlling disease?

00:03:08 So the transmission of information from cell to cell takes place whenever there is fertilization of the egg by the sperm.

00:03:15 In this particular instance, of course, the sperm cell brings the genetic information which is within that cell

00:03:21 directly into the egg cell where this now mixes.

00:03:26 But recently there have been examples of the passage of genetic material from one cell to the next

00:03:35 by a virus particle, for example, or merely by mixing cells together as they grow in culture.

00:03:42 One can observe a passage of genetic material from one cell to the next, DNA in fact.

00:03:48 Well this is, in some of your own experiments, you've seen this movement of DNA from one cancer cell to another.

00:03:54 From one cancer cell to another cancer cell.

00:03:57 And recently we've observed this sort of passage from a cancer cell to a normal, to a non-cancer cell.

00:04:03 The idea here is that if this does in fact happen, if this can in fact happen,

00:04:08 we may have here an explanation of the metastatic spread of cancer.

00:04:13 In the cell that you, in the cancer cell that you observed,

00:04:17 sending its little bridge of material into a normal cell and perhaps transmitting DNA across that bridge,

00:04:24 did the normal cell become infected and turn malignant?

00:04:29 I'm sure that the normal cell has acquired genetic material it never possessed before,

00:04:34 but it's still a question as to whether or not this has acquired a new biological function.

00:04:38 This is in fact what we're working on.

00:04:40 If you did discover that this were true, then this would obviously have great implications

00:04:46 for an understanding of the spread of cancer and possibly for its control.

00:04:49 Right, this is an objective.

00:04:51 Can cancer spread in this particular way?

00:04:54 Can we transfer genetic information from one cell to another?

00:04:57 This has bearing both in attempts to elucidate what cancer is,

00:05:02 the genesis of cancer, and also other heritable diseases, of which there are many.

00:05:07 I want to move for a moment now to Dr. Beale, whose work is in a wholly different direction,

00:05:16 although I'm sure has many links in common as all chemistry and all physiology does.

00:05:23 You're working in the area of drugs in the mind,

00:05:26 and this is an area that has frightened many people in recent years.

00:05:33 Do you think that the kind of work you're doing is leading to a serious new understanding

00:05:39 of mental illness itself?

00:05:42 Yes, let me say this, that the drugs that have been investigated and synthesized

00:05:49 have actually led to an understanding of the mechanism of brain function.

00:05:55 We can say today almost categorically that emotion is chemically controlled,

00:06:02 that an emotionally stable person has a chemical equilibrium in the brain,

00:06:09 which if disturbed will lead to a psychiatric disturbance.

00:06:15 And the drugs that we have at our disposal today have elucidated the mechanism of these hormones

00:06:24 and pointed to the fact that emotional balance may be balanced on a chemical knife edge,

00:06:31 that you have opposing neurohormones in the brain,

00:06:35 which must be balanced in order to ensure emotional stability.

00:06:40 What sort of chemicals have you worked on, chemicals in their relationship to the mind?

00:06:48 We got into this field rather fortuitously.

00:06:51 We had worked on drugs for peptic ulcer,

00:06:55 and when it came to the clinical testing of these drugs,

00:06:59 we observed that these patients suddenly almost went into outer limbo.

00:07:07 They hallucinated and they were psychotic.

00:07:14 And in further investigating the possible mechanism of action of these agents,

00:07:19 we found that these were blocking agents of a very important neurohormone,

00:07:26 namely acetylcholine, which is responsible for the neurotransmission of all nerve impulses

00:07:34 emanating from the central nervous system.

00:07:37 And by blocking apparently acetylcholine in the brain,

00:07:42 we initiated or induced an imbalance which was reflected in a psychotic state

00:07:49 lasting anywhere from eight to 36 hours.

00:07:52 What did it do for the ulcers?

00:07:54 It cured the ulcers.

00:07:58 But I take it that the drug is not used for curing ulcers at this point,

00:08:04 at least in the molecular form that you first derived it.

00:08:07 That's very true.

00:08:08 But the interesting thing was that it led to an understanding also of the cure of mental depression

00:08:17 because depressed patients going through several of these episodes remitted to the disease

00:08:27 and were free of the disease for several months.

00:08:32 You used a word there which I want to get back to in a moment,

00:08:35 and the word that you used in connection with mental depression was cure.

00:08:40 Good to hear.

00:08:41 But let me move to Dr. Dorfman for a moment

00:08:46 and ask you, Dr. Dorfman, coming from Syntex Laboratories,

00:08:50 we know that your work is, Syntex Research that is,

00:08:53 you know that your work is connected with hormones and fertility control.

00:08:57 Where do you stand in this quest at the moment?

00:09:00 Well, first I might say that our work has started

00:09:05 and is progressing in a manner somewhat different than Dr. John Beale's

00:09:10 in the sense that we started looking for one thing and found something else.

00:09:15 Fortunately, we had a rather wonderful background

00:09:19 due to the immense work that was done in the chemistry of hormones

00:09:24 and the physiology of reproduction

00:09:26 that permitted Dr. Pincus and Rock in their classical studies

00:09:31 to pinpoint what should be in the pill,

00:09:35 to design a pill with some considerable thought and direction.

00:09:42 And if I might say what our work is at the present time

00:09:46 is to take some of these very fine early advances

00:09:51 and carry them to a much more refined technique.

00:09:55 And I'll explain it in this way.

00:09:57 That in the original pill,

00:10:00 used by over 10 million women perhaps throughout the world,

00:10:05 and which is essentially 100 percent effective,

00:10:10 it's not 100 percent but would be 99.99 and et cetera,

00:10:15 that this particular pill had a design

00:10:19 which meant that the normal reproductive processes

00:10:23 were essentially cut out of the system.

00:10:28 This meant that ovulation didn't take place.

00:10:31 There could be no contact between a sperm and a fertilizable ovum.

00:10:37 And secondly, there was in its place the substitution of hormonal agents

00:10:45 which so simulated the normal menstrual cycle

00:10:49 that the cycle superimposed was indistinguishable

00:10:54 from what the woman had experienced throughout her life.

00:10:59 But we recognized the fact that we took something away

00:11:03 and then we added something and leaving a little subtraction,

00:11:07 or perhaps more important, the subtraction of ovulation.

00:11:12 And now our entire effort is directed toward the permitting

00:11:18 of the normal rhythm, the normal ebb and flow of the hormones,

00:11:24 the normal changes, for example, in the reproductive tract of the woman,

00:11:30 the function of the pituitary gland,

00:11:33 those hormones in the brain and related to the brain.

00:11:39 That these, our objective is to keep these processes

00:11:43 normally marching along as they normally would.

00:11:47 But instead, attempting to interfere with highly specific changes,

00:11:54 modifying, for example, the effectiveness of the sperm,

00:12:00 preventing, for example, the sperm and the ovum of arriving

00:12:04 at the right place at the right time.

00:12:07 One might be at the right place at the wrong time, for example.

00:12:12 So our entire objective then is to move toward a normal physiology,

00:12:18 reproductive physiology, and interfering with selective points

00:12:22 in the reproductive cycle.

00:12:24 And it's your basic assumption, then, I gather,

00:12:28 that the normal physiology in this area is hormonally governed in a sense,

00:12:35 that by understanding how those chemicals are operating in the human body,

00:12:39 you can pick out these points at which to attack the problem.

00:12:43 Yes, these points have been identified through very painstaking work

00:12:48 in humans and in animals over many, many years,

00:12:52 and this knowledge continues to grow.

00:12:55 But our knowledge already is rich enough so that we can point

00:13:00 to specific important spots at which this can be attacked.

00:13:05 And if I were to give you a specific example,

00:13:08 we have already been able to go through various phases of control of fertility.

00:13:16 The first phase I have already described,

00:13:19 which was the discovery of the addition of a certain set amount

00:13:26 of an estrogenic female hormone and a progestational agent,

00:13:32 if you will, a second female hormone added for 20 of the 28 days of the cycle.

00:13:38 These are the hormones that put part of the process to rest.

00:13:44 Secondly, these were modified, but still, these were mechanisms

00:13:49 by which something was taken away and something was put back.

00:13:54 In our newest efforts at the present time,

00:13:58 very small concentrations, low dosages, if you will,

00:14:03 of progestational agents without estrogen are being shown

00:14:07 to affect the reproductive process in such a manner

00:14:12 that a minimum amount of change occurs in the normal cycling physiology.

00:14:18 This is what's been discussed as the mini-dose or the mini-pill.

00:14:21 This indeed, I believe, was coined by one of our very important periodicals,

00:14:27 that is, not scientific but excellent and we need not name here,

00:14:32 as a mini-pill, and the mini-pill is indeed,

00:14:39 looks as if an important advance in the control of fertility.

00:14:44 I would like, however, during our discussion,

00:14:47 to look at a second phase of fertility control.

00:14:52 Many of us have been so struck by the success of the pill,

00:14:57 including myself over the last 15 or 16 years,

00:15:01 that we sometimes forget the cases of sterility,

00:15:06 and it is indeed some of the same physiology that pertains to...

00:15:11 Induces sterility?

00:15:13 Induces fertility and changes the outlook for many couples.

00:15:20 Yes, well, when Rock and Pincus were first working,

00:15:23 weren't they working with the idea of working against sterility for fertility?

00:15:30 Yes, part of the program was exactly that,

00:15:33 and there was early evidence that in some instances,

00:15:38 sterile women could be modified so that a child could be born.

00:15:43 But perhaps more important advances have been made in this area

00:15:48 in which pituitary hormones chemically purify to a reasonable extent,

00:15:54 as well as certain agents as clomiphene,

00:15:58 which stimulate ovulation in women who normally do not ovulate.

00:16:05 You mentioned, Dr. Bendick, early,

00:16:10 that it wasn't just in the control of cancer

00:16:13 that this information mechanism from cell to cell might prove useful.

00:16:20 You suggested that perhaps the ability,

00:16:24 if we ever get to the point where we can harness bridges

00:16:29 so that DNA can be carried from one cell to another,

00:16:32 we might affect other diseases.

00:16:34 What sorts of defects did you have in mind?

00:16:37 Well, if you don't hold me to suggesting...

00:16:40 I don't make you promise that you're going to produce these in the laboratory by any means.

00:16:44 I think it's interesting to consider principles,

00:16:49 new principles in treatment,

00:16:51 regardless of whether or not they'll ever become practical.

00:16:54 There's a disease, for example, of a newborn called galactosemia.

00:16:58 The little child, of course, won't go on to hell,

00:17:01 end up, as a matter of fact, with some neurological disturbance

00:17:05 because of the inability to metabolize the sugar present in the milk.

00:17:09 This is what became popularly known as one of the inborn errors of metabolism, right?

00:17:14 I think it's rather clear now that there is an enzyme

00:17:17 which ordinarily would handle such a sugar missing in the cells of such a child.

00:17:22 The enzyme is missing because there is a deletion,

00:17:25 an absence of a particular genetic factor, an absence of a gene.

00:17:28 I can imagine that one can treat this disease by providing the cell with a missing gene.

00:17:33 For example, having cells of such a child grow in culture in the presence of DNA,

00:17:38 the genetic material, from a competent cell.

00:17:41 Perhaps if such a cell could be transformed,

00:17:43 perhaps these cells can be put back again in the child.

00:17:46 But I don't want to be concerned right now with the practical aspect,

00:17:49 but rather with the possibility that the genetics of a cell can be manipulated,

00:17:54 can be altered, can be influenced.

00:17:57 I think the genetics of cells are under the influence of hormones,

00:18:00 but this is a second-order level,

00:18:02 talking about the primary control which is inherent in the genetic material.

00:18:06 And so one can imagine, in principle at least,

00:18:09 the treatment where one furnishes a cell with genetic material it did not have before.

00:18:15 Hopefully this would integrate and become part of the cell.

00:18:18 This sounds to me that the principle is there,

00:18:23 and you can draw up what the principle would be,

00:18:26 but that an enormous amount of further research would be necessary

00:18:30 to take that principle and apply it first in a laboratory system

00:18:35 and then later in a living system.

00:18:38 Yes. If one wanted to take the trouble to apply it for a practical goal,

00:18:43 the concern of most of us is to see whether the principle has validity.

00:18:47 In order to understand how the genetic materials function,

00:18:50 what means genetic disease? Is cancer a genetic disease, for example?

00:18:54 These are critical questions, and it seems to me if we can sharpen up our questions,

00:18:58 perhaps then we might be able to take advantage of this

00:19:01 in the development of new methods of treatment.

00:19:05 There certainly should be no reason why in a civilization such as ours

00:19:10 these questions can't be sharply put in the laboratory and then worked on.

00:19:16 I assume one ingredient is money. I assume another ingredient is talent.

00:19:21 These are two ingredients that we're supposed to have a lot of in the United States.

00:19:26 I think one needs more.

00:19:28 What?

00:19:29 Imagination.

00:19:31 Well...

00:19:32 The word talent may cover that, you might say.

00:19:35 No, I think what one wants to do, or one has to do,

00:19:38 is to imagine the principles which are involved.

00:19:42 Now, to have a talent to imagine, maybe a talent to do...

00:19:46 I think perhaps that may not be in the chemistry and man program.

00:19:51 Well, if you're a real reductionist, you could of course say

00:19:54 that you can improve the chemistry of people that bring out their talent.

00:19:57 I think if we have the resources, the support, and the talent,

00:20:01 we could then use this if a principle has been enunciated

00:20:04 and then take advantage of a principle which has been enunciated and clarified.

00:20:08 But I don't think that just the use of talent and money

00:20:11 will clarify a problem which hasn't been clarified.

00:20:14 I think we have to clarify and crystallize the fundamental question.

00:20:19 I would agree with you that really what we have to...

00:20:23 We want the ingenious way of approaching an old problem,

00:20:28 a question asked in such a way that to a certain brain somewhere

00:20:34 a new methodology arises and that you can start dissecting little things.

00:20:39 And we've all seen it in our lifetime many times,

00:20:42 and we see the big pushes as a result of these very exciting advances.

00:20:48 For example, we set up the following proposition.

00:20:51 It is possible, this is the proposition,

00:20:53 it is possible to cure or to treat cancer with a chemical substance

00:20:57 if we make the right one.

00:20:58 Okay, this is the principle.

00:21:00 If it turns out the principle is wrong, it would make no difference

00:21:03 how much money or how much talent we brought to bear on the problem.

00:21:06 This is what I had in mind, the question of crystallizing the question.

00:21:10 I know it's an important question, how do we treat cancer?

00:21:13 Well, you can't do this simply by spending money and importing talent.

00:21:16 I don't think so.

00:21:17 I think you can do this possibly by asking what is cancer?

00:21:21 What is a cancer cell?

00:21:22 How does this operate?

00:21:23 What are the controls?

00:21:24 Are there hormonal controls, for example?

00:21:27 Are there synthetic substances which might, for example, influence?

00:21:30 And so on.

00:21:31 This is what I had in mind.

00:21:32 Well, in a sense, Dr. Beal is approaching his area of work in that fashion

00:21:37 by asking what are the principles that govern certain emotional states in people

00:21:42 and then looking at the hormonal systems that operate on those states

00:21:48 and then tailor-making molecules to affect those systems, isn't that?

00:21:54 That's very true.

00:21:55 The deal today was essentially three neurohormones in the brain.

00:22:01 Norepinephrine, which is the aggressive type of hormone,

00:22:05 acetylcholine, which is more of a tranquilizing transmitter,

00:22:10 and serotonin, which could be both.

00:22:13 We don't know the exact role yet of serotonin.

00:22:17 What drugs will do, they will interfere with the storage, with the uptake,

00:22:25 with the release of these hormones.

00:22:28 For instance, a well-known antidepressant drug will interfere with the uptake,

00:22:35 reuptake of released norepinephrine.

00:22:39 For instance, for a stimulus to reach the transmitter cell,

00:22:46 norepinephrine has to be released from its storage cell.

00:22:51 As soon as it's released, it's immediately trapped again,

00:22:55 and the stimulus is terminated.

00:22:58 Now in mental depression,

00:23:00 there may be either a deficiency of the supply of norepinephrine

00:23:05 or there may be an error of metabolism.

00:23:08 Maybe norepinephrine is broken down too quickly.

00:23:12 With drugs at our command now,

00:23:15 we can supply an overabundance at the receptor site of norepinephrine

00:23:22 to counteract the mental depression.

00:23:26 You used the word counteract that time.

00:23:28 You didn't use the word cure.

00:23:30 Well, you mentioned that because there is no cure for any of these diseases.

00:23:36 There is merely a remission of the symptoms,

00:23:40 and whether the etiology is chemical or environmental

00:23:45 really does not matter because we interfere with the chemical transmission of a disease,

00:23:53 and in so doing, we're able to control it.

00:23:56 It certainly would seem that there are environmental causes to these problems too

00:24:02 because you talked before about being on a chemical knife edge,

00:24:06 and certainly various things can push one over a chemical knife edge.

00:24:11 One can be pushed by another chemical,

00:24:13 but one can also be pushed by...

00:24:16 a kid can be pushed by fear of the draft,

00:24:18 or somebody can be pushed because a Negro family moves next door and he flips.

00:24:23 I might mention one example.

00:24:25 It was carried out a long time ago at the Worcester Foundation

00:24:29 where the urinary levels of a coach

00:24:33 and the urinary levels of the football team of norepinephrine and epinephrine were measured.

00:24:40 The coach, being full of anxiety, put out a lot of epinephrine or adrenaline,

00:24:46 whereas the football players who were ready for aggression and action

00:24:52 put out a lot of the noradrenaline or norepinephrine.

00:24:55 So here the stress situation in one case produced a certain amount of anxiety

00:25:01 which was reflected in the output of adrenaline,

00:25:05 whereas in the football players this similar stress

00:25:09 put out the aggression hormone norepinephrine or noradrenaline.

00:25:14 I might add that I was one of the co-directors at the Worcester Foundation at that time

00:25:20 and carefully followed many of these,

00:25:23 and even to the place of the psychoanalyst and his patient

00:25:28 who were also studied in similar fashions.

00:25:31 But I would like to ask you, Dr. Beale,

00:25:35 about the role of the steroids in your field.

00:25:40 I mean, we have a strong feeling about the action of some of our steroid compounds,

00:25:47 particularly the androgens which give you a sort of a sense of well-being.

00:25:52 Progesterone, through its metabolites more than as a compound per se,

00:25:59 seems to have an effect on body temperature.

00:26:02 It has an effect perhaps also on quieting, if you will.

00:26:09 I will not use those terms that you will eventually use them in a more precise manner.

00:26:15 And of course the use of corticoids or the misuse of corticoids frequently,

00:26:20 not frequently but infrequently I should say, ending in psychotic episodes.

00:26:27 Would you comment on this?

00:26:29 Yes, I think that any stress situation may deplete certain organs of certain hormones.

00:26:38 But secondarily to it, the end result will still be a manipulation

00:26:45 or a reflection in the neurohormonal picture.

00:26:50 I think that the stress situation which does bring about hormonal changes

00:26:55 of the hormone type that you allude to

00:26:58 will eventually affect the neurotransmitter hormones in the brain and act upon them.

00:27:06 Adrenaline, of course, is also a hormone of the adrenal glands,

00:27:10 so your point is well taken.

00:27:13 Let me suggest to you that Arthur Kessler not too long ago in Ghost in the Machine

00:27:19 suggested that the drugs you've been working on and combinations thereof

00:27:24 are merely a first step toward a sophisticated range of aids

00:27:28 to promote a coordinated, harmonious state of mind.

00:27:32 Do you think it's possible also that the society we live in can contribute to that?

00:27:37 Yes, I think we're moving in that direction.

00:27:41 We can always also move in the opposite direction.

00:27:44 We have drugs that can bring total emotional chaos, as you well know.

00:27:50 Many of the natural alkaloids that South American Indians play with

00:27:58 induce some very erratic types of behavior,

00:28:03 and these, curiously enough, bear the skeleton structure of the neurotransmitter hormones.

00:28:14 Well, and I'll have to stop there.

00:28:16 Unfortunately, we could go on for hours,

00:28:18 but I have time only to say thank you to all three of you

00:28:21 for a very illuminating discussion on three widely ranging subjects.

00:28:27 ♪♪

00:28:33 Our guests for this program were Dr. Aaron Bendick,

00:28:36 member of Sloan-Kettering Institute for Cancer Research,

00:28:39 Dr. John Beale, vice president for research and development, Aldrich Chemical Company,

00:28:44 and Dr. Ralph I. Dorfman, director, Institute of Hormone Biology,

00:28:48 and vice president for research of Syntex Laboratories.

00:28:53 The moderator was David Perlman, science editor of the San Francisco Chronicle.

00:29:00 We wish to thank Lederle Laboratories Division, American Cyanamid Company,

00:29:05 and Syntex Laboratories, Incorporated,

00:29:08 for their cooperation in providing visuals used on this program.