Asimov, Isaac - The Human Brain The Human Brain

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HUMAN BRAIN

ITS CAPACITIES AND FUNCTIONS

BY ISAAC ASIMOV

ILLUSTRATED BY

ANTHONY RAVIELLI

A SIGNET BOOK from IMEW AIVIERICAIM LIBRARY

TUMECMIRRCM

To Gloria and William Saltzberg, who guarded the manuscript

All rights reserved including the right to reproduce this book or parts thereof in any form. For information address the publishers of the hardcover edition, Houghton Mifflin Company, 2 Park Street, Boston, Massachusetts 02107.

FOURTH PRINTING

08101417 TRADEMARK HEO. fl.B. F*T. OFF. AND FOREIGN COUNTBIEB REGISTERED TRADEMARK——MARC A BBOIBTBABA HBCHO EN CHICAGO, C.S.A.

SIGNET, SIGNET CLASSICS, SIGNETTE, MENTOR AND PLUME BOOKS

are published by The New American Library, Inc.,

1301 Avenue of the Americas, New York, New York 10019

FIRST PRINTING, FEBRUARY, 1965

PRINTED IN THE UNITED STATES OF AMERICA

ACKNOWLEDGMENTS

CONTENTS

Introduction Our Hormones

To Professors John D. Ifft and Herbert H. Wotiz for their reading of the manuscript and their many helpful suggestions, I would like to express my appreciation and gratitude.

LA.

ORGANIZATION

SECRETIN

AMINO ACIDS

STRUCTURE AND ACTION

MORE POLYPEPTIDE HORMONES

2 Our Pancreas

DUCTLESS GLANDS

INSULIN

INSULIN STRUCTURE

GLUCAGON

EPINEPHRINE

3 Our Thyroid IODINE THYROXINE

THYROID-STIMULATING HORMONE PARATHYROID HORMONE POSTERIOR PITUITARY HORMONES

CONTENTS

4 Our Adrenal Cortex

CHOLESTEROL OTHER STEROIDS CORTICOIDS ACTH

5 Our Gonads and Growth

PLANT HORMONES

GROWTH HORMONE

METAMORPHOSIS

ANDROGENS

ESTROGENS

GONADOTROPHINS

6 Our Nerves

ELECTRICITY AND IONS THE CELL MEMBRANE POLARIZATION AND DEPOLARIZATION THE NEURON ACETYLCHOLINE

7 Our Nervous System

CEPHALIZATION THE CHORDATES THE PRIMATES APES AND MEN

8 Our Cerebrum

THE CEREBROSPINAL FLUID THE CEREBRAL CORTEX ELECTHOENCEPHALOGHAPHY THE BASAL GANGLIA THE HYPOTHALAMUS

9 Our Brain Stem and Spinal Cord

THE CEREBELLUM THE CRANIAL NERVES

103

108

112

117

121

125

132

139

143

»49 154

161

168

177

183

188

195

204

CONTENTS

THE SPINAL NERVES

THE AUTONOMIC NERVOUS SYSTEM

10 Our Senses

TOUCH PAIN TASTE SMELL

11 Our Ears

HEARING

THE EXTERNAL AND MIDDLE EAR

THE INTERNAL EAP

ECHOLOCATION

THE VESTIBULAR SENSE

12 Our Eyes

LIGHT

THE EYEBALL WITHIN THE EYE THE RETINA COLOR VISION

13 Our Reflexes

RESPONSE

THE REFLEX ARC

INSTINCTS AND IMPRINTING

CONDITIONING

14 Owr Mind

LEARNING

REASON AND BEYOND

PSYCHOBIOCHEMISTRY

A FINAL WORD

Index

209

214

220

227

235

239

243

248

256

262

265

269

275

283

288

294

298

302

307

312

324 33i 338

343

INTRODUCTION

In 1704, a Scottish sailor named Alexander Selkirk was a member of the crew of a ship sailing the South Seas. He quarreled with the captain of the ship and asked to be marooned on an island named Mas a Tierra, which is one of the Juan Fernandez Islands in the South Pacific, about 400 miles west of central Chile.

He remained on the island from October 1704 to February 1709, a period of almost four and one-half years, before being taken off by a ship that passed by. He survived the period well and went back to sea, attaining the position of first mate by the time of his death. The story of his years of isolation was written up in an English periodical in 1713, and it proved to be a fascinating story.

The tale intrigued the English author Daniel Defoe, among others, who proceeded to write a fictional treatment of such a marooning, and improved it in some ways. His sailor was marooned in the Caribbean (perhaps on the island of Tobago) and he lived there for twenty-eight (!) years.

The name of the sailor and of the novel was Robinson Crusoe, and it has remained a classic for two and a half centuries and will undoubtedly continue to remain so for an indefinite time in the future. Part of the interest in the book arises out of Defoe's masterly way of handling details and of making the account sound real. But most of the interest, I think, arises out of being able to witness one man alone against the universe.

INTRODUCTION

Crusoe is an ordinary human being, with fears and anxieties and weaknesses, who nevertheless by hard labor, great ingenuity, and much patience builds a reasonable and even a comfortable life for himself in the wilderness. In doing so, he conquers one of man's greatest fears, solitude. (In cultures where direct physical torture is frowned upon, hardened criminals are placed "in solitary" as the ultimate punishment.)

If Robinson Crusoe fascinates us, surely it is the fascination of horror. Which of us would be willing to take his place in isolation, regardless of what physical comforts we might be able to take with us? What it amounts to is that a society consisting of a single human being is conceivable (for one generation at least) but in tbe highest degree undesirable. In fact, to make a society viable, it is a case, up to a certain point at least, of "the more the merrier." Nor is it entirely a matter of company, or even of sexual satisfaction, that makes it well for a society to consist of a good number of individuals. It is tbe rare human being who could himself fulfill every variety of need involved in the efficient conduct of a society. One person may have the muscular development required to chop down trees and another the ingenuity to direct the construction of a house and a third the patience and delicacy required in good cooking.

Even if one presupposes a quite primitive society, a number of specializations would be in order, including, for instance, someone who understood some rule-of-thumb medicine, someone who could manage animals, someone with a green thumb who could keep a garden under control, and so on. And yet if such a many-person society has its obvious advantages over Robinson Crusoe alone, it also has some disadvantages. One person may be lonely, but at least he is single-minded. Two people may quarrel, in fact probably will; and large numbers of people left to themselves will certainly be reduced to factionalism, and energy that should be expended against the environment will be wasted in an internal struggle. In other words, in the list of specialties we must not forget the most important of all, the tribal chieftain.

He may do no work himself, but in organizing the work of the others, he makes the society practical. He directs the order of business, decides what must be done and when, and, for that matter, what must cease to be done. He settles quarrels and, if necessary, enforces the peace. As societies grow more complex, the task of the organizer grows more difficult, at a more rapid pace than does the task of any other specialist. In place of a chieftain, one finds a hierarchy of command, a ruling class, an executive department, a horde of bureaucrats.

All this has a bearing on the biological level.

There are organisms that consist of a single cell, and these may be compared to human societies of a single individual (except that a single cell can reproduce itself and persist into the indefinite future, whereas a single human being can survive for only one lifetime). Such single-cell organisms live and flourish today in competition with multicellular organisms and may even in the long run survive when the more complicated creatures have met their final doom. Analogously, there are hermits living in caves even today in a world in which cities like New York and Tokyo exist. We can leave to philosophers the question as to which situation is truly superior, but most of us take it for granted it is better to be a man than an amoeba, and better to live in New York than in a cave.

The advance from unicellularity to multicellularity must have begun when cells divided and then remained clinging together. This does indeed happen now. The one-celled plants called algae often divide and cling together; and the seaweeds are huge colonies of such cells. The mere act of clinging together, as in seaweeds, involves no true multicellularity, however. Each cell in the group works independently and is associated with its neighbor only by being pushed against it.

True multicellularity requires the establishment of a "cellular society" with needs that overbalance those of the individual cell. In multicellular organisms, the individual cells specialize in order to concentrate on the performance of some particular function

XVI INTRODUCTION

even to the point where other quite vital functions are allowed to fade or even to lapse completely. The cell, then, loses the ability to live independently, and survives as part of the organism only because its inabilities are made up for by other cells in the organism that specialize in different fashion. One might almost regard the individual cell of a multicellular organism as the parasite of the organism as a whole.

(It is not too farfetched to make the analogy that the human citizens of a large modern city have become so specialized themselves as to be helpless if thrown on their own resources. A man who could live comfortably and well in a large city, performing his own specialized function, and depending on the vast network of services offered by the metropolis — and controlled by other equally but differently specialized citizens — would, if isolated on Robinson Crusoe's island, quickly be reduced to animal misery. He would not survive long.)

But if cells by the trillions are specialized, and if their various functions are organized for the overall good of the organism, there must, in analogy to what I have said about human societies, be cells that specialize as "organizers." The job is a perfectly immense one; far more terrifyingly complex on the cellular level of even a fairly simple creature than any conceivable job of analogous sort could be in the most complex human society.

In The Human Body" I discussed in some detail the structure and operation of the various organs of the body. The operation is obviously complexly interrelated. The various portions of the alimentary canal performed their separate roles in smooth order. The heart beats as a well-integrated combination of parts. The bloodstream connects the various portions of the body, performing a hundred tasks without falling over its own capillaries. The lungs and kidneys form complicated but efficient meeting grounds of the body and the outer environment.

Organization is clearly there, but throughout The Human Body

* The Human Body was published in 1963, and the book you are reading now may be considered a companion piece.

INTRODUCTION xvii

I glossed over the fact. In this book, however, I shall gloss over it no longer. In fact, this book is devoted entirely and single-mindedly to the organization that makes multicellular life possible and, in particular, to the organization that makes the human body a dynamic living thing and not merely a collection of cells. The brain is not the only organ involved in such organization, but it is by far the most important. For that reason I call the book The Human Brain, although I shall deal with more than the brain. The whole is generally greater than the sum of its parts, despite Euclid, and if in The Human Body I considered the parts, in The Human Brain I shall try to consider the whole.

THE HUMAN BRAIN

ITS CAPACITIES AND FUNCTIONS

OUR HORMONES

ORGANIZATION

Even primitive man felt the need for finding some unifying and organizing principle about his body. Something moved the arms and legs, which of themselves were clearly blind tools and nothing more. A natural first tendency would be to look for something whose presence was essential to life. An arm or leg could be removed without necessarily ending life; or even diminishing its essence, however it might hobble a man physically. The breath was another matter. A man just dead possessed the limbs and all the parts of a living man but no longer had breath. What is more, to stop the breath forcibly for five minutes brought on death though no other damage might be done. And, to top matters off, the breath was invisible and intangible, and had the mystery one would expect of so ethereal a substance as life. It is not strange, then, that the word for "breath" in various languages came to mean the essence of life, or what we might call the "soul." The Hebrew words nephesh and makh, the Greek pneuma, the Latin spiritus and anima all refer to both breath and the essence of life.

Another moving part of the body which is essential to life is the blood; a peculiarly living liquid as breath is a peculiarly living gas. Loss of blood brings on loss of hie, and a dead man does not bleed. The Bible, in its prescription of sacrificial rites, clearly

2 THE HUMAN BRAIN

indicates the primitive Israelite notion (undoubtedly shared with neighboring peoples) that blood is the essence of life. Thus, meat must not be eaten until its blood content has been removed, since blood represents life, and it is forbidden to eat living matter. Genesis 9:4 puts it quite clearly: "But flesh with the life thereof, which is the blood thereof, shall ye not eat."

It is but a step to pass from the blood to the heart. The heart does not beat in a dead man, and that is enough to equate the heart with life. This concept still lingers today in our common feeling that all emotion centers in the heart. We are "brokenhearted," "stouthearted," "heavyhearted," and "lighthearted."

Breath, blood, and heart are all moving objects that become motionless with death. It may be an advance in sophistication to look beyond such obvious matters. Even in the earliest days of civilization, the liver was looked upon as an extremely important organ (which it is, though not for the reasons then thought). Diviners sought for omens and clues to the future in the shape and characteristics of the liver of sacrificed animals.

Perhaps because of its importance in divining, or because of its sheer size — it is the largest organ of the viscera — or because it is blood-filled, or for some combination of these reasons, it began to be thought by many to be the seat of life. It is probably no coincidence that "liver" differs from "live" by one letter. In earlier centuries, the liver was accepted as the organ in charge of emotion; and the best-known survival of that in our language today is the expression "lily-livered" applied to a coward. The spleen, another blood-choked organ, leaves a similar mark. "Spleen" still serves as a synonym for a variety of emotions; most commonly anger or spite.

It may seem odd to us today that, by and large, the brain was ignored as the seat of life; or as the organizing organ of the body. After all, it alone of all internal organs is disproportionately large in man as compared with other animals. However, the brain is not a moving organ like the heart; it is not blood-filled like the liver or spleen. Above all, it is out of the way and hidden behind

OURHORMONES 3

a close concealment of bone. When animals, sacrificed for religious or divining purposes, were eviscerated, the various abdominal organs were clearly seen. The brain was not.

Aristotle, the most renowned of the ancient thinkers, believed that the brain was designed to cool the heated blood that passed through it. The organ was thus reduced to an air-conditioning device. The modem idea of the brain as the seat of thought and, through the nerves, the receiver of sensation and the initiator of motion was not definitely established until the i8th century.

By the end of the igth century, the nervous system had come into its own, and actually into more than its own. It was recognized as the organizational network of the body. This was the easier to grasp since by then mankind had grown used to the complicated circuits of electrical machinery. The nerves of the body seemed much like the wires of an electrical circuit. Cutting the nerve leading from the eye meant blindness for that eye; cutting the nerves leading to the biceps meant paralysis for that muscle. This was quite analogous to the manner in which breaking a wire blanked out a portion of an electrical mechanism. It seemed natural, then, to suppose that only the nerve network controlled the body. For instance, when food leaves the stomach and enters the small intestine the pancreas is suddenly galvanized into activity and pours its digestive secretion into the duodenum. The food entering the intestine is bathed in the digestive juice and digestion proceeds.

Here is an example of excellent organization. If the pancreas secreted its juices continuously that would represent a great waste, for most of the time the juices would be expended to no purpose. On the other hand, if the pancreas secreted its juices intermittently (as it does), the secretions would have to synchronize perfectly with the food entering the intestine, or else not only would the secretions be wasted but food would remain imperfectly digested.

By igth-century ways of thinking, the passage of food from the stomach into the small intestine activated a nerve which then

4 THEHUMANBHA1N

carried a message to the brain (or spinal cord). This, in response, sent a message down to the pancreas by way of another nerve, and as a result of this second message the pancreas secreted its juices. It was not until the beginning of the 2Oth century that, rather unexpectedly, the body was found to possess organization outside the nervous system.

SECRETIN

In 1902 two English physiologists, William Maddock Bayliss and Ernest Henry Starling, were studying the manner in which the nervous system controlled the behavior of the intestines and of the processes of digestion. They made the logical move of cutting all the nerves leading to the pancreas of their experimental animals. It seemed quite likely that the pancreas would fail to secrete digestive juices at all, once1 the nerves were cut, whether food passed into the small intestine or not.

That was not what happened, to the surprise of Bayliss and Starling. Instead, the denervated pancreas behaved promptly on cue. As soon as food touched the intestinal lining, the pancreas began pouring forth its juice. The two physiologists knew that the stomach contents were acid because of the presence of considerable hydrochloric acid in the stomach's digestive secretions. They therefore introduced a small quantity of hydrochloric acid into the small intestine, without food, and the denervated pancreas produced juice. The pancreas, then, required neither nerve messages nor food, but only acid; and the acid needed to make no direct contact with the pancreas itself but only with the intestinal lining.

The next step was to obtain a section of intestine from a newly killed animal and soak it in hydrochloric acid. A small quantity of the acid extract was placed within the bloodstream of a living animal by means of a hypodermic needle. The animal's pancreas reacted at once and secreted juice, although the animal was fasting. The conclusion was clear. The intestinal lining reacted to the trigger action of acidity by producing a chemical

THE HUMAN BRAIN

that was poured into the bloodstream. The bloodstream carried the chemical throughout the body to every organ, including the pancreas. When the chemical reached the pancreas it somehow stimulated that organ into secreting its juice.

Bayliss and Starling named the substance produced by the intestinal lining secretin (see-kree'tin; "separate" L)," since it stimulated a secretion. This was the first clear example of a case in which efficient organization was found to be produced by means of chemical messages carried by the bloodstream rather than electrical messages of the nerves. Substances such as secretin are in fact sometimes referred to rather informally as "chemical messengers."

The more formal name was proposed in 1905, during the course of a lecture by Bayk'ss. He suggested the name hormone ("to arouse" G). The hormone secreted by one organ, you see, was something that aroused another organ to activity. The name was adopted, and ever since it has been quite clear that the organization of the body is built on .two..levels: the electrical systernjjf brain, spinal cord,._nerves, and sense organs; and the. chemical systenxof the various hormones and honntrne-elaboratuig,.aEgans.

Although the electrical organization of the body was recognized before the chemical organization was, in this book I shall reverse the order of time and consider the chemical organization first, since this is the less specialized and the older of the two. Plants and one-celled animals, after all, without a trace of anything we would recognize as a nervous system nevertheless react to chemical stimuli.

* In this book I shall follow the practice initiated in The Human Body of giving the pronunciation of possibly unfamiliar words. I shall also include the meaning of the key word from which it is derived with the initial — L, indicating the derivation to be from the Latin and G indicating it to be from the Greek. In this case, the derivation from "separate" refers to the fact that a cell forms a particular substance and separates that substance, so to speak, from itself, discharging it into the bloodstream, into the intestines, or upon the outer surface of the body. A secretion is thought of as being designed to serve a useful purpose, as, for instance, is true of the pancreatic juice. Where the separated material is merely being disposed of, rt is an excretion ("separate outside" L); thus urine is an excretion.

OUR HORMONES J

In line with this mode of progression, let us begin by looking at secretin more closely; from its behavior and properties we shall be able to reach conclusions that will apply to other and far more glamorous hormones. For example, a question may arise as to what terminates hormone action. The gastric contents arrive in the small intestine. The acidity of those contents stimulates the production of secretin. The secretin enters the bloodstream and stimulates the production of pancreatic secretion. So far, so good; but there comes a time when the pancreas has produced all the juices it need produce. What now stops it?

For one thing, the pancreatic secretion is somewhat alkaline fan alkaline solution is one with properties the reverse of those of an acid solution; one will neutralize the other, and produce a mixture neither acid nor alkaline). As the pancreatic secretion mixes with the food, the acid qualities the latter inherited from the stomach diminish. _As jhe acidity decreases, the spark that stimulates the formation of secretin dies c5wji.

In other words, the action of secretin brings about a series of events that causes the formation of secretin to come to a halt. The formation of secretin is thus a self-limiting process. It is like the action of a thermostat which controls the oil furnace in the basement. When the house is cold, the thermostat turns on the furnace and that very action causes the temperature to rise to the point where the thermostat turns off the furnace. This is called "feedback," a general term for a process by which the results brought about by some control are fed back into the information at the disposal of the control, which then regulates itself according to the nature of the result it produces. In electrical circuits we speak of input and output; but in biological systems we speak of stimulus and response. In this case, the successful response is sufficient in itself to reduce the stimulus.

This sort of feedback is surely not enough. Even though secretin is no longer formed, what of the secretin that has already been formed and which, one might expect, remains in the bloodstream and continues to prod the pancreas? This, however, is

THE HUMAN BRAIN

OUR HORMONES

taken care of. The body contains enzymes" specifically designed to catalyze the destruction of hormones. An enzyme has been located in blood which has the capacity of hastening the breakup of the secretin molecule, rendering the hormone inactive. Enzymes are very often named for the substance upon which they act, with the addition of the suffix "ase," so this enzyme to which I have referred is secretinase (see-kree'tih-nays).

There is consequently a race between the production of secretin by the intestinal linings and the destruction of secretin by secretinase. While the intestinal linings are working at full speed, the concentration of secretin in the blood is built up to stimulating level. When the intestinal linings cease working, not only is no further secretin formed but any secretin already present in the blood is quickly done away with. And in this fashion, the pancreas is turned on and off with a sure and automatic touch that works perfectly without your ever being aware of it.

AMINO ACIDS

Another legitimate question could be: What is secretin? Is its nature known or is it merely a name given to an unknown substance? The answer is that its nature is known but not in full detail.

Secretin is a protein, and proteins are made up of large molecules, each of which consists of hundreds, sometimes thousands, sometimes even millions of atoms. Compare this with a water molecule (H2O), which contains 3 atoms, 2 hydrogens and i oxygen; or with a molecule of sulfuric acid (H2SC>4), which contains 7 atoms, 2 hydrogens, i sulfur, and 4 oxygens.

It is understandable, therefore, that the chemist, desiring to know the exact structure of a protein molecule, finds himself faced with an all but insuperable task. Fortunately, matters are eased

* Enzymes are proteins thai behave as catalysts — they hasten particular reactions when present in small quantities. That is all we need to know for our present purposes. IF you are interested in the nature and the method of operation of enzymes, I refer you to my book Life and Energy (1962).

somewhat by the fact that the atoms within the protein molecule are arranged in subgroupings called amino acids (the first word is pronounced either "a-mee'noh" or "a'mih-noh"; you may take your pick — I prefer the first ) .

By gentle treatment with acids or with alkali or with certain enzymes, it is possible to break up the protein molecule into its subgroup amino acids instead of its separate atoms. The amino acids are themselves rather small molecules made up of only 10 to 30 atoms and they are comparatively simple to study.

It has been found, for example, that all the amino acids isolated from protein molecules belong to a single family of compounds, which can be written as the following formula:

NH2

COOH

The C at the center of the formula represents a carbon atom (C for carbon, of course). Attached to its right, in the formula as shown, is the four-atom combination COOH, which represents a carbon atom, two oxygen atoms, and a hydrogen atom. Such a combination gives acid properties to a molecule and it is called a carboxylic acid group (carbon plus oxygen plus acid). Attached to the left is a three-atom combination, NH2, which represents a nitrogen atom and two hydrogen atoms. This is the online group, because it is chemically related to the substance known as "ammonia." Since the formula contains both an amine group and an acid group this type of compound is called an amino acid.

In addition, attached to the central carbon is an H, which simply represents a hydrogen atom, and an R, which represents a side-chain. It is this R, or side-chain, that is different in each amino acid. Sometimes the side-chain is very simple in structure; it may even be nothing more than a hydrogen atom in the very simplest case. In some amino acids the side-chain can be quite

1O THEHUMANBRAIN

complicated and may be made up of as many as 18 atoms. For our own purposes, we don't have to know the details of the structure of the side-chains for each amino acid. It is enough to know that each structure is distinctive.

Amino acids combine to form a protein by having the amino group of one amino acid connected to the carboxylic acid group of its neighbor. This is repeated from amino acid to amino acid so that a long "backbone" is formed. From each amino acid unit in the chain a side-chain sticks out, and it is the unique pattern of side-chains that makes each type of protein molecule different from all others.

There are more than two dozen amino acids to be found in various protein molecules, but of these only 21 can be considered as being really common. To give ourselves a vocabulary we can use, I shall name these:

1. Glycine ("sweet" G, because of its sweet taste),

2. Alanine (a name selected for euphony alone, apparently),

3. Valine (from a compound called valeric acid, to which it is chemically related),

4. Leucine ("white" G, because it was first isolated as white crystals),

5. Isoleucine (an isomer of leucine; isomers are pairs of substances with molecules containing the same number of the same type of atoms, but differing in the arrangement of the atoms within the molecules),

6. Praline (a shortened version of "pyrrolidine," which is the name given to the particular atom arrangement in proline's side-chain),

7. Phenylalanine (a molecule of alanine to which an atom combination called the phenyl group is added),

8. Tyrosine ("cheese" G, from which it was first isolated),

9. Tryptophan ("trypsin-appearing" G, because it appeared, when first discovered, in the fragments of a protein molecule that had been broken up by the action of an enzyme named trypsin), 10. Serine ("silk" L, from which it was first isolated),

OUR HORMONES 11

11. Threonine (because its chemical structure is related to that of a sugar called threose),

12. Asparagine (first found in asparagus),

13. Aspartic acid (because it resembles asparagine; although aspartic acid possesses an acid group, COOH, in the side-chain and asparagine possesses a similar group, CONHz, with no acid properties),

14. Glutamine (first found in wheat gluten),

15. Glutamic acid (which differs from glutamine as aspartic acid differs from asparagine),

16. Lysine ("a breaking up" G, because it was first isolated from protein molecules that had been broken up into their sub-groupings),

17. Histidine ("tissue" G, because it was first isolated from tissue protein),

18. Arginine ("silver" L, because it was first isolated in combination with silver atoms),

19. Methionine (because the side-chain contains an atom grouping called the "methyl group," which is in turn attached to a sulfur atom, called theion in Greek),

20. Cystine (sis'teen; "bladder" G, because it was first isolated in a bladderstone),

21. Cysteine (sis'tih-een; because it is chemically related to cystine).

I shall have to use these names fairly frequently. To save space, let me give you the commonly used abbreviations for each of them, a system first proposed and used in the 1930^ by a German-American biochemist named Erwin Brand. Since most of the abbreviations consist of the first three letters of the name, they are not difficult to memorize:

glycine gly

alanine ala

valine val

leucine leu

asparagine asp'Ntb

aspartic acid asp

glutamine ghrNH2

glutamic acid glu

THE HUMAN BRAIN

isoleucine

proline

phenylalanine

tyrosine

tryptophan

serine

threonine

ileu

pro

phe

tyr

try

ser

thr

lysine histidine lys his

arginine methionine arg met

cystine cysteine cy-S-cy-SH

Of the abbreviations that are more than the first three letters of the names, ileu, asp-NH2, and ghrNH2 should be clear. The abbreviations for cystine and cysteine are more cryptic and deserve some explanation, for they will be important later on.

Cystine is a double amino acid, so to speak. Imagine two central carbon atoms, each with a carboxylic acid group and an amine group attached. The side-chain attached to one of these central carbon atoms runs into and coalesces with the side-chain attached to the other. Where the side-chains meet are two sulfur atoms. We might therefore symbolize cystine as cy-S-S-cy, the two S's being the sulfur atoms that hold the two amino acid portions together.

Each amino acid portion of cystine can make up part of a separate chain of amino acids. You can get the picture if you imagine a pair of Siamese twins, each one holding hands with individuals in a different chain. The two chains are now held together and prevented from separating by the band of tissue that holds the Siamese twins together.

Similarly, the two amino acid chains, each holding half a cystine molecule, are held together by the S-S combination of the cystine. Since chemists are often interested in the makeup of a single amino acid chain, they can concentrate on the half of the cystine molecule that is present there. It is the "half-cystine" they usually deal with in considering protein structure and it is this that is symbolized by cy-S-.

One way of breaking the S-S combination and separating the two amino acid chains is to add two hydrogen atoms. One hydro-

OURHORMONES 13

gen atom attaches to each of the sulfur atoms and the combination is broken. From -S-S-, you go to -S-H plus H-S-. In this way, one cystine molecule becomes two cysteine molecules (there's the relationship that has resulted in two such similar names, hard to distinguish in speaking except by exaggeratedly and tire-somely pronouncing the middle syllable in cysteine). To show this, cysteine is symbolized cy-SH.

STRUCTURE AND ACTION

Now if I return to secretin and describe it as a protein molecule, we know something of its structure at once. What's more, it is a small protein molecule, with a molecular weight of 5000. (By this is meant that a molecule of secretin weighs 5000 times as much as a hydrogen atom, which is the lightest of all atoms.)

A molecular weight of 5000 is high if we are discussing most types of molecules. Thus, the molecular weight of water is 18, of sulfuric acid 98, of table sugar 342. However, considering that the molecular weight of even average-sized proteins is from 40,000 to 60,000, that a molecular weight of 250,000 is not rare and that proteins are known with molecular weights of several millions, you can see that a protein with a molecular weight of merely 5000 is really small.

This is true of protein hormones generally. The hormone molecule must be transferred from within the cell, where it is manufactured, to the bloodstream. It must in the process get through, or diffuse through, the cell membrane and the thin walls of tiny blood vessels. It is rather surprising that molecules as large as those with a molecular weight of 5000 can do so; but to expect still larger molecules to do so would certainly be expecting too much. In fact the molecules of most protein hormones are so small, for proteins, that the very name is sometimes denied them.

When the amino acid chain of a protein molecule is broken up into smaller chains of amino acids by the action of the enzymes in the digestive juices, the chain fragments are called peptides

14 THE HUMAN BRAIN

("digest" G). It has become customary to express the size of such small chains by using a Greek number prefix to indicate the number of amino acids in it: a dipeptide ("two-peptide" G) is a combination of two amino acids, a tripeptide ("three-peptide" G) of three, a tetrapepttde {"four-peptide" G) of four, and so on.

Where the number is more than a dozen or so but less than a hundred, the chain is a polypeptide ("many-peptide" G). Secretin and other hormones of similar nature are built up of amino acid chains containing more than a dozen and less than a hundred amino acids and are therefore sometimes called polypeptide hormones rather than protein hormones.

Having said that secretin is a polypeptide hormone, the next step, logically, would be to decide which amino acids are to be found in its molecule and how many of each. This, unfortunately, is not an easy thing to determine. Secretin is not manufactured in large quantities, and in isolating it from duodenal tissue a variety of other protein molecules are also obtained. The presence of such impurities naturally complicates analysis.

In 1939, however, secretin was produced in crystalline form (and only quite pure proteins can be crystallized). These crystals were analyzed and it was reported that within each secretin molecule there existed 3 lysines, 2 arginines, 2 prolines, i histi-dine, i glutamic acid, i aspartic acid, and i methionine. This is a total of 11 amino acids in a molecule which, from the data available, seems to contain 36 amino acids altogether. Using the Brand abbreviations, the formula for secretin, as now known, would be:

Iys3arg2pro2hisiglui asp imet 1X25

X standing for those amino acids still unknown.

Even if with further progress all the amino acids in the secretin molecule were determined, that would not give us all we need to determine the exact structure of the secretin molecule. There would still remain the necessity of discovering the exact order of the various amino acids within the chain. If you knew that a certain four-digit number was made up of two 6"s, a 4, and a 2, you

OUR HORMONES 15

would still be uncertain as to the exact number being referred to. It might be 6642, 2646, 4662 or any of several other possibilities.

There are fixed methods for calculating the number of possible patterns that can be built up of different sets of units and the results are startling. Suppose that the 36 amino acids of the secretin molecule consisted of two of each of 18 different amino acids. The total number of possible arrangements would be somewhat in excess of 1,400,000,000,000,000,000,000,000,000,000,000,000. This may sound incredible but it is quite true. This, mind you, is for a small protein molecule. The situation for even an average-sized one is far, far more complicated, and this helps account for the difficulties biochemists have in attempting to work out protein structure.

It also speaks amazingly well for the fact that biochemists, since World War II, have actually developed ingenious techniques that have made it possible for them to work out the exact order of the amino acids (out of trillions upon uncounted trillions of possible orders) in particular protein molecules.

Emphasizing the complexity of structure of a protein molecule, as I have just done, gives rise to the natural wonder that cells can elaborate such complex molecules correctly, choosing one particular arrangement of amino acids out of all the possible ones. This, as a matter of fact, is perhaps the key chemical process in living tissue, and in the last ten years much has been discovered about its details. Unfortunately, this book is not the place to consider this vital point, but if you are interested, you will find it in some detail in my book The Genetic Code.

Even if we grant that the cell can elaborate the correct protein molecule, can it do it so quickly from a cold start that the spur of the acid stimulation of the stomach contents suffices to produce an instant flood of secretin into the bloodstream? This would perhaps be too much to expect, and, as a matter of fact, the start is not a cold one.

The secretin-forming cells of the intestinal lining prepare a molecule called prosecretin ("ahead of secretin") at their leisure.

THE HUMAN BRAIN

This they store and therefore always have a ready supply of it. The prosecretin molecule requires, apparently, one small chemical change to become actual secretin. The stimulus of acid is not, therefore, expected to bring about a complete formation of a polypeptide molecule, but only one small chemical reaction. It is logical to suppose that prosecretin is a comparatively large molecule, too large to get through the cell membrane and therefore safely immured within the cell. The influx of acid from the stomach suffices to break the prosecretin molecule into smaller fragments, and these fragments — secretin — diffuse out into the bloodstream. The prosecretin might be thought of as resembling a perforated block of stamps. It is only when the stamps are torn off at the perforations and used singly that they bring about the delivery of ordinary letters; but the blocks can be bought and kept in reserve for use when and as needed.

Another question that may well arise is this: How do hormones (and secretin in particular, since I am discussing that hormone) act to bring about a response? Oddly enough, despite more than a half century of study, and despite amazing advances made by biochemists in every direction, the answer to that question remains a complete mystery. It is a mystery not only with respect to secretin but with respect to all other hormones. The mechanism of action of not a single hormone is indisputably established. At first, when secretin and similar hormones were discovered and found to be small protein molecules that were effective in very small concentration," they were assumed to act as enzymes. Enzymes are also proteins that are effective in very small concentration. Enzymes have the ability to hasten specific reactions to a great degree and it seemed very likely that hormones might do the same.

When secretin reached the pancreas, it might hasten a key reaction that, in the absence of secretin, would proceed very slowly. This key reaction might set in motion a whole series of reactions

• As little as 0.005 milligrams of secretin (that is, less than one five-millionth of an ounce) is sufficient to elicit a response from a dog's pancreas.

OURHORMONES 17

ending with the formation and secretion of quantities of pancreatic juice. A small stimulus could in this way easily produce a large response. It .would be like the small action of pulling a lever in a firebox, which would send a signal to a distant firehouse, arouse the firemen, who would swarm upon their fire engines, and send them screaming down the road. A large response for pulling a lever. Unfortunately, this theory does not hold up. Ordinary enzymes will perform their hastening activity in the test tube as well as in the body and, in fact, enzymes are routinely studied through their ability to act under controlled test-tube conditions.

In the case of hormones, however, this cannot be done. Few hormones have ever displayed the ability of hastening a specific chemical reaction in the test tube. In addition, a number of hormones turned out to be nonprotein in structure and, as far as we know, all enzymes are proteins. It seems, then, that the only conclusion to be drawn is that hormones are not catalysts. A subsidiary theory is that hormones, although not themselves enzymes, collaborate with enzymes — some enzyme, that is, which is designed to hasten a certain reaction and will not do so unless a particular hormone is present. Or perhaps there is a whole enzyme system that sets up a chain of reactions intended to counteract some effect. The hormone by its presence prevents one of the enzymes in the reaction chain from being active. It inhibits ("to hold in" L) the enzyme. This stops the entire counteraction, and the effect, which is ordinarily prevented, is permitted to take place, Thus, the pancreas might always be producing secretions but for some key reaction that prevents it. By blocking that key reaction, secretin may allow the pancreatic juice to be formed. This seems like a backward way of doing things, but such a procedure is not unknown in man-made mechanisms. A burglar alarm may be so designed that an electric current, constantly in being, prevents it from ringing. Break the electric current, by forcing a door or a window, and the alarm, no longer held back, begins to ring.

THE HUMAN BHAIN

Unfortunately, here too the cooperation between a particular hormone and a particular enzyme is very difficult to demonstrate. Even where some cooperation, either to accelerate or to inhibit the action of an enzyme, is reported for some hormone, the evidence remains in dispute.

Still another theory is that the hormone affects the cell membrane in such a way as to alter the pattern of materials that can enter the cell from the bloodstream. To put this in human terms, one might suppose that the workers constructing a large skyscraper one day were presented with loads of aluminum siding. They would on that day undoubtedly work on the face of the building as far as they could. If, instead, large loads of wiring arrived but no aluminum siding, work would have to switch to the electrical components of the building.

In similar fashion, the hormone action might determine cellular action by permitting one substance to enter the cell and prohibiting another from doing so. It may be that only when secre-tin acts upon the cell membranes of the pancreas is the pancreas supplied with some key material needed to manufacture its digestive juice.

But this theory, too, is unproved. The whole question of the mechanism of hormone action remains open, very open.

MORE POLYPEPTIDE HORMONES

I have been concentrating on secretin, so far, to a much greater extent than is strictly necessary for its own sake, because secretin is a minor hormone, as hormones go. Nevertheless, it has the historical interest of being the first hormone to be recognized as such and, in addition, much of what I have said in this chapter applies to other hormones as well.

But it is important to stress the fact that there are other hormones. There are even other hormones that deal with pancreatic secretion. If secretin is purified and added to the bloodstream, the pancreatic juice that is produced is copious enough and alka-

OUR HORMONES 19

line enough, but it is low in enzyme content, and it is the enzymes that do the actual work of digestion. A preparation of secretin that is less intensively purified brings about the formation of pancreatic juice adequately rich in enzymes.

Evidently a second hormone, present in the impure preparation but discarded in the pure, stimulates enzyme production. Extracts containing this second hormone have been prepared and have been found to produce the appropriate enzyme-enriching response. This hormone is pancreozymin (pan'kree-oh-zy'min; which is a shortened form of "pancreatic enzymes").

Secretin seems to have a stimulating effect on the liver too, causing it to produce a more copious flow of its own secretion, whicb is called bile. The bile produced in response to secretin is low in material {ordinarily present) called bile salt and bile pigment. The gallbladder, a small sac attached to the liver, contains a concentrated supply of liver secretion, with ample content of bile salt and bile pigment. This supply is not called upon by secretin, but still another hormone produced by the intestinal lining will stimulate the contraction of the muscular wall of the gallbladder and will cause its concentrated content to be squirted into the intestine. This hormone is cholecystokinin (kol'eh-sis-toh-ky'nin; "to move the gallbladder" G).

The secretion of cholecystokinin is stimulated by tbe presence of fat in the stomach contents as they enter the intestine. This makes sense, since bile is particularly useful in emulsifying fat and making it easier to digest. A fatty meal will stimulate the production of unusually high quantities of cholecystokinin, which will stimulate the gallbladder strongly, which will squirt a greater-than-usual supply of bile salt (the emulsifying ingredient) into the intestine, which will emulsify the fat that started the whole procedure and bring about its digestion.

I have mentioned that one of the effects of secretin is to neutralize the acidity of the stomach contents by stimulating the production of the alkaline pancreatic juice. This is necessary because the enzymes in pancreatic juice will only work in a slightly

2O THE HUMAN BRAIN

alkaline medium and if the food emerging from the stomach were to remain acid, digestion would slow to a crawl. Part of this desirable alkalizing effect would be negated if the stomach were to continue to produce its own acid secretions at a great rate after the food had left it. However necessary those secretions might be while the stomach was full of food, they could only be harmful if produced in an empty stomach and allowed to trickle into the intestine. It is not surprising, then, that yet another function of the versatile secretin has been reported to be the inhibition of stomach secretions.

This is more efficiently done, however, by a second hormone designed just for the purpose. Several of the different substances in food serve to stimulate the intestines to produce a substance called enterogastrone (en'ter-oh-gas'trohn; "intestine-stomach" G, that is, produced by the intestirre and with its effect on the stomach). Enterogastrone, unlike most hormones, inhibits a function rather than stimulates one. It has been suggested that substances which are like hormones in every respect except that they inhibit instead of arousing be called chalones {kal'ohnz; "to slacken" G). Nevertheless, the name has not become popular, and the word "hormone" is used indiscriminately, whether the result is arousal {as "hormone" implies) or the opposite.

But if food in the upper intestine releases a hormone inhibiting stomach secretion of digestive juices, then food in the stomach itself ought to bring about the release of a hormone stimulating that secretion. After all, when the stomach is full, those juices are wanted. Such a hormone has indeed been detected. It is produced by the cells of the stomach lining and it is named gastrin ("stomach" G).

Other hormones that affect the flow of a particular digestive secretion one way or another have been reported as being produced by the stomach or small intestine. None of them have been as well studied as secretin, but all are believed to be polypeptide in nature. The only real dispute here is over the structure of gastrin. There are some who believe that the gastrin molecule is

OUR HORMONES 21

made up of a single modified amino acid. All these hormones collaborate to keep the digestive secretions of the stomach and intestines working with smooth organization, and they are all lumped together as the gastrointestinal hormones.

If polypeptide hormones bring about the production of digestive juices, the compliment is, in a way, returned. There are digestive juices that produce polypeptide hormones in the blood. This was discovered in 1937, when a group of German physiologists found that blood serum and an extract of the salivary gland mixed were capable of bringing about the contraction of an isolated segment of the wall of the large intestine. Neither the serum nor the salivary extract could accomplish this feat singly. What happens, apparently, is that an enzyme extracted from the saliva has the ability to break small fragments off one of the large protein molecules in the blood (like tearing individual stamps off a large block of them). The small fragments are polypeptide hormones capable of stimulating the contraction of smooth muscle under some conditions and its relaxation under other conditions.

The enzyme was named kailikrein (kal-ik'ree-in) and it, or very similar enzymes, have been located in a number of other tissues. The hormone produced by kalh'krein was named kalli-din (kal'ih-din). It exists in at least two separate and very similar varieties, called kaUidin I and kallidin II. The actual function of kallidin in the body is as yet uncertain. It lowers blood pressure, for one thing, by stretching the small blood vessels and making them roomier. This causes the vessels to become a bit leakier, a condition that in turn may allow fluid to collect in damaged areas, forming blisters, while also allowing white blood corpuscles to get out of the blood vessels more easily and collect at these sites.

A substance similar to kallidin is produced in blood by the action of certain snake venoms. The net effect on tissues is similar in various ways to that produced by a compound called histamine but is somewhat slower in establislu'ng itself (30 seconds against

22 THEHUMANBHAIN

5 seconds). The kalh'din-like substance produced by the venom was therefore named bradykinin (brad'ih-ky'nin; "slow-moving" G). Eventually, bradykinin, kallidin, and all similar hormones were grouped under the name kinins. There are kinins, ready made, in the venom of the wasp. These are injected into the bloodstream when the wasp stings and are probably responsible, at least in part, for the pain and the swelling that comes with the accumulation of fluid as the small blood vessels grow leaky.

The molecules of the kinins are simpler than are those of the gastrointestinal hormones. Being made up of no more than 9 or 10 amino acids, they are scarcely even respectable polypeptides. The comparative simplicity of their structure has made it possible for biochemists to work out the exact order of the amino acids. Bradykinin, for instance, turned out to be identical with kallidin I and to have a molecule made up of 9 amino acids. These, in order, and using the Brand abbreviations, are:

arg-pro-pro-gly-phe-ser-pro-phe-arg

Kalladin II has a tenth amino acid, lysine (lys), which occurs at the extreme left of the bradykinin chain.

And yet, knowing the exact structure, however satisfying that may be in principle to biochemists, doesn't help in one very important respect. Even with the structure in hand, they can't tell exactly how the kinins bring about the effects they do.

OUR PANCREAS

DUCTLESS GLANDS

The word "gland" comes from the Latin word for acorn, and originally it was applied to small scraps of tissue in the body which seemed acomlike in shape or size. Eventually the vicissitudes of terminology led to the word being applied to any organ that had the prime function of producing a fluid secretion.

The most noticeable glands are large organs such as the liver and pancreas. Each of these produces quantities of fluid which are discharged into the upper reaches of the small intestine through special ducts. Other smaller glands also discharge their secretions into various sections of the alimentary canal. The six salivary gknds discharge saliva into the mouth by way of ducts. There are myriads of tiny glands in the lining of the stomach and the small intestine, producing gastric juice in the first case and intestinal juice in the second. Each tiny gland is equipped with a tiny duct.

In addition, there are glands in the skin, sweat glands and sebaceous glands, that discharge fluid to the surface of the skin by way of tiny ducts. (The milk-producing mammary glands are modified sweat glands, and milk reaches the skin surface by way of ducts.)

But there arose the realization that there were organs producing secretions that were not discharged through ducts either to

24 THEHUMANBRAIN

the skin or to the alimentary canal. Instead, their secretions were discharged directly into the bloodstream, not by means of a duct but by diffusion through cell membranes. A controversy arose as to whether organs producing such secretions ought to be considered glands; as to whether it was the secretion or the duct that was crucial to the definition. The final decision was in favor of the secretion, and so two types of glands are now recognized: ordinary glands and ductless glands. (The simple term "gland" can be used for both.)

The nature of the secretion is differentiated by name as well. Secretions that left the gland (or were separated from it, in a manner of speaking) and were led to the skin or alimentary canal are exocrine secretions (ek'soh-krin; "separate outside" G). Secretions that left the gland but remained in the bloodstream so as to circulate within the body, are endocrine secretions (en'doh-krin; "separate within" G). The former term is rarely used but the latter is common to the point where the phrase endocrine glands is almost more frequently used than "ductless glands." The systematic study of the ductless glands and their secretions is, for this reason, called endocrinology.

The gastrointestinal hormones, discussed in Chapter i, are produced by cells of the intestinal lining which are not marked off in any very noticeable way, making it difficult to define actual glands in that case. It is better to say, simply, that the intestinal lining has glandular functions. This js an exception. In the case of virtually all other hormones definite glands are involved. Often these glands constitute separate organs. Sometimes they are groups of cells marked off, more or less clearly, within organs dedicated principally to other functions. An interesting example of the latter is that of a group of endocrine glands inextricably intermingled with an exocrine gland, and a very prominent one, too. I refer to the pancreas.

Since the i/th century at least, the pancreas has been known to discharge a secretion into the intestines, and in the early igtb century, the digestive function of that secretion was studied.

OURPANCREAS 25

The pancreas has a prominent duct and produces a secretion that contains so many different digestive enzymes that it is actually the most important single digestive juice in the body. There seemed no particular reason to think that the pancreas had any secretory function other than this one.

However, the cellular makeup of the pancreas showed curious irregularities. A German anatomist, Paul Langerhans, reported in 1869 that amid the ordinary cells of the pancreas were numerous tiny clumps of cells that seemed marked off from the surrounding tissue. The number of these cell clumps is tremendous, varying from perhaps as few as a quarter million in some human beings to as many as two and a half million in others. Still, the individual clump is so small that all of them put together make up only i or 2 per cent of the volume and mass of the pancreas. Since the human pancreas weighs about 85 grams (3 ounces) the total mass of these clumps of cells in man would be in the neighborhood of one gram. The clumps have received the romantic-sounding name of islets of Langerhans in honor of their discoverer.

The islets, whatever their function, can have nothing to do wim, the ordinary secretion of the pancreas. This is shown by the fact that when the pancreatic duct is tied off in an animal, the ordi-! nary cells of the pancreas wither and atrophy (as muscles do;r when because of paralysis they are not put to use). The cells of the islets, nevertheless, remain vigorous. Their function is not interfered with by the tying off of the duct so that if they have glandular function, it is ductless in nature. „ --•

Furthermore, if the pancreas is removed from the body of an experimental animal, one would fully expect that digestion would be interfered with; but there seemed no reason at first to suspect that anything else would happen. It was certainly not expected that the removal would be fatal; and if predigested food were fed the animal, it seemed reasonable to suppose the animal would not even be seriously discommoded.

Nevertheless, when two German physiologists removed the

20 THEHUMANBRAIN

pancreas of a dog, in 1889, they found that a serious and eventually fatal disease was produced that seemed to have nothing to do with digestion at all but which, instead, strongly resembled a human disease known as diabetes mellitus (dy'uh-bee'teez meh-h/tus). Grafting the pancreas under the skin kept the dog alive, although in the new position its duct was clearly useless. Whatever the pancreas did to prevent diabetes mellitus, then, had nothing to do with the ordinary pancreatic juice which in normal life was discharged through that duct.

When, a little over a decade later, Bayliss and Starling worked out the concept of a hormone, it seemed very likely that the islets of Langerhans were ductless glands producing a hormone and that lack of this hormone brought on diabetes mellitus.

Diabetes mellitus is a disease that has been recognized among human beings since ancient times. It is one of a small group of diseases characterized by the production of abnormally high quantities of urine, so that water seemed simply to pass through the body in a hurry. This gave rise to the name "diabetes," from a Greek word meaning "to pass through." The most serious variety of the disease is characterized by an abnormally sweet urine. (This was first attested to by the fact that flies swarmed about the urine of such a diabetic, but eventually some curious ancient physician must have confirmed the fact by means of the taste buds.) The word "mellitus" is from the Greek word for honey. Diabetes mellitus may therefore, in popular terminology, be called "sugar diabetes" and often is referred to simply as "diabetes" without any modifier.

Diabetes mellitus is a common disease since between i and 2 per cent of the population in Western countries develop it at some time during their life. There are well over a million diabetics in the United States alone. Its incidence increases in middle age, is more common among overweight people than in those of normal weight, and is one of the few diseases that is more common among women than among men. It tends to run in families, so that relatives of diabetics are more apt to develop the disease than are

£ ISLET OF LANGERHANS

LOCATION OF PANCREAS AND

SPLEEN

28 THEHUMANBRAIN

people with no history of diabetes in their family. The symptoms include excessive hunger and thirst and yet, even by eating and drinking more than normally, the untreated diabetic cannot keep up with the inefficiency of his body in handling foodstuffs. Urination is excessive and there is a gradual loss of weight and strength. Eventually, the diabetic goes into a coma and dies.

The disease is incurable in the sense that a diabetic can never be treated in such a way as to become a nondiabetic and require no further treatment. However, he can submit to a lifelong treatment that will enable him to live out a reasonably normal existence (thanks to the developments of this century), and this is by no means to be scorned.

INSULIN

For a generation, attempts were made to isolate the hormone of

the islets of Langerhans.

Success finally came to a thirty-year-old Canadian physician, Frederick Grant Banting, who in the summer of 1921 spent time at the University of Toronto in an effort to solve the problem. He was assisted by a twenty-two-year-old physician, Charles Herbert Best. Banting and Best took the crucial step of tying off the pancreatic duct in a living animal and waiting seven weeks before killing the animal and trying to extract the hormone from its pancreas.

Previous attempts had failed because the hormone is a protein and the enzymes within the ordinary cells of the pancreas, some of which are particularly designed for protein digestion, broke up the hormone even while efforts were being made to mash up the pancreas. By tying off the duct. Banting and Best caused the pancreas to atrophy and its ordinary cells to lose their function. The hormone could now be isolated from the still-vigorous islets and no protein-destroying enzymes were present to break up the hormone. Once methods for producing the hormone were worked out, patients with diabetes mellitus could be treated suc-

OURPANCREAS 29

cessfully. For his feat, Banting received the Nobel Prize in Medicine and Physiology in 1923.

Banting suggested the name of "isletin" for the hormone, since it was produced in the irier£~oFT3^ge7Ka"ns. However, before the hormone had actually Been isolated, the name insulin ("island" L) had been advanced, anq it was the Latinized form of the name that was adopted, Insii1'" *c one of a group of hormones that acts to coordinate the thousands of different chemical reactions that are constantly proceeding within living tissue. All these thousands of reactions are intermeshed in an exceedingly complicated fashion, and any substantial change in the rate at which any one of these reactions proceeds will affect other reactions that make use of substances produced by the first reaction. The reactions that are thus secondarily affected will in turn affect still other reactions, and so on."

This interconnectedness, this mutual dependence, is such, that a drastic slowdown of a few key reactions, or even in only one, may be fatal, and sometimes quickly so. There are some poisons that in tiny quantities act quickly and put a sudden end to life by virtue of their ability to stop key reactions. It is rather like an intricate display of canned goods, or an elaborate house of blocks, in which the removal of one can or one block can lead to a quick and complete shattering of order.

But if the general pattern of metabolism is so intricate as to be vulnerable to the intrusion of a bit of alien poison, it might also be vulnerable to the general wear-and-tear of normal events. In our analogy, even if no one came up to a display and deliberately removed a can from the bottom row, there would still be the chance that the vibration of traffic outside, the thud of footsteps within the store, the accidental touch of a toe, might push a can out of place. Presumably, store employees passing such a display would notice if a can were dangerously off-center and push it back into position. It would be even more convenient if the dis-

* It is to this vast complex of chemical reactions within living tissue that we refer when we speak of metabolism ("to throw into a different position" G).

3O THEHUMANBRAIN

play were somehow so organized that a can out of position would automatically trip a circuit that would set up a magnetic field to pull it back into place.

Our metabolism, better organized than the displays in a store, has just such self-regulating features. Let's take an example. After a meal, the carbohydrate content of the food is broken down to simple sugars, mostly one called glucose ("sweet" G). This diffuses across the intestinal wall and into the bloodstream.

If the bloodstream accepted the glucose in full flood and if matters ended there, the blood would quickly grow thick and syrupy with the glucose it carried, and the heart, no matter how strongly it might work, would have to give up. But this does not happen. A short vein called the_pprtfll_Lein carries the glucose-laden blood to the liver, and in that organ the sugar is filtered out of the blood and stored within the liver cells as an insoluble, starch-like material called g!ycogen_(gly'koh-jen; "sugar producer" G). The blood emerging from the liver immediately after a meal will usually have a glucose content of no more than 130 milligrams per cent" as a result of the storage work of the liver. This quickly drops further to somewhere between 60 and 90 milligrams per cent. This range is called the "fasting blood glucose." Glucose is the immediate fuel of the cells. Each cell absorbs all the glucose it needs from the blood, then breaks it down, through a complicated series of reactions, to carbon dioxide and water, liberating energy in the process. With each cell drawing upon the glucose, the total glucose supply in the blood might be expected to last only a matter of minutes. The glucose is not used up, however, because the liver is perfectly capable of breaking down its stored glycogen to glucose and delivering that into the bloodstream at a rate just calculated to replace the amount being abstracted by cells.

And so the liver is involved in maintaining the glucose level in the blood in two different ways, one opposed to the other, and

• A milligram (mg.) per cent is one milligram per hundred milliliters of blood.

OURPANCREAS 31

both involving a number of intricately related reactions. When the glucose supply is temporarily greater than needed, as after a meal, glucose is stored in the liver as gfycogen. When the glucose supply is temporarily smaller than needed, as during fasting intervals, glycogen is broken down to glucose. The net result is that the level of glucose in the blood is fin health) maintained within narrow limits; with a concentration never so high as to make the blood dangerously viscous; nor ever so low as to starve the cells.

But what keeps the balance? Meals can be large or small, frequent or infrequent. Fasting intervals may be long. Work or exercise may be greater at one period than at another so that the body's demands for energy will fluctuate. In view of all these unpredictable variations, what keeps the liver maintaining the balance with smooth efficiency?

In part, at least, the answer is insulin.

The presence of insulin in the bloodstream acts somehow to lower the blood glucose level. If for any reason, then, the glucose level should rise unexpectedly above the normal range, that high level in the blood passing through the pancreas stimulates the secretion of a correspondingly high quantity of insulin and the blood glucose level is pushed down to the normal range again. As the blood glucose level drops the stimulus that produces the insulin flow falls off, and so does the insulin. When the blood glucose level reaches the proper point, it falls no lower. Naturally, there is an enzyme in the blood designed to destroy insulin. This insulinase sees to it that no insulin remains to push the blood glucose level too low.

Again the condition is one of feedback. The condition to be corrected stimulates, of itself, the correcting phenomenon. And the response, as it corrects the condition, removes the very stimulus that calls it forth.

In the diabetic the capacity of the islets of Langerhans to respond to the stimulus of high glucose concentration fails. (Why this should be is not known, but the tendency for such failure is

32 THE HUMAN BRAIN

inherited.) As a result, the rise in glucose concentration after a meal is counteracted with increasing sluggishness as the extent of islets' failure increases. In fact, clinicians can detect the onset of diabetes at an early stage by deliberately flooding the blood with glucose. This is done by having the suspected person drink a quantity of glucose solution after a period of fasting. Samples of blood are then withdrawn before the meal and periodically afterward, and the glucose content is measured. If, in such a glucose-tolerance test, the rise in glucose concentration is steeper than is usually the case and if the return to normal is slower, then the patient is probably in the early stages of diabetes.

If the disease is not detected and is allowed to progress, the islets of Langerhans continue to fail to an increasing extent. The insulin supply goes lower and the glucose concentration becomes permanently high and, then, higher. When the concentration reaches a level of 200 rag. per cent or so (rather more than twice normal) the glucose threshold is passed and some glucose is lost through the kidneys. This is a waste of good food, but it is the best thing to be done under the unfortunate circumstances. If the glucose were allowed to continue to pile up, the blood would become dangerously, even fatally, viscous.

Ordinarily, the urine contains only traces of glucose, perhaps as little as i mg. per cent. In untreated diabetics, the concentration rises a thousandfold and is easily detected. By the time sugar is detected in the urine, however, the disease has progressed uncomfortably far.

The islets of Langerhans, having once failed, cannot have their function restored by any treatment known to man. The patient can, nevertheless, be supplied with insulin from an outside source. The insulin taken from the pancreas of a slaughtered steer is as effective in reducing the blood glucose concentration as is the insulin supplied by the patient's own pancreas. One or two milligrams of insulin per day will do the job.

The difficulty is that, whereas the patient's own pancreas in its days of health and vigor supplied insulin in the precise quantity

OUR PANCREAS

needed and in a continuous but varying flow, insulin from the outside must be supplied in set quantities that can be made to match the need only approximately. The adjustment of the body's metabolism must therefore proceed by jerks, with the glucose concentration being driven too low'at the first flood of insulin and being allowed to drift too high before the next installment. It is as though you placed the thermostat of your furnace under manual control, pushing it up and down by hand and trying to attain a continuously equable temperature.

It is for this reason that a diabetic, even under insulin treatment, must watch his diet carefully, so that he places as little strain as possible upon the blood glucose level. (You could control the thermostat manually with somewhat greater success if there were no sudden cold snaps to catch you by surprise.) The use of externally produced insulin has the disadvantage also of requiring hypodermic injection. Insulin cannot be taken by mouth, for it is a protein that is promptly digested in the stomach and broken into inactive fragments.

A possible way out lies in an opposite-tack approach. The insulin-destroying enzyme insulinase can be put out of action by certain drugs. Such drugs, which can be taken by mouth, would therefore allow a diabetic's limited supply of insulin to last longer and could, at least in some cases, replace the hypodermic needle.

INSULIN STRUCTURE

It is easy to observe that insulin lowers the blood glucose level. This level, however, is the result of a complex interplay of many chemical reactions. How does insulin affect those reactions in order to bring about a lowering of the level? Does it affect just one reaction? More than one? All of them?

In the search for answers to these questions, suspicion fell most strongly on a reaction catalyzed by an enzyme called hexokinase (hek'soh-ky'nays). This was chiefly the result of work by the

THE HUMAN BRAIN

OUR PANCREAS

husband-and-wife team of Czech-American biochemists, Carl Ferdinand Cori and Gerty Theresa Cori, who had worked out much of the detail of the various reactions involved in glucose breakdown and had, for that reason, shared in the Nobel Prize in Medicine and Physiology for 1947. The Coris maintained that the hexokinase reaction was under continual inhibition under ordinary circumstances and that the action of insulin was to counteract this inhibition and to allow the reaction to proceed. They were able to demonstrate how the effect on that one reaction would account for the lowering of blood glucose concentration.

However, this seems to have been too simple an explanation. The metabolism of the diabetic is disordered in various ways. Although it is possible to account for a variety of disorders through the effect of the upsetting of a single reaction f so interconnected is the metabolic web), to account for all the disorders in diabetes mellitus out of the one hexokinase reaction required a great deal of complicated reasoning that grew the less convincing as it grew more complicated. The most recent experiments seem to indicate instead that insulin exerts its effect on the cell membranes. The rate at which cells absorb glucose depends partly on the difference in concentration of glucose within and without the cell; and also on the nature of the cell membrane through which the glucose must pass.

To make an analogy: if men are entering a building from the street, the rate at which they will enter will depend partly on the number of men trying to get in. It will also depend on the width of the door or on the number of open doors. After a certain point of crowding is reached, only a certain number of men can enter the building each second, no matter how many men are in the street pushing to get in. An attendant, however, who quickly opens two more doors at once triples the rate of entry.

Apparently insulin molecules attach themselves to the membranes of muscle cells and of other types of cells as well and act to increase the permeability of those membranes to glucose. (In

effect, opening additional doors.) So, when glucose floods the bloodstream after a meal, insulin is produced. This opens the "membrane doors" and the glucose concentration in blood is rapidly reduced, since it vanishes within the cells, where it is either utilized or stored. In the diabetic, glucose knocks at the various cell membranes, but in the absence of insulin it knocks to a certain extent in vain. It cannot enter with sufficient speed and it therefore accumulates in the blood. Obviously, anything else that will facilitate entry of glucose into the cells will, at least partially, fill the role of insulin. Exercise is one thing that will, and regular exercise is usually prescribed for the diabetic.

We must inevitably ask: What is it that insulin does to the cell membrane to increase the facility with which glucose enters? It is partly in the hope of answering this question (and partly out of sheer curiosity) that biochemists attempted to determine the exact structure of the insulin molecule.

The molecule of insulin is a polypeptide, as are those of the gastrointestinal hormones, but it is more complicated. While the secretin molecule is made up of 36 amino acid units, the insulin molecule is made up of about 50. Since the problem of secretin's exact structure has not been solved, one might reasonably suppose that insulin's exact structure would also be still unknown; but the drive for a solution to the problem in the case of insulin, which is involved in mankind's most serious "metabolic disease," is far greater than the drive to solve the problem of the structure of the gastrointestinal hormones, which have little clinical importance. In addition, far greater quantities of pure insulin are available for analysis.

By the late 1940*5 it had been discovered that insulin had a molecular weight of a trifle under 6000. (Its molecules have a tendency to double up and to join in even larger groups so that molecular weights of 12,000 and even 36,000 had been reported at first.) The molecule was then found to consist of two chains of amino acids held together by cystine molecules after the fashion explained on page 12. When the chains were pulled apart,

OUR PANCREAS

36 THE HUMAN BRAIN

one (chain A) turned out to consist of 21 amino acids, while the other (chain B) consisted of 30.

The individual amino acids in each chain were easily determined by breaking down the chains separately and then analyzing for the different amino acids." But, as I explained in the previous chapter, knowing the individual amino acids is only the beginning. One must also know the exact order in which they are arranged. The 21 amino acids of chain A can be arranged in any of about 2,800,000,000,000,000 ways. The 30 amino acids of chain B offer more leeway, obviously, and can be arranged in any of about 510,000,000,000,000,000,000,000,000 different ways.

The problem of determining the exact arrangements in the actual molecule of insulin obtained from the ox pancreas, out of all the possibilities that could exist, was tackled by a group headed by the British biochemist Frederick Sanger. The method used was to break down the amino acid chains only partway by the use of acid or of various enzymes. The breakdown products were not individual amino acids but small chains containing two, three, or four amino acids. These small chains were isolated and studied and the exact order of the amino acids determined. (Two amino acids can only be placed in two different orders, A-B and B-A. Three amino acids can be placed in six different orders: A-B-C, A-C-B, B-C-A, B-A-C, C-A-B, and C-B-A. Even four amino acids can only be placed in 24 different orders. The possible arrangements in the case of the small fragments can be checked and the correct one chosen without insuperable difficulty. At the most, a couple of dozen possibilities are involved and not a couple of quintillion.)

Once all the small chains are worked out, it becomes possible to fit them together. Suppose that chain A has only one molecule of a particular amino acid that we shall call q, and suppose that two short chains of three amino acids each have been located,

* The method of doing this involves a procedure called paper chromatography that was first developed in 1944 and has succeeded in revolutionizing biochemistry. If you are interested in this, you will find the procedure described in some detail in the chapter "Victory on Paper" in my book Only a Trillion (1957)-

one being r-s-q and the other q-p-o. Since only one q is present, there must be a five amino acid sequence in the original molecule that goes r-s-q-p-o. You will then get either r-s-q or q-p-o, depending on which side of the q the chain breaks.

It took eight years for Sanger and his group to work out the complete jigsaw puzzle. By 1955 they had put the fragments together and determined the structure of the intact molecule. It was the first time the structure of any naturally occurring protein molecule had ever been determined in full, and for this Sanger was awarded the Nobel Prize in Chemistry for 1958.

The formula of the molecule of ox insulin, in Brand abbreviations, is as follows:

glu-glu'val-ileu-gly asp-NH2 cyS-cyS-ser-Ieu-tyr-glu-leu-glu-asp-tyr-cyS cyS-ala-ser-val cyS-gly-serhis-leu-val-glu-ala-leu-tyr-leu-val-cyS leU'his'glu-asp-val-phe gly ala-lys-pro-thr-tyr-phe-phe-glyarg'glu

ox INSULIN

Unfortunately, nothing in the structure of the molecule gives biochemists any clue as to why insulin affects the cell membrane as it does.

It might be possible to tackle the matter by comparing the structures of insulin produced by different species. Swine insulin is just as effective for the diabetic as ox insulin is. If the two insulins differ in molecular structure, then only that which they possess in common need perhaps be considered necessary to their functioning, and attention could be focused to a finer point. When swine insulin was analyzed, it was found to differ from ox

38 THE HUMAN BRAIN

insulin only in the three amino acids italicized in the formula given above, the three that are pinched off in a comer, so to speak, between the two cystine groups.

Whereas in ox insulin the three amino acids are ala-ser-val, in swine insulin they are thr-ser-ileu. These same three amino acids and only these three also vary in the insulin molecules of other species. In sheep it is ala-gly-cal, in horses it is thr-gly-ileu, and in whales it is thr-ser-ileu. Of these three the one at the left can be either alanine or threonine, the one in the middle can be either serine or glycine, and the one at the right can be either valine or

isoleucine.

While many other species remain to be tested, it does not seem likely that startling differences will be found. Furthermore, any change imposed on the insulin molecule by chemical reaction from without, unless the change is a rather trifling one that does not seriously affect the complexity of the molecule, produces loss of activity. Whatever it is that insulin does to the cell membrane, all, or virtually all, of the molecule is involved, and that is about as much as can be said. At least so far.

GLUCAGON

Where a hormone exerts its push in a single direction, as insulin does in the direction of lowered glucose concentration in the blood, it would be reasonable to suspect that another hormone might exist which exerts an opposing effect. This would not result in a cancellation of effect, but rather in an equilibrium that can be shifted this way and that more delicately and accurately through the use of two opposing effects than through either alone. You can see this best perhaps when you consider that a tottering ladder is most easily steadied by being held with both hands, the two pressing gently in opposing directions.

There does exist such an "opposition hormone" for insulin, one also produced in the islets of Langerhans. This second hormone is far less well known than insulin because there is no

OUR PANCREAS

clinical disorder that is clearly associated with it; nothing, that is, corresponding to diabetes mellitus.

The islets of Langerhans contain two varieties of cells, named alpha cells and beta cells. (Scientists very often, perhaps too often, follow the line of least resistance in distinguishing a series of similar objects by use of the first few letters of the Greek alphabet.} The alpha cells are the larger of the two types and are situated at the outer regions of the islets, making up about 25 per cent of their total volume. At the centers of each islet are the smaller beta cells. It is the beta cells that produce the insulin, and the alpha cells produce the hormone with the opposing effect.

This second hormone was discovered when, soon after Banting's discovery of a method of insulin preparation, some samples were found to induce an initial rise in blood glucose concentration before imposing the more usual lowering. Something that exerted an effect opposed to that of insulin was therefore searched for and located. The new hormone was found to bring about an acceleration of the breakdown of the glycogen stored in the liver. The glycogen was broken down to glucose, which poured into the bloodstream. In this fashion the blood glucose level was raised.

When the presence of a hormone is only suspected by the effects it brings about, it is named after those effects in many cases; this new hormone was therefore named hyperglycemic-glycogenolytic factor (hy'per-gly-see'mik gly'koh-jen'oh-lih'tik; "high-glucose, glycogen-dissolving" G) in order to mark the manner in which it raised the blood glucose level and lowered the quantity of glycogen in the liver. Since biochemists don't really like long names any more than do the rest of us, this was quickly abbreviated to HGF. In recent years an acceptable name, shorter than the first, has become popular — glucagon (gloo'kuh-gon).

By 1953 glucagon had been prepared in pure crystalline form and was easily shown to be a polypeptide with a molecule made up of a single chain containing 29 amino acids. At first thought

4O THE HUMAN BRAIN

it might have seemed that perhaps glucagon was a fragmented insulin molecule, but a closer look disproved that. By 1958 the order of the amino acids had been worked out, by use of the methods introduced by Sanger. Here it is:

his-ser-glu-NHg-gly thr-phe-thr-ser-asp-tyr-ser--lys-tyr-leu-asp-ser-arg-arg-ala-glu-NH2-asp-phe--va!-glu-NH2-try-h'u-met-asp-XH2-thr

GLUCAGON

There is, as you see, no similarity in this chain to either of the chains in insulin. As a matter of fact, some of the amino acids present in glucagon (methionine, say) are not present in insulin at all, while others {as, for example, isoleucine) which are present in insulin are not present in glucagon. There is no question but that insulin and glucagon are two completely different hormones.

EPINEPHRINE

Insulin and glucagon are by no means the only hormones that affect the metabolism of carbohydrates in a manner that shows up in the level of glucose concentration in the blood. Another hormone with such an effect is produced by two small yellowish organs, roughly pyramidlike in shape, about one or two inches in length in the adult and weighing about 10 grams (& ounce) each. They lie in contact with the upper portion of either kidney and are the first organs I have had occasion to mention that are completely endocrinological in functioning.

Because of their location, the organs are called the adrenal glands (ad-ree'nul; "near the kidneys" L), or suprarenal glands {syoo'pruh-ree'nul; "above the kidneys" L); see illustration,

page 75-

The adrenal glands are made up of two sections, an outer and an inner, and these are different in cellular makeup, in function, and in origin. In the more primitive fish, the material corre-

OURPANCREAS 41

spending to the two sections of the adrenal glands exists separately. What is in us the outer portion is an elongated structure in these fish, about as long as the kidneys. Our inner portion forms two lines of small collections of cells, running nearly twice the length of the kidney. In amphibians, reptiles, and birds, the glandular material is more compact and the two sets of cells become intermingled. Among the mammals compactness reaches the extreme, and one set of cells entirely encloses the other.

The outer portion of the adrenal glands, which makes up about nine tenths of the mass of the organs is the adrenal cortex. (kawr'-teks; "bark" L, because it encloses the inner portion as the bark encloses a tree). The inner portion is the adrenal medulla (meh-dul'uh; "marrow" L, because it is within the outer portion as marrow is within a bone). The hormone to be discussed now is formed in the medulla.

As long ago as 1895 it was known that extracts of the adrenal glands had a powerful action in raising the blood pressure. In 1901 a pure substance was obtained from the glands by the Japanese biochemist Jokichi Takamine and this markedly raised the blood pressure even in very tiny quantities. The name by which this compound is best known is Adrenalin (ad-ren'uh-lin), which, however, is only one of many trade names for the material. The proper chemical name for the compound is epinephrine (ep'ih-nef'rin; "on the kidney" G).

The year after Takamine's feat, Bayliss and Starling demonstrated the possibility of chemical coordination in the absence of nerve action. Once that was clearly understood, it was recognized that epinephrine was a hormone. It was the first hormone to be isolated in pure form, and the first hormone to have its structure determined. This is less remarkable than it might otherwise appear; of all known hormones, epinephrine has the simplest structure.

Where secretin, insulin, and glucagon are all made up of chains of several-dozen amino acids, epinephrine is, in its essentials, a modified version of a single amino acid, tyrosine. This is most

THE HUMAN BBAIN

OUR PANCREAS

clearly shown by comparing the chemical formulas. Even if you are not familiar with such formulas and don't understand the details of what is represented, the resemblance between the two substances will still be clear:

CHOH

CHjNHCH,

EPINEPHHINE

CH,

NH.CHCOOH

Chemists have had little difficulty in showing that the adrenal medulla manufactures its epinephrine out of tyrosine.

As far as its effect on carbohydrate metabolism is concerned, epinephrine resembles glucagon in hastening the breakdown of glycogen to glucose so that the blood level of glucose rises. The difference is this: glucagon works under normal conditions; epinephrine works in emergencies. To state it differently, glucagon maintains a more or less steady effect designed to help keep the glucose level constant (in cooperation with the opposite action of insulin) under the ordinary fluctuations of glucose supply and glucose consumption. Epinephrine, in contrast, is called into play under conditions of anger or fear, when a massive supply of glucose is quickly needed to supply the energy requirements of a body about to engage in either fight or flight.

Then, too, where glucagon mobilizes only the glycogen supplies of the liver (supplies that are for the general use of the body), epinephrine brings about the breakdown of the glycogen in muscle as well. The muscle glycogen is for use by the muscles only, and by stimulating its breakdown epinephrine makes possible the

drawing on private energy supply by the muscles (which will be primarily concerned in the fight-or-flight situation).

Epinephrine has other effects on the body beside the mobilization of its glucose reserves. For one thing, there is the effect on blood pressure, by which its existence was first recognized, and its ability to speed the heartbeat and the breathing rate. These last effects are brought about via the interplay of epinephrine and the nervous system, something I shall discuss in more detail in Chapter 9. I might pause to mention, though, that the two levels of organization, the chemical (hormones) and the electrical (nerves) are by no means independent, but are interrelated.

The situation, incidentally, whereby a single modified amino acid functions as a hormone (and is classified as one) is represented by more than one case. There is histamine, for another example, a compound very similar in structure to the amino acid histidine, as the following formulas show:

CH,

NHtCHCOOH

HISTIDINE

OH,

NHjCH,

HISTAMINE

In small concentrations histamine stimulates the secretion of hydrochloric acid by the glands in the stomach lining. There are biochemists who suspect that gastrin (one of the gastrointestinal hormones pointed out in the previous chapter, see p. 20) is really histamine. This is by no means certain yet.

As in the case of epinephrine, histamine affects blood pressure and other facets of the body mechanism. (The kinins, described on page 22, have some effect similar to histamine.) Histamine is

THE HUMAN BRAIN

believed responsible for some of the unpleasant accompaniments of allergies (runny nose, swelling of the mucous membrane of nose and throat, constriction of the bronchioles, and the like). Apparently the foreign protein, or other substance, which sparks the allergic reaction does so by stimulating the production of histamine. Drugs that counteract the effect of histamine (anti-histamines) relieve these symptoms.

OUR THYROID

IODINE

There is still another hormone that is a modified amino acid, one a bit more complicated in structure than either epinephrine or histamine is. To discuss it properly, I shall begin by introducing a new organ. The prominent cartilage in the neck, commonly called the "Adam's apple," is more correctly termed the thyroid cartilage. The word "thyroid" is from a Greek term meaning "shieldlike," in reference to the large oblong shields carried by Homeric and pre-Homeric warriors which had a notch on top for the chin to rest upon. You can feel the notch on top of the thyroid cartilage if you put your finger to your neck.

Now at the bottom of the thyroid cartilage is a soft mass of yellowish-red glandular tissue about two inches high, a bit more than two inches wide, and weighing an ounce or a little less. It exists in two lobes, one on either side of the windpipe, with a narrow connecting band running in front of the windpipe just at the bottom boundary of the thyroid cartilage. Seen from the front, the gland resembles a letter H. The gland, for some centuries, has borrowed its name from the cartilage it hugs and is therefore known as the thyroid gland even though there is nothing shieldlike about it.

Before the end of the igth century, the function of the thyroid gland was not known. It is somewhat more prominent in women

POSTERIOR LOBE

OUB THYROID

LOCATION OF

FRONT VIEW PARATHYROIDS OF THYROID

than in men, and for that reason the opinion was variously maintained that the thyroid was nothing more than padding designed to fill out the neck (of women especially) and make it plumply attractive. There were regions of Europe where the thyroid {again, particularly in women) was enlarged beyond the normal size, and this, which meant a somewhat swollen neck, was accepted as an enhancement of beauty rather than otherwise. An enlarged thyroid gland is referred to as a goiter ("throat" L).

The cosmetic value of a goiter was rather deflated when it came to be recognized about 1800 or so that the condition could be associated with a variety of undesirable symptoms. Confusingly enough, goitrous individuals were apt to have either of two op-posing sets of symptoms. Some were dull, listless, and apathetic,* with soft, puffy tissues, cool, dry skin, and slow heartbeat. In con- j trast, some were nervous, tense, unstable, with flushed, moist skin) and fast heartbeat. And finally, as you might guess, there were people with goiters who showed neither set of symptoms and were reasonably normal.

That this connection of the goiter and at least one set of symptoms was no coincidence was clearly demonstrated in 1883, when several Swiss surgeons completely removed goitrous thyroids from 46 patients. (Switzerland is one of the regions where goiter was common.) The thyroids had enlarged to the point where they were interfering with surrounding tissue, and there seemed no logical argument against removal. Unfortunately, in those patients the symptoms of the dull, Listless variety appeared and intensified. To remove the entire thyroid appeared not to be safe.

Then in 1896 a German chemist, E. Baumann, located iodine in the thyroid gland. Not much was present, to be sure, for the best modern analyses show that the human thyroid at most contains 8 milligrams (or about 1/2000 ounce) of iodine. About four times the amount is distributed throughout the rest of the body. The rest of the body, however, is so much more massive than the thyroid that the iodine content there is spread thin indeed. The iodine concentration in that one organ, the thyroid

48 THE HUMAN BRAIN

gland, is more than 60,000 times as high as is the concentration anywhere else in the body.

Certainly this sounds significant now, but it didn't seem so in 1896. Iodine had never been located in any chemical component of the human body, and it seemed reasonable to suppose that it was an accidental contaminant. The fact that it was present in such small quantities made this seem all the more probable, for it was not yet understood in 1896 that such things as "essential trace elements" existed; elements that formed parts of hormones or enzymes and were therefore necessary to proper functioning of the body and even to life itself, without having to be present in more than tiny quantities.

It was a decade later, in 1905, that David Marine, an American physician just out of medical school, took Baumann's discovery seriously. Coming to the American Midwest from the East, he wondered if the relative frequency of goiter in the Midwest had anything to do with the relative poverty of the soil in iodine." Perhaps the iodine was not merely an accidental contaminant, but formed an integral part of the thyroid; and perhaps in the absence of iodine the thyroid suffered a disorder that evidenced itself as a goiter.

Marine experimented upon animals with diets low in iodine; they developed goiter, showing the dull, listless set of symptoms. He added small quantities of iodine to the diet and cured the condition. By 1916 he felt confident enough to experiment on girls and was able to show that traces of iodine in the food cut down the incidence of goiter in humans. It then took another ten years to argue people into allowing small quantities of iodine compounds to be added to city water reservoirs and to table salt. The furious opposition to such procedures was something like

* Iodine is actually a rare element; the sea is richer in iodine than the land is, Seaweed is a major source of iodine because plant cells actively concentrate the iodine of the sea. The iodine in soil is often there only because storms spray the coastline with droplets of ocean water that evaporate, leaving the tiny bits of salt content to he blown far inland. The salts contain iodine, and as a matter of course land near the sea would, all things being equal, be richer in iodine than areas far inland.

OUR THYROID

the similar opposition to fluoridation today. Nevertheless, iodina-tion won out; iodized salt is now a commonplace; and goiter, in the United States at least, is a rarity.

The symptoms that accompany goiter depend on whether the goiter forms in response to an iodine deficiency or not. The thyroid gland consists of millions of tiny hormone-producing follicles, each filled with a colloidal (that is, jellylike) substance called, simply enough, qollaidf "gluelike" G ) . The colloid contains the iodine and so does the hormone it produces.

If the iodine supply in the diet is adequate, and if for any reason the thyroid increases in size, the number of active follicles may be multiplied as much as ten or twenty times and the hormone is produced in greater-trifm-nftrrrjaj gnantitiflCi Th° na^vnil,'

set of symptoms are produced, and this tis, huperthifTotdism. If, on the contrary, there is a d°ft"'Jf"-?y nf jfldin^, the thyroid may en large in an effort to compensate. The effort inevitably must be unsuccessful. No matter how/many follicles form and how much colloid is produced, the thyroid hormone cannot be manufactured without iodine. In that easel despite the goiter, the hormone is produced in less-than-normajl quantities and the du.!L iJStlfiJJ.'i ,S£* of symptoms results. This islhypothurotdism.''

The two forms of goiter can be distinguished by name. The form of goiter associated with hypothyroidism is simply ioduiZi deficiency ^oitgr, a self-explanatory name. The form of goiter associated with hyppT-thyroijism isexophthalmic goiter (ek'sof-thal'mik; "eyes out" G) because the most prominent symptoms are bulging eyeballs. The latter form is also called Graves' disease, because it was well described by an Irish physician, Robert James Graves, in 1835. In hypothyroidism, the puffy flabbiness of the tissues seems to be brought about by an infiltration of mucuslike

* "Hyper" is from a Greek word meaning "over" and "above," and "hypo" is from the Greek for "under" or "below." The former prefix is commonly used to indicate any condition involving overactivity of an organ or the production or occurrence of some substance in greater-than -normal quantities. The latter prefix is used to indicate the opposite. It is a pity that opposites should sound so alike and offer such chance of confusions, but it is too late to correct the Greek language now.

5O THEHUMANBRAIN

materials, and the condition is therefore called (mik'suh-dee'muh; "mucus-swelling" G).

The symptoms in either direction, that of hyperthyroidism or hypothyroidism, can be of varying intensity. A reasonable measure of the intensity was first developed in 1895 by a German physician, Adolf Magnus-Levy, and that was partly a result of accident. At the time, physiologists had developed methods for measuring the uptake of oxygen by human beings and deducing the rate at which the metabolic processes of the body were operating. Naturally, this rate increased with exercise and decreased during rest. By arranging to have a fasting person lie down in a comfortably warm room and under completely relaxed conditions it was possible to obtain a minimum waking value for the rate of metabolism. This was the basal metabolic rate, usually abbreviated BMR, and it represented the "idling speed" of the human body.

Magnus-Levy was briskly and eagerly applying BMR measurements to the various patients in the hospital at which he worked in order to see whether the BMR varied in particular fashion with particular diseases. Obviously if it did, BMR determinations could become a valuable diagnostic tool and could help in following the course of a disease. Unfortunately, most diseases did not affect the BMR. There was one important exception. Hyperthyroid individuals showed a markedly high BMR and hypothyroid individuals a markedly low one. The more serious the condition the higher (or lower) the BMR was.

In this way the overall function of the thyroid hormone was established. It controlled the basal metabolic rate, the idling speed. A hyperthyroid individual had, to use an automotive metaphor, a racing engine; a hypothyroid individual had a sluggish one. This lent sense to the two sets of symptoms. With the chemical reactions within a body perpetually hastening, a person would be expected to be keyed-up, tense, nervous, overactive. And with those same reactions slowed down, he would be dull, listless, apathetic.

OUBTHYROID 51 THYROXINE

The search for the actual thyroid hormone started as soon as the importance of iodine in the thyroid gland was recognized. In 1899 an iodine-containing protein was isolated from the gland. This had the properties associated with a group of proteins called "globulins" and was therefore named thyroglobulin (thy'roh-glob'-yoo-lin). It could relieve hypothyroid symptoms as well as mashed-up thyroid could, and do it in smaller quantities; so it might be considered at least a form of the thyroid hormone.

However, thyroglobulin is a large protein molecule, possessing a molecular weight, we now know, of up to 700,000. It is far too large to get out of the cell that formed it and into the bloodstream in intact form. For this reason it quickly seemed clear that thyroglobulin was at best merely the stored form of the hormone, and that what passed into the bloodstream were small fragments of the thyroglobulin molecule.

Iodine assumed increasing significance as biochemists labored in this direction. The thyroid gland, rich in iodine though it might be compared with the rest of the body, is still only about 0.03 per cent iodine. Preparations of thyroglobulin itself were 30 times or so as rich in iodine as was the intact thyroid gland and contained up to almost i per cent iodine. Furthermore, when the thyro-globuhn molecule was broken down, the most active fragments had iodine contents as high as 14 per cent. Iodine was clearly the key. It was even possible to add iodine to quite ordinary proteins, such as casein (the chief protein of milk}, and to produce an artificial iodinated protein containing some degree of thyroid hormone activity.

Finally, in 1915 the American chemist Edward Calvin Kendall isolated a small molecule that had all the properties of the thyroid hormone in concentrated form and yet seemed to be a single amino acid. Since it was found in the thyroid and since it controlled the rate of oxygen utilization in the body, the molecule was named thyroxine (thy-rok'sin}.

52 THE HUMAN BRAIN

An additional decade was required to determine the exact molecular structure of this amino acid. It turned out to be related to tyrosine, differing in its possession of a sort of doubled side-chain. You can see this clearly in the formulas below:

NHtCHCOOH

TYHOSINE

NH.CHCOOH

THYBOXINE

The most unusual point about the structure of the thyroxine molecule is the fact that it contains four iodine atoms, symbolized in the formula above by I. (If the four iodine atoms were removed, what would be left of the molecule would be named thyronine.)

The four iodine atoms are quite heavy, much heavier than all 31 carbon, hydrogen, nitrogen, and oxygen atoms making up the rest of the molecule." For that reason, iodine makes up about 63 per cent of the weight of the thyroxine molecule.

Apparently the thyroid gland traps the small traces of iodine

* Of all the atoms that are essential to life, iodine is by far the heaviest. The four most common atoms in the body are all quite light. Thus, if the weight of the hydrogen atom is considered i, then carbon has an atomic weight of la, nitrogen of 14, and oxygen of 16. Compare this with iodine, which has an atomic weight of 127.

OURTHYROID 53

present in food, adds them to the tyrosine molecule, doubles the side-chain, and adds more iodine to form thyroxine. (This can be done artificially, to a certain extent, by adding iodine to casein, as I mentioned above,) The thyroxine molecules are then united with other, more common amino acids and stored as the large thyroglobulin molecule. At need, the thyroxine content of the thyroglobulin is stripped off and sent out into the bloodstream.

For some thirty-five years after the discovery of thyroxine, it was considered the thyroid hormone. In 1951 the British biochemist Rosalind Pitt-Rivers and her co-workers isolated a very similar compound, one in which one of the iodine atoms was absent from the molecule, leaving only three in place. The new compound, with its three iodine atoms, is tri-iodothyronine, and is rather more active than thyroxine. For this reason I shall refer hereafter to "thyroid hormone" rather than to any one particular compound.

Now where thyroid hormone is severely deficient, the BMR may drop to half its normal value; where it is quite excessive, the BMR may rise to twice or even two and a half times its normal value. The thyroid control can therefore push the rate of metabolism through a fivefold range.

Yet what is it that thyroxine, tri-iodothyronine, and possible related compounds do to bring about such changes? What particular reaction or reactions do they stimulate in order to lift the entire level of metabolism? And how does iodine play a role? This is perhaps the most fascinating aspect of the problem, because no compound without iodine has any thyroid hormone activity whatever. Furthermore, there is no iodine in any compound present in our body except for the various forms of thyroid hormone.

By now you should not be surprised at learning that there is no answer as yet to these questions. The answer, when it comes, will have to explain more than a simple raising or lowering of the BMR, since that is by no means the only effect of the thyroid hormone. It plays a role in growth, in mental development, and in sexual development.

THE HUMAN BRAIN

OUR THYROID

It sometimes happens that children are born with little or no thyroid tissue. Such children live but one can scarcely say more than that. If the condition is not corrected by the administration of hormone, the deficient creatures never grow to be larger than the normal seven- or eight-year-old. They do not mature sexually and are usually severely retarded mentally. They are often deaf-mutes. (These symptoms can be duplicated in animals if the thyroid is removed while they are young; actually it was in this fashion that the symptoms just described were first associated with the thyroid gland.)

Such virtually thyroidless unfortunates are called cretins (kree'tinz). The word is from a southern French dialect and means "Christians." The use of this word is not intended as a slur on religion but is, rather, an expression of pity, as we might say "poor soul." It could also be a hangover from an earlier day, reflecting the widespread belief among many primitive peoples that any form of mental aberration is a sign that the sufferer is touched by a god. (And do we not sometimes say of a madman that he is "touched in the head"?)

This inability of a thyroidless child to develop into an adult is also evidenced among the lower vertebrates; most startlingly among the amphibians. In amphibians the change from the young to the adult forms involves such dramatic overhauls of body structure as the replacement of a tail by legs, and of gills by lungs. Such changes cannot be carried through partway without killing the creature. The change is either completed or it is not begun.

If thyroid tissue is removed from a tadpole, the change is never begun. The creature may grow, yet it remains a tadpole; but if thyroid extract is added to the water in which the tadpole is swimming, it makes the change and becomes a frog. In fact, if thyroid extract is added to the water in which small tadpoles are swimming (tadpoles too small to produce their own hormone and change to frogs in the course of nature) the change nevertheless takes place. Tiny frogs are produced, much smaller than those produced under normal conditions.

There are creatures called axolotls, which are amphibians that remain tadpoles, so to speak, throughout life. They remain water creatures with gills and tail, but differ from ordinary tadpoles in that they can develop sexual maturity and reproduce themselves. They evidently are naturally hypothyroid, but through evolutionary processes have managed to survive and adjust to their lot. Now if the axolotl is supplied thyroid extract, it undergoes the change that in nature it does not. Legs replace the tail, lungs replace gills, and it climbs out upon land, a creature forever cut off from the rest of its species.

The sensitivity of amphibians to thyroid hormone is such that tadpoles have been used to test the potency of samples of thyroid extracts.

THYROID-STIMULATING HORMONE

One would expect the thyroid hormone to be produced in amounts matching the needs of the body. Where the rate of metabolism is high, as during exercise or physical labor, the hormone is consumed at a greater-than-normal rate and the thyroid gland must produce a correspondingly greater amount. The reverse is true when the body's needs are low, as when it is resting or asleep.

In the case of insulin, the blood glucose level can act as a feedback control. No such opportunity seems to be offered the thyroid gland. At least no blood component is, as far as we know, clearly affected by the quantity of thyroid hormone produced, and so there is no shifting level of concentration of some component to act as a thyroid control.

The concentration of thyroid hormone in the blood must itself vary. If body metabolism rises, so that the hormone is more quickly consumed, its blood level must show a tendency to drop. If body metabolism is low, the blood level of the hormone must show a tendency to rise. It might seem, then, that the thyroid could respond to the level of its own hormone in the blood passing through itself. This is clearly dangerous. Since the thyroid pro-

56 THE HUMAN BRAIN

duces the hormone, the blood concentration in its own vicinity would always be higher than in the remainder of the body, and it would receive a blurred and distorted picture of what is going on. (It would be something like an executive judging the worth of his ideas by the opinions of his yes-men.)

The solution is to put a second gland to work; a gland in a different region of the body. The second gland turns out to be, in this case, a small organ at the base of the brain. This is the pituitary gland (pih-tyoo'ih-tehr'ee; "phlegm" L). The name arises from the fact that, since the gland is located at the base of the brain just above the nasal passages, some of the ancients thought its function was to supply the nose with its mucous secretions. The idea held force till about 1600.

This, of course, is not so; the only secretions produced by the pituitary are discharged directly into the bloodstream. Nevertheless, the name persists, although there is the alternative of hypophysis cerebri .(hy-pofth-sis cehrAih-bree; "undergrowth of the brain" G}, or simply hypophysis. This term, which came into use about half a century ago, is at least accurately descriptive.

In man the pituitary gland is a small egg-shaped structure about half an inch long, or about the size of the final joint of the little finger; see illustration, page 46. It weighs less than a gram, or only about 1/40 of an ounce, but don't let that fool you. In some respects it is the most important gland in the body. The location alone would seem to indicate that — just about at the midpoint of the head, as though carefully hidden in the safest and most inaccessible part. The gland is connected by a thin stalk to the base of the brain, and rests in a small depression in the bone that rims the base.

The pituitary is divided into two parts, which {as in the case of the adrenal glands) have no connection with each other functionally. They do not even originate in the same way. The rear portion, or posterior lobe, originates in the embryo as an outgrowth of the base of the brain, and it is the posterior lobe that remains attached to the brain by the thin stalk. The forward portion, or

OUR THYROID

anterior lobe, originates in the embryo as a pinched-off portion of the mouth. The anterior lobe loses all connection with the mouth and eventually finds itself hugging the posterior lobe. The two are lumped together as a single gland only by this accident of meeting midway and ending in the same pkce. (In some animals, there is an intermediate lobe as well, but in man this is virtually absent.) Both lobes produce polypeptide hormones. The anterior lobe produces six hormones that have been definitely isolated as pure, or nearly pure, substances, and these may be spoken of, generally, as the anterior pituitary hormones. (The existence of several other hormones is suspected.)

Of the six anterior pituitary hormones, one has the function of stimulating the secretion of the th'yroid gland. This is easily shown, since removal of the pituitary in experimental animals causes atrophy of the thyroid gland, among other unpleasant effects. This also takes place in cases of hypopituitarism, where the secretions of the pituitary gland fall below the minimum required for health. The symptoms of this disease (which are quite distressing since they tend to show up in young women and to induce premature aging, among other things) were described by a German physician named Morris Simmonds, so the condition is often called Simmonds' disease.

On the positive side, the administration of preparations of pituitary extracts to animals can cause the thyroid gland to increase in weight and become more active. It is reasonable, therefore, to suppose that at least one of the anterior pituitary hormones is concerned with thyroid function. The hormone has been isolated and has been labeled the thyroid-stimulating hormone, a name usually abbreviated as TSH. It may also be called the thyrotrophic hormone (thy'roh-troh'fic; "thyroid-nourishing" G).a

* There is a tendency to use the suffix "tropic" in place of "trophic" in the case of TSH and certain other hormones. The suffix "tropic" is from a Greek word meaning "to turn" and makes, no sense in this connection. Unfortunately, the difference lies in but one letter and few biochemists seem to be terribly concerned over the proper meaning of a Greek suffix, so "thyrotropic" is a fairly common term and may become even more common.

58 THEHUMANBRAIN

With two hormones at work, a mutual feedback can take place. A lowering of the thyroid hormone concentration in the blood stimulates a rise in TSH production; and a rise in thyroid hormone concentration inhibits TSH production. Conversely, a rise in TSH concentration in the blood stimulates a rise in thyroid hormone production; and a fall in TSH concentration inhibits thyroid hormone production.

Now suppose that, as a result of racing metabolism, inroads are made on the thyroid hormone supply, causing the blood level to drop. As the blood passes through the anterior pituitary, the lower-than-normal level of thyroid hormone stimulates the secretion of additional TSH, and the blood level of TSH rises. When the blood passes through the thyroid carrying its extra load of TSH, the secretion of thyroid hormone is stimulated and the demands of the high metabolic rate are met.

If the thyroid hormone should now be greater than the body's requirements, its blood level will rise. This rising thyroid hormone level will cut off TSH production, which will in turn cut off thyroid hormone production. By the action of the two glands in smooth cooperation, the thyroid hormone level will be maintained at an appropriate blood level despite continual shifts in the body's requirements for the hormone.

The working of the "thyroid-pituitary axis" can, understandably, be imperfect. The mere fact that a second gland is called into action means there is another link in the chain, another link that may go wrong. It is likely, for instance, that hyperthyroidism arises not from anything wrong with the thyroid itself but from a flaw in the anterior pituitary. The secretion of TSH can, as a result, be abnormally high and the thyroid kept needlessly, and even harmfully, overactive. (The anterior pituitary serves as regulating gland, after this fashion, for several other glands in the body. It is this that makes it seem to be the "master gland" of the body.)

TSH is not one of the anterior pituitary hormones that have been prepared in completely pure form, and so information about

OUR THYROID

its chemical structure is as yet a bit fuzzy. Its molecular weight, as it is formed, may be about 10,000; this would mean that its polypeptide chain could contain nearly a hundred amino acids. However, there seem to be signs that the chain can be broken up into smaller portions without loss of activity. This ability to confine the area of activity to a relatively small region of the whole molecule is true of some other hormones as well (though it does not seem to be true of insulin).

PARATHYROID HORMONE

Behind the thyroid gland are four flattened scraps of pinkish or reddish tisue, each about a third of an inch long. Two are on either side of the windpipe, one of each pair being near the top of the thyroid, and one near the bottom. These are the parathyroid glands ("alongside the thyroid" G): see illustration, page 46.

The parathyroids were first detected (in the rhinoceros, of all animals) in the middle igth century, and little attention was paid them for some decades. If physicians or anatomists thought of them at all, it was to consider them as parts of the thyroid. There were cases when, in removing part or all of the thyroid, these scraps of tissue were casually removed as well. This proved to have unexpectedly drastic consequences. The removal of the thyroid might result in severe myxedema, but the patient at least remains alive. In contrast, with the removal of the parathyroids, death follows fairly quickly and is preceded by severe muscular spasms. Experiments on animals, which proved more sensitive to loss of the parathyroids than men were, showed that muscles tightened convulsively, a situation called tetany (tet'uh-nee; "stretch" G). This resembled the situation brought on by abnormally low concentration of calcium ion" in the blood and it was found that

" Some atoms or groups of atoms have a tendency to lose one or more of the tiny electrons that form component parts of themselves. Or they may gain one or more electrons from outside. Since electrons carry a negative electric charge, atoms that lose them possess a positive charge, and those that gain them possess a negative one. Atoms charged either way can be made to move through a fluid in response to an electric field, and are therefore called ions (eye'onz; "wander" C).

THE HUMAN BRAIN

OUR THYROID

calcium ion levels in the blood were indeed abnormally low in animals that had been deprived of the parathyroids. As tetany progressed and worsened, the animal died, either out of sheer exhaustion or because the muscles that closed its larynx did so in a tight death grip so that, in effect, the animal throttled itself and died of asphyxiation. By the 1920*3, surgeons grew definitely cautious about slicing away at the thyroid and supremely careful about touching the parathyroids.

As is now understood, the parathyroid hormone is to the calcium level in the blood as glucagon is to the glucose level. Just as glucagon mobilizes the glycogen reservoir in the liver, bringing about its breakdown to glucose, which pours into the blood, so the parathyroid hormone mobilizes the calcium stores in bone, bringing about its breakdown to calcium ions in solution, which pours into the blood.

The blood contains from 9 to 11 mg. per cent of calcium ion,0 so the total quantity of calcium ion in the blood of an average human being is something like 250 milligrams (less than 1/100 ounce), whereas there is something like 3 kilogVams (or about 6)4 pounds) of calcium ion in the skeleton of the body. This means there is 12,000 times as much calcium in the skeleton as in the blood, so bone is a really effective reservoir. A small amount of calcium withdrawn from bone — not enough to affect perceptibly the strength and toughness of the skeleton — would suffice to keep the blood content steady for a long time.

The properties of an ion are quite different from those of an uncharged atom. Thus, calcium atoms make up an active metal that would be quite poisonous to living tissue, but calcium ions are much blander and are necessary components of living tissue. Nor are calcium ions metallic; instead they make up parts of substances classified by chemists as "salts." The difference between ordinary atoms and ions is expressed in symbols. The calcium atom is symbolized as Ca. The calcium ion, which has lost two electrons and carries a double positive charge, is Ca-*"*-.

* Calcium ion is essential to blood coagulation, and to the proper working of nerve and muscle. To do its work properly, calcium ion must remain within a narrow range of concentration. If it rises too high or drops too low, the entire ion balance of the blood is upset; neither nerves nor muscles can do iheir work; and the body, through a failure in organization, dies. It is the proper functioning of the parathyroid gland which keeps this from happening.

Under the influence of the parathyroid hormone, those cells whose function it is to dissolve bone are stimulated. Bone is eroded at a greater-than-normal rate and the calcium ion thus liberated pours into the bloodstream. As this happens, phosphate ion also enters the bloodstream, for calcium ion and phosphate ion are knit together in bone and one cannot be liberated without the other. The phosphate ion does not remain in the blood but is excreted through the urine. It is possible that parathyroid hormone has as another function the stimulation of the excretion of phosphate ion in the urine.

It is the calcium ion level in the blood that controls the rate of secretion of parathyroid hormone (just as the blood glucose level controls that of insulin). If the diet is consistently low in calcium, so that there is a chronic danger of subnormal levels in the blood, the parathyroids are kept active and bone continues to be eroded away. If the diet is adequate in calcium, the raised level in blood acts to inhibit the activity of the parathyroid and the bone erosion subsides. It was reported in 1963 that the parathyroid produces a second hormone, calcitonin, acting in opposition to tbe parathyroid hormone, as insulin acts in opposition to glucagon. Calcitonin acts to reduce the calcium ion level of the blood. In addition, other processes (in which vitamin D is somehow involved — but that is another story) act to bring about buildup of bone, and any bone previously lost is replaced. Any excess calcium beyond what is needed is excreted through the urine.

It is possible for the parathyroids to remain overactive even when the blood level is adequately high. This can take place when a parathyroid tumor greatly increases the number of hormone-producing cells and the condition is hyperparathyroidism. In such a case, bone erosion continues unchecked, while the body survives by continually dumping excess calcium ion into the urine. Eventually bones may be weakened by calcium loss to the point where they will break under ordinary stresses, and such apparently reasonless breakage may be the first noticeable symptom of the disease.

THE HUMAN BRAIN

OURTHYROID

The parathyroid hormone was isolated in pure form in 1960. It is a small protein molecule with a molecular weight of 9500 and a structure consisting of a chain of 83 amino acids. The molecule can be broken into smaller units, and a chain of 33 amino acids is found to exert the full effect of the parathyroid hormone. Why the other 50, then? The best guess seems to be that the additional 50 are needed to increase the stability of the molecule as a whole. (To use an analogy, only the blade of a knife cuts, and yet the wooden handle, though contributing nothing to the actual cutting, makes the knife easier to hold and therefore more useful generally.)

The exact order in which amino acids occur in the parathyroid hormone has not vet been worked out.

POSTERIOR PITUITARY HORMONES

Now that we have examples of how hormones like insulin and glucagon can maintain the level of concentration of an organic substance such as glucose, and of how hormones like those of the parathyroid gland can maintain the level of concentration of an inorganic substance such as calcium ion, it would round out matters to produce a hormone that controls the level of concentration of the water in which both inorganic and organic substances are dissolved. Water enters and leaves the body in a variety of ways. We take in water with the food we eat and with the fluids (particularly water itself) we drink. We lose water through perspiration, through the expired breath, through the feces, and, most of all, through the urine. Water loss can be increased or decreased with circumstances. The most common way in which we are subjected to unusually great water loss is through perspiration caused by unusual heat or by strenuous physical activity. We make up for that by drinking more water than usual at such times.

This is the "coarse control." There is a "fine control" too, which enables the body to adjust continuously (within limits) to minor

changes and fluctuations in the rate of water loss, so we are not as slavishly tied to the water tap as we would otherwise be. In the fine control, the kidneys are involved. The blood, in passing through the kidneys, is filtered. Wastes pass out of the blood vessels and into the renal tubules. The phrase "pass out" is actually too weak a term. The wastes are flushed out by the lavish use of water; more water than we could ordinarily afford to lose. However, as the blood filtrate passes down the tubules, water is re-absorbed. What eventually enters the ureter and travels down to the bladder is a urine in which the waste materials are dissolved in comparatively little water. If the body is short of water, re-absorption takes place to the maximum of which the body is capable, and the urine is concentrated, scanty, and dark in color. (Desert mammals can conserve water to the point where the urine is so scanty as to be almost nonexistent; we do not have that talent.) If, on the contrary, we drink considerable water or other fluids, so that the body finds itself with more than it needs, the re-absorption of water in the tubules is repressed by the necessary amount and the urine is dilute, copious, and very light in color.

In the early i94o's, it was discovered that this ability of the body to control reabsorption of water in the tubules in order to help keep the body's water contents at a desirable level was mediated by a hormone. Extracts from the posterior lobe of the pituitary gland seemed to have a powerful effect on the manner in which water was reabsorbed. These extracts, usually called pituitrin, encouraged the reabsorption of water and therefore diminished the volume of urine. Now any factor which increases urine volume is said to be diuretic (dy'yoo-ret'ik; "to urinate" G). The posterior pituitary extract had an opposite effect and was therefore felt to contain an antidiuretic hormone, usually referred to by the abbreviation ADH.

In addition, as it turned out, pituitrin possesses two more important abilities. It tends to increase blood pressure through a contraction of blood vessels. This is referred to as vasopressor ( vas'oh-pres'or; "vessel-compressing" L ) activity. It also induces

THE HUMAN BRAIN

contractions of the muscles of the pregnant uterus at the time it becomes necessary to force the fully developed fetus out into the world. This is called the oxytocic (ok'see-toh'sik; "quick birth" G) effect. And, as a matter of fact, the preparation can be used to encourage a quick birth by forcing a uterus into action at some convenient moment. Oxytocin also contracts certain muscle fibers about ducts in the nipples, bringing about the ejection of milk. Oxytocin production is stimulated during the period of milk production by the sucking of the infant at the nipple.

The American biochemist Vincent du Vigneaud and his associates obtained two pure substances from the posterior pituitary extracts, of which one possessed the blood-pressure-raising effect and was named vasopressin and the other possessed the uterus-stimulating effect and was named oxytocin. There was no need to search for a third hormone with the antidiuretic effect: vasopressin possessed it in full. By the mid-1950's, therefore, the phrase "antidiuretic hormone" vanished from the medical vocabulary. ADH was vasopressin and the latter term was sufficient.

Du Vigneaud found oxytocin and vasopressin to be unusually small peptides, with molecular weights just above 1000. Analysis of these peptides by the methods worked out by Sanger was not difficult. Du Vigneaud found both to possess molecules made up of no more than 8 amino acids. He worked out the order in which they appeared:

cyS—Scyv tyr-ileu-gluNH2.aspNH2-pro-leu-glyNH.;

. cyS—Scy \ tyr-phe-gluNH,.aspNH2-prO'argglyNH2

OUR THYROID ge

two amino acids of the eight different. That is enough, nevertheless, to make their properties completely different and shows what a minor alteration in the nature of the side-chains can do. (On the other hand, vasopressin obtained from hog pituitaries contains a lysine in place of the arginine in the above formula— which is for vasopressin taken from cattle—and that change makes no significant difference.)

Du Vigneaud, having determined the structure of these two hormones, went a step further. He built up an amino acid chain, placing the amino acids in the order analysis had told him was correct. In 1955 he prepared synthetic molecules that showed all the oxytocic, vasopressor and antidiuretic functions of the natural molecules. Thereby he was the first to synthesize a natural active protein (albeit a very small one), and for that feat was, that very year, awarded the Nobel Prize in Chemistry.

It happens occasionally that vasopressin may fail to be produced in adequate quantities in a particular individual. When this happens, water is not properly reabsorbed in the kidney tubules and urination becomes abnormally copious. In bad cases, where water is not reabsorbed at all, the daily volume of urine may reach twenty or thirty quarts, and water must then be drunk in equally voluminous quantities. Such a disease, with water "passing through" so readily, rightly deserves to be considered a form of diabetes.

Since the ordinary wastes present in urine are not increased in this condition but are merely spread thin through the large quantity of water produced, the urine becomes very little removed from tap water. It lacks the odor and amber color of ordinary urine. In particular, when compared with the sugar-filled urine of the sufferer of diabetes mellitus, it lacks a taste. The condition is therefore diabetes insipidus (in-sip'ih-dus; "tasteless" L).

VASOPRESSIN

As you see, the two molecules are very much alike, with only

OUR ADRENAL CORTEX

CHOLESTEROL

So far, all the hormones I have discussed are based on the amino acid. Some, such as thyroxine, epinephrine, and histamine have molecules that are modifications of single amino acids; tyrosine in the first two cases, histidine in the last. Other hormones are chains of amino acids, made up of as few as eight members or as many as a hundred. There are, however, certain hormones that are completely unrelated in structure to the amino acid, and their story begins with that usually painful and certainly unromantic phenomenon we know as gallstones.

In 1814 a white substance with a fatty consistency was obtained from gallstones and was named cholesterin (koh-les'ter-in; "solid bile" G). The name was reasonable enough since gallstones precipitated out of the bile and could therefore be looked upon as a kind of solidified bile. Investigations into the molecular structure of the substance met with frustrating lack of success for over a century, but one fact that eventually turned up after some decades was that the molecule possessed one oxygen-hydrogen combination (-OH) as part of its structure. This is a group occurring, characteristically, in alcohols, and, toward the end of the igth century, it became conventional to give the alcohols names ending with the suffix "ol." For this reason, cholesterin came to be called cholesterol, and the family of compounds of which it was a member came to be called the sterols.

OUR ADRENAL CORTEX 67

As time went on, it was discovered that many compounds clearly related to cholesterol did not possess the -OH group and were therefore not entitled to names with the "ol" suffix. In the 1930*5 a more general term was proposed to include the entire class of compounds, both with and without the -OH group. The name proposed was steroid ("sterol-like" G).

And by then the molecular structure of cholesterol was finally worked out. The molecule is made up, it turned out, of 27 carbon atoms, 46 hydrogen atoms, and just i oxygen atom. Seventeen of the carbon atoms are arranged in a four-ring combination, which can be schematically presented as follows:

STEROID NUCLEUS IN CHOLESTEROL

The carbon atoms are arranged, you see, in three hexagons and one pentagon, joined together as shown. At every angle of these rings you can imagine a carbon atom as existing. The lines connecting the angles are the "bonds" connecting the carbon atoms. The rings are lettered from A to D and the angles (or carbon atoms) are numbered from i to 17, according to the conventional system shown above, which is accepted by all chemists. This particular four-ring combination of carbon atoms is called the steroid nucleus.

Each carbon atom has at its disposal four bonds by which connections may be made with other atoms. The carbon atom at position 2, for example, is making use of two of its bonds already, one for attachment to carbon-i and another for attachment to carbon-3. This means that two bonds still remain and each of these can be attached to a hydrogen atom.' (A hydrogen atom

* It is conventional in such schematic formulas as I am using in this chapter to

THE HUMAN BRAIN

has only one bond at its disposal.) As for the carbon at position 10, that is making use of three of its bonds, one leading to car-bon-i, one to carbon-g, and one to carbon-g. It has only one bond left over.

Sometimes a carbon atom is held to the neighboring carbon atom by two bonds; this is referred to as a double bond. Suppose such a double bond exists between positions 5 and 6. In that case, carbon-5 is connected by two bonds to carbon-6, by a third bond to carbon-10 and by a fourth bond to carbon-4. All its bonds are used up.

Now let's return to cholesterol. Of its 27 carbon atoms, 17 are accounted for by the steroid nucleus. There remain 10. Of these, i is attached to the lone remaining bond of carbon-io and i to the lone remaining bond of carbon-13. The final 8 form a chain (with a detailed structure that need not concern us) attached to carbon-17, with finally, a double bond between carbons 5 and 6.

What of the lone oxygen atom? This is attached to carbon-3-The oxygen atom has the capacity to form two bonds. One of these is taken up by the carbon-3 attachment, but the other is joined to a hydrogen atom, forming the -OH combination that is characteristic of alcohols. This gives us all the information we need to present a schematic formula for the cholesterol molecule:

(30-27)

CHOLESTEROL

leave out the hydrogen atoms that are connected to carbon atoms, for simplicity's sake. Therefore wherever there are bonds left unaccounted for in a formula, as is true of those two extra bonds of carbon-z, you may safely assume that hydrogen atoms are attached.

OUR ADRENAL CORTEX 69

I have gone into detail on the cholesterol molecule for two reasons: first, it is an important molecule in itself and, second, it is the parent substance of other molecules at least as important. The importance of cholesterol is attested by the mere fact that there is so much of it in the body. The average 7O-kilogram (154-pound) man contains some 230 grams, or just about half a pound, of the substance. A good deal of it is to be found in the nervous system (which is reason enough to stress the compound in this book). About 3 per cent of the weight of the brain is cholesterol. Considering that 80 per cent of the brain is water, you can see that cholesterol makes up some 15 per cent, nearly a sixth, of the dry weight of the brain.

It is present elsewhere, too. The bile secreted by the liver contains 2# to 3 per cent of dissolved matter, and of this about 1/20 is cholesterol. The bile in the gallbladder is stored in concentrated form, and the cholesterol content there is correspondingly enriched. The cholesterol in the bile may not really seem like a large quantity (about 1/10 of a per cent all told) but it is enough to cause trouble at times. The quantity of cholesterol in the bile within the gallbladder is just about all that the liquid can hold, since cholesterol is not particularly soluble in body fluids. It is not uncommon to have crystals of cholesterol precipitate out of the bile. On occasion such crystals conglomerate to form sizable gallstones that may block the cystic duct through which bile ordinarily passes into the small intestine. It is this blockage that produces the severe abdominal pains with which sufferers from gallstones are all too familiar.

Of the dissolved material in blood, about 0.65 per cent is cholesterol. This, too, is sufficient to make trouble on occasion. There is a tendency for cholesterol to precipitate out of blood and onto the inner lining of arteries, narrowing the bore, and roughening the smoothness. This condition, atherosclerosis, is currently the prime killer of mankind in the United States. (Mankind, literally, since men are affected more often than women.)

Cholesterol, although only very slightly soluble in water, is freely soluble in fat and is therefore to be found in the fatty por-

THE HUMAN BRAIN

tions of foods. Animal fats are far richer in cholesterol than plant fats are. In addition, there is some evidence to the effect that the body can handle cholesterol more efficiently if the diet contains a sizable quantity of fat molecules marked by several double bonds between carbon atoms. These are called polyunsatwated fats and are of considerably more common occurrence in plant fats than in animal fats. For this reason, the last few years have seen a swing in American dietary habits away from animal fat and toward plant fat.

Nevertheless, increasing consciousness of the dangers of atherosclerosis must not cause us to think of cholesterol as merely a danger to life. It is, in fact, vital to life. It is a universal component of living tissue and no cell is entirely without it. It is rather frustrating, as a consequence, to be forced to confess that biochemists have only the haziest notion of what it actually does in living tissue.

OTHER STEROIDS

There are other steroids in the body, which may be formed out of cholesterol or which are, perhaps, formed simultaneously with cholesterol by similar chemical processes. The bile, for instance, contains steroids called bile acids in concentrations seven or eight times that of cholesterol itself. (The bile acids create no troubles, though, because unlike cholesterol they are fairly soluble and do not come out of solution to form stones.)

The molecules of the bile acids differ from that of cholesterol chiefly in that the eight-carbon chain attached to carbon-i7 (in cholesterol) is chopped off at the fifth carbon. That fifth carbon forms part of a carboxyl group (-COOH), and it is the acid property of this carboxyl group that gives the bile acids their name.

There are several varieties of bile acids. One has a single hy-droxyl group attached to carbon-3, as in the case of cholesterol. Another has a second hydroxyl group attached to carbon-iz, and

OUR ADRENAL CORTEX j-l

still another has a third hydroxyl group attached to carbon-/. Each of these bile acids can be combined at the carboxyl group to a molecule of the amino acid, glycine, or to a sulfur-containing compound called "taurine." These combinations make up the group of compounds called bile salts. The bile salts have an interesting property. Most of the molecule is soluble in fat. whereas the carboxyl group and its attached compound is soluble in water. The bile-salt molecule therefore tends to crowd into any interface that may exist between fat and water, with the fat-soluble portion sticking into the fat and the water-soluble portion sticking into the water.

Ordinarily the interface represents a greater concentration of energy than does the body of either liquid, so the amount of interface is kept to a minimum. If oil and water are both poured into a beaker, the interface is a flat plane between the two. If the mixture is shaken violently bubbles of oil are formed in water, and bubbles of water are formed in oil. The energy of shaking is converted into the energy of the additional interface formed; but when the shaking ceases, the bubbles break and the interface settles back into the minimum area of the flat plane.

The presence of bile salts in the interface, however, lowers its energy content. This means that the interface can be easily extended so that the churning of the food within the small intestine easily breaks up fatty material into bubbles and then smaller bubbles. (The smaller the bubbles, the larger the area of interface for a given weight of fat.) Furthermore, the bubbles that are formed have little tendency to break up again, as bile salt crowds into every new interface formed. The microscopic fat globules eventually formed are much easier to break up through the digestive action of enzymes than large masses of fat would be, because enzymes are not soluble in fat and can only exert their effects on the edges of the bubbles.

A rather drastic change of sterol structure often occurs when one is exposed to ultraviolet light. The bond between carbon-g and carbon-xo breaks and ring B opens up. The resulting struc-

THE HUMAN BRAIN

OUR ADRENAL CORTEX

ture is no longer, strictly speaking, a steroid, since the steroid nucleus is no longer intact. However, the molecule remains so clearly related to the steroids that it is usually discussed as though it were part of the group.

Many of these "broken steroid" molecules possess vitamin D activity; that is, they somehow encourage the normal deposition of bone. That deposition cannot take place in the absence of vitamin D. The broken steroid developed from cholesterol itself does not have vitamin D properties. Nevertheless, cholesterol is almost invariably accompanied everywhere in the body by small quantities of a very similar sterol that differs from cholesterol itself only in that it has a second double bond located between carbon-/ and carbon-8. This second compound, when broken by ultraviolet light does have vitamin D properties. There is cholesterol and its double-bonded partner in the fat layers in the skin. The ultraviolet of sunlight can reach it, forming the vitamin when it does so. For this reason vitamin D is called the "sunshine vitamin," and not because it, or any vitamin — or any material substance whatever for that matter — is in sunshine itself.

If vitamin D were formed by the body, particularly if it were secreted by some organ of the body, it would certainly be very tempting to consider it a hormone. It might even be considered a hormone that like the recently discovered calcitonin (see p. 61) opposed the action of the parathyroid hormone (depositing bone, whereas parathyroid hormone erodes it) as glucagon opposes the action of insulin. Since the body does not form vitamin D directly but must have it formed by the action of sunlight or, failing that, by absorbing such trace quantities as may be present in the food, it is called a vitamin.

A number of classes of steroids not formed in the human body are nevertheless found in the living tissue of other species. Almost invariably these have profound effects when administered to human beings even in small quantities. There are such steroids in the seeds and leaves of the purple foxglove. The drooping purple flowers look like thimbles, and the Latin name of the genus

is Digitalis (dih-jih-tal'is; "of the finger" L, which is what thimbles certainly are). The steroids in digitalis are something like the bile acids in structure except that the carboxyl group on the side-chain combines with another portion of the chain to form a fifth ring that is not part of the four-ring steroid nucleus. This five-ring steroid combines with certain sugarlike molecules to form glycosides (gly'koh-sidez; "sweet" G, in reference to the sugar). Such compounds are used in the treatment of specific heart disorders and are therefore called the cardiac glycosides (kahr'dee-ak; "heart" G).

The cardiac glycosides are helpful and even life-saving in the proper doses, but in improper doses can, of course, kill. Steroids similar to those in the cardiac glycosides are found in the secretions of the salivary glands of toads, and these are called toad poisons. Another group of steroids, found in certain plants are called saponins (sap'oh-ninz; "soap" L, because they form a soapy solution). They are poisonous, too.

But why do steroids have such profound physiological effects in small quantities? For one thing, many of them, like the bile salts, tend to crowd into interfaces. Many physiological effects are dependent on the behavior of substances at interfaces. By changing the nature of those interfaces, steroids succeed in changing the behavior of substances generally and of the physiological effects dependent on that behavior.

For living tissue the most important interface of all is that between the cell and the outside world. The boundary of a cell is its membrane, which is an extremely thin structure. It is so thin that only in the 1950*5, with the aid of the best electron microscopes available, could it really be studied. It appears to consist of a double layer of phosphorus-containing fatlike molecules (phospholipid), coated on each side with a single thickness of protein molecule. It is through this thin membrane that substances enter and leave the cell. Entry or exit may be by way of tiny pores existing in the membrane, or that are formed, but such entry or exit, whatever the mechanism, cannot be a purely passive

THE HUMAN BRAIN

thing. Some atoms and molecules can pass through more easily and rapidly than can other atoms and molecules of similar size. The fact that the cell membrane is made up of both phospho-lipid and protein may be significant here. The phospholipid is largely fat-soluble and the protein is largely water-soluble. It may be that the manner in which a particular substance can (or cannot) get through the cell membrane depends on the manner of its relative solubility in fat and in water.

In Chapter i, I mentioned the theory that hormones achieved their effects by altering the manner in which the cell membranes allowed the entry and exit of particular substances. One can imagine a peptide molecule layering itself over the cell membrane and substituting for the original pattern of side-chains a new pattern that might, for instance, encourage the entry of glucose at greater-than-normal rates, thus lowering the glucose-concentration in blood. (This, as you may remember, is the effect of insulin.}

Now it would seem reasonable that, if a protein molecule could accomplish this by altering the pattern of the protein portion of the membrane, a fat-soluble molecule such as a steroid might also do so by altering the pattern of the phospholipid portion of the membrane. It may be in this fashion that vitamin D encourages the growth of bones, by altering the membrane of bone cells to permit the entry of calcium ions at a greater-than-normal rate. It may also explain the workings of other steroids that not only have hormone functions, as vitamin D does^ but are elaborated by special glands and therefore carry the name of hormones, too.

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