Home
Up

The following article from The Medical Record is being presented as a service to the general public interested in the history of the solution to the cancer problem. John Beard (1857-1924) was Lecturer of Comparative Embryology at the Edinburgh University Medical School. As a result of first hand zoological and embryological research, Beard concluded that cancer was trophoblastic. Trophoblast is the first differentiated cell to arise after the zygote is formed by union of sperm and egg. This cell goes on to form the placenta and is the source cell for the entire placenta. None of the cells comprising the placenta are incorporated into the human body, but neatly surround the entire fetus like a baloon. Somehow the body destroys this tissue resulting in the birth of the individual. Beard believed that cancer was this trophoblast manifesting in the wrong time and place. Furthermore, he believed that normal trophoblast is eventually destroyed by the mother and fetus through their pancreatic secretions, that the totality of these enzymes constitute the cause of birth. Beard therefore made the logical inference that these enzymes, "ferments", would therefore act against cancer as well. Thus began what we believe to be the first rational therapy for cancer. Later experimentation proved he was on to something, as the following report he subitted to the Medical Record indicates. Today we can say with absolute certainty that he was right at least as far as the fundemental identity of cancers are concerned, as proven by laboratory and clinical research, for example, the work of Dr. Hernan Acevedo. The following paper represents only a single item of a series being prepared for the internet, all of which will also be included along with other material in the Collected Works of John Beard and Related Matter, being prepared for publication (in book and CD-ROM).

R.S.Cathey,
Orchard House,
Portland, Oregon
12 March, 1997

[Terms: amylopsin: amylase, diastase, a pancreatic enzyme acting on starches and glycogen; trypsin: a pancreatic enzyme acting on proteins]

TRYPSIN AND AMYLOPSIN IN CANCER.

TO THE EDITOR OF THE MEDICAL RECORD:

SIR:---The published report (MEDICAL RECORD, May 19, 1906, p.809) of a discussion before the Medical Society of the County of New York tempts the writer to offer the following remarks as a preliminary note, based upon the result of his scientific study of eclampsia. The medical profession in America can easily test the truth of the writer's contention, by using diastase in any case of pregnancy where there is the slightest threatening of eclampsia.

The "trypsin" treatment of cancer had not long been in use, when in January last some French and Italian physicians informed me of certain bad symptoms of vomiting, nausea, pain in the back, "sleeping in any position," mental and physical torpor, etc., following injections. In answer to their requests for scientific advice, I urged them to treat it as they would the vomiting of pregnancy, and for myself I began to study eclampsia. For the treatment is based upon the introduction of an artificial "critical period" (vide J. Beard, "Certain Problems of Vertebrate Embryology," 1896, and "The Span of Gestation," 1897, Jena, Gustav Fischer), and its course would naturally be the same as the events from the seventh week of a normal gestation. It was soon seen that no rational treatment of eclampsia existed. There was an extensive experimental study of it in the Archiv fur Gynakologie (Vol. 76, 1905, pp. 507 to 585) by Professor Zweifel, as well as a lecture by him in the Munchener medizinische Wochenschrift for February 13, 1906. His article bears the title "Zur Aufklarung der Eklampsie." It would take up much space to describe his results. Briefly, he sets it down to the formation of sarcolactic acid in the fetal blood and placenta. In my opinion his conclusions rest upon very thin ice, and there may well have been other substances. However that may be, I have gone behind it all, to the true source of the mischief.

As Professor Zweifel himself found, the diastatic ferment is absent in the fetal blood. The reason of this is not far to seek. In the days of long ago, and as now happens in most marsupials, birth took place at the critical period, and the milk-nutrition was initiated. In this the diastatic ferment is of no use.

When, as she did, Nature prolonged the gestation, in order to bring the young into the world in more perfect form, she deferred in so doing more and more the start of mammary nutrition. In prolonging the gestation she forgot to introduce diastase at an earlier period, and the "memory" remained that it was not needed until the milk-period had passed. Consequently there is an absence of the diastatic ferment during all fetal life. Usually the difficulties caused by this can be got over, if the maternal pancreas form sufficient diastase. But if there be any failure in this respect, the consequences may well be disastrous. In a way the difficulties may be said to have been usually overcome, but pregnancy, from the seventh week onward, owing to this absence of the diastatic ferment, is a sorry business. Probably in all cases the oral or hypodermic administration of diastase during the last months of pregnancy would be of great benefit to the mother. In certain forms of cancer, more especially uterine cases, it cannot with safety be dispensed with. When the patient becomes drowsy, it is called for. In some cases, not in all, symptoms of eclampsia, varying in degree, arise in the "trypsin" treatment of cancer. The comparison between this and the phenomena of gestation proves to the embryologist that it is and can only be the absence or the insufficiency of diastase which causes it. In a gestation without eclampsia there must be something being formed either by the mother or fetus which prevents its arising. If eclampsia ensue, the want of diastase alone can be at its basis. Therefore, in the treatment of cancer by pancreatic ferments injected into the blood it is most desirable that a pure trypsin alone without much diastase should not be employed, and if bad symptoms arise, these should be met by the giving of sterile hypodermic injections of 5 per cent. diastase solution up to 40 minims daily. The like treatment is called for in cases of eclampsia, or where it is threatened.

It is becoming more and more evident that, in the treatment of cancer by the pancreatic ferments, after some few weeks of the trypsin injections, say four, if not earlier, this injection should be replaced in the treatment, until the remains of the degenerating tumor be removed, by injections of the diastatic ferment, up to 40 minims daily. There is not a particle of doubt in my mind that such injections would also remove the symptoms of eclampsia in pregnancy. JOHN BEARD, M.D.

University Lecturer in Comparative Embryology.
EDINBURGH, SCOTLAND, June 4, 1906.

From:Science Vol. 104, No. 2700, 1946 p.302

Trophoblast Elements in Cancer In confirmation of the findings of Roffo (Bol. Inst. med. exp. Estud. Cancer, 1944, 21, 419-588) that, when injected into immature white rats, an extract of the blood or urine of cancer patients causes enlargement of the uterus and the formation of corpora lutea in the female animals, we have obtained from cancer patients of both sexes, by urinary extraction, preparations having pronounced estrogenic as well as gonadotropic properties. Nonmalignant, nonpregnant controls were negative. It is our conclusion on the basis of studies now in progress (Science, 1946, 103, 25), that the estrogenic factor (termed "steroid E" by Roffo) arising from the definitive malignant elements is identical with the steroids produced by the syncytial trophoblast of pregnancy (Jones, Gey, and Gey. Johns Hopk. Hosp. Bull., 1943, 72, 23-38). The only so-called false positives observed by Roffo were those in which pregnancy urine was used. Moreover, 20 days after implanting human trophoblast into the eye of a virgin doe, we found uterine and ovarian changes which duplicated those reported above for the immature rat recipients of cancer urine (J. clin. Endo-crinol., in press). It is well known that chorionepithelioma, genital as well as primary extragenital in both sexes; many ovarian and most testicular cancers; the chorionic (trophoblastic) or malignant phase of many teratomata; and even some cases of carcinoma simplex are responsible for the presence of chorionic (cytotrophoblastic) prolan in sufficient quantities in the blood or urine to produce a positive Aschheim-Zondek reaction. In these tumors the prolan titer tends to vary directly with the concentration of cytotrophoblast (Langhans cells), being almost beyond detection in the absence of overt trophoblast. Using rodents as indicators, it is impossible to distinguish accurately between anterior pituitary and chorionic prolans. In pregnancy and in the malignant tumors cited, the chorionic prolan is present in such excess of pituitary prolan that diagnosis becomes a matter of quantitation. In the past, attempts to recover chorionic prolan from the blood or urine of all cancer cases showing no *overt* trophoblast have been thwarted by cross- reactions with pituitary prolan. Employing the technics of chromatographic adsorption (Katzman, Godfrid, Kain, and Doisy. J. biol.Chem., 1943, 148, 501-507) and the use of the African clawed toad (*Xenopus laevis*) as a specific indicator of chorionic prolan, these obstacles are overcome. Employing a combination of such technics, we have obtained egg extrusion in *Xenopus laevis* through the injection of 1 cc. of the concentrate of as little as 800 cc. of urine from nongenital cancer in the human male. Controls of the same age were negative. Although sufficient determinations have not yet been made to warrant the conclusion that specific steroids and/or cytotrophoblastic prolans are present in all cases of cancer, our preliminary results would suggest this. In conclusion, it would appear significant that many of the most malignant exhibitions of cancer are known to yield a readily detectable quantity of gonadotropin, duplicated only by that produced by the trophoblast cell; that now tumors of lesser malignancy are found to yield this same gonadotropin; and, finally, that the only cell never observed in the benign state in the male or, aside from the canalization of pregnancy, in the female is the trophoblast cell. Parallel to this is the finding in cancer of a steroid duplicated only by the syncytial trophoblast. These data would seem further to substantiate the unitarian nature of all exhibitions of cancer and to suggest the trophoblast elements (however masked morphologically) as the

constant malignant component.

ERNST T. KREBS, JR.

*University of California Medical School, San Francisco*

CHARLES GURCHOT

*San Francisco, California*

The ROBERT CATHEY RESEARCH SOURCE.

All pages Copyright © 1996 R.S.Cathey, except where specified otherwise.

We are happy to present the following classic monograph by the Krebs and Beard, submitted to the Medical Record in 1949, and published in 1950. This is only one of an expanding series of essays and monographs by Dr.Krebs and associates on the science of cancer and its rationale treatment utilizing metabolic and dietary protocols: specifically, empowering the endogenous pancreatic enzymes, and/or supplementing same; and the dietary inclusion of nitrilosides, the specific antineoplastic compounds found ubiquitously in nature, but hardly at all in the common faire of civilization.

(Uploaded to RCRS July 21, 1996. Note:this Article is best viewed with Netscape 2.01, or versions permitting superscripts.)

MEDICAL RECORD

by Ernst T. Krebs, Jr.,* Ernst T. Krebs, Sr.,**
and Howard H. Beard***

It is veritably impossible to find, among the hundreds of valid experimental contributions to our knowledge of cancer made during the past half century, an experimentally established datum that would controvert the thesis of the basic biological uniformity characterizing all exhibitions of cancer.

To the experimentalist who does not overtly accept an unitarian thesis of cancer, such a thesis is still implicit in the commonplace facts of his science. The classic experiments of Warburg on the respiratory pattern of cancers of various species and tissue origins reveal a high uniformity from tumor to tumor.¹ Correlatively, the Coris find the lactic acid and sugar content of the various exhibitions of cancer to be highly uniform.² Williams and his co-workers report a pronounced degree of uniformity in the concentration of eight B vitamins in a great variety of animal and human tumors, regardless of the tissue of origin or the manner of their induction.³ Robertson makes similar observations for vitamin C.⁴ The addition of various substrates to malignant tumors of various types yields highly uniform respiratory responses.⁵ Shack describes an almost complete uniformity in cytochrome oxidase content in a number of mouse tumors. ⁶ Greenstein finds that the presence of any exhibition of cancer uniformly results in a depression of the liver catalase. ^7,8 Maver and Barrett describe substantial evidence for an immunological uniformity among malignant tumors.⁹ Greenstein reports an impressive degree of uniformity in enzyme concentration among malignant tissues, regardless of their means of induction, tissue of origin or species of origin. ¹⁰ Others describe a uniformly low content of such aerobic catealytic systems as cytochrome, succinic, and d-amino acid oxidases, cytochrome-c, catalase and flavin.^{11,12,13,14,15,16,17}

Further phenomena of uniformity are observed in the elevated water and cholesterol content of malignant tumors as well as other primitive tissues.^18,19 The induction by a single steroid carcinogen, such as methylcholanthrene, of malignant exhibitions as diverse as leukemia and malignant melanoma, attests to a basically uniform etiology. The uniformity of various exhibitions of cancer in respiratory properties, lactic acid production, vitamin content, enzyme content, action on a given substrate, effect on liver catalase, cytochrome oxidase content immunological properties, and many other characteristics is correlative to an uniformity of
------
^*We wish to acknowledge the helpful suggestions and criticisms on the trophoblastic thesis from Clifford L. Bartlett, M.D., Pasadena, California; John Bodman, M.D., London, England; and Arthur Harris, M.D., North Hollywood, California.

[Page 150..of Annual Collection]

malignant tumors in the ability to metastasize, in their amenability to heterotransplantability, ^{21, 22} and in their autonomy, invasiveness and erosiveness. Indeed, there is no known basic property unique to any single exhibition of cancer---the only variation being a morphological one partially conditioned by admixed benign or somatic components.

The degree in the uniformity of the factors described increases with the increasing malignancy with which the tumor is exhibited. Thus with an increasing degree of malignancy, all malignant exhibitions converge toward a common tissue type. For this reason the cells of the most malignant of all exhibitions of cancer should epitomize the properties of the malignant component in all other exhibitions of cancer. That this is the case, we shall observe in the pages that follow.

We have glanced briefly at data that are commonplace to cancer research. The logical consequences of these data have, however, seldom been examined. Since the phenomenon of cancer is truly an unitarian one, then, of logical necessity, the variations in the biological malignancy of different exhibitions of cancer must be a function of the concentration of a cell of an intrinsically uniform malignancy.

In accounting for the nature and origin of the single cell type comprising the constant malignant component in the varying morphological exhibitions of cancer, we find one of two alternatives open. The definitively malignant cell either has its normal counterpart in the life-cycle or the malignant cell is without a normal cellular counterpart and, therefore, arises as a spontaneous generation. Since spontaneous generation is an untenable postulate, the only alternative is that the malignant cell has its counterpart in the life-cycle. The question then arises whether this counterpart is a relatively developed cell or the most primitive cell in the life-cycle. Since the primitivity of the cancer cell is a commonplace, in looking for its cellular counterpart in the life-cycle we turn to the most primitive cell in this cycle. This is the trophoblast cell. Then as a logical corollary of the unitarian thesis, we should find the trophoblast as the constant malignant component in all exhibitions of cancer: the malignancy of the cancer varying directly with its concentration of trophoblast cells and inversely with its concentration of somatic cells.

If the unitarian thesis is valid, then the most malignant exhibition of cancer possible should be comprised almost completely of frank trophoblast cells; and, in being so comprised, should epitomize the cellular and other phenomena shared by exhibitions of a lesser malignancy. The most highly malignant exhibitions of cancer known are the chorionepitheliomas comprised of frank trophoblast cells, cytologically, endocrinologically and otherwise indistinguishable from normal pregnancy trophoblast cells. If cancer is an unitarian phenomenon whose malignancy is a function of the concentration of trophoblast cells within a given tissue, then the greater the concentration of such cells within a tissue the higher the malignancy of the tissue and the more profound its cytological deviation from the cytology normal to the tissue. If the unitarian thesis is valid, then the single exception to this generalization would comprise the most malignant of all exhibitions of cancer: that involving the pathologic exhibition of the normally or "physiologically" malignant pregnancy trophoblast. It is, therefore, most significant that when pregnancy trophoblast is malignantly exhibited as primary uterine chorionepithelioma there is no ascertainable cytological, endocrinological or other intrinsic change whatever from the normal trophoblast cell. As Boyd has phrased it, "microscopically the chorionepithelioma is an exaggeration of the condition normally found in pregnancy."²³ All other tumors represent an attenuation of the condition of their normal tissue of origin.

But if cancer is, as an unitarian phenomenon, trophoblastic then we should expect to find occasionally in the male---where trophoblast never normally exists---at least some cases in which the failure in somatic resistance to the definitive malignant cell (trophoblast cell) is so complete that the trophoblast is frankly exhibited as such in the fiercely malignant testicular or primary extra-genital chorionepitheliomas.^{24, 25, 26, 27, 28} The chorionepitheliomas are unquestionably the most malignant tumors in either sex, and the degree of their malignancy is routinely determined by measuring the gonadotrophin their trophoblast cells excrete.^{29, 30, 31}

If the trophoblast cell, presented outside the normal canalization or checks of pregnancy, is truly the cancer cell, then it must be impossible for the trophoblast cell or its hormone---"chorionic" gonadotrophin---ever to be found in the male or, aside from the canalization of normal pregnancy, in the female except in a malignant fashion. Neither the trophoblast cell nor its hormone has ever been so found except as cancer. And whenever the trophoblast cell or its hormone has been found in the male or the non-pregnant female, the associated malignancy is observed to vary directly with the urinary excretion of trophoblast cell-produced gonadotrophin.

Even a superficial examination of the trophoblast cell indicates that it possesses such properties of the cancer cell as invasiveness, erosiveness, autonomy and ability to metastasize throughout the organs of the host.^{32, 33} Indeed, though normally canalized to physiological ends, the pregnancy trophoblast in carrying the conceptus from anatomically outside of the maternal host to implantation within the uterine wall must behave in a profoundly malignant fashion. No malignant cell invades any tissue any more rapidly and completely than the pregnancy trophoblast does the human uterus in the first few weeks of gestation.

If the trophoblast cell, then, is instrinsically malignant, this malignancy should become especially apparent when the trophoblast is removed from the normal extrinsic checks and controls surrounding it in its normal canalization of pregnancy. Maximov is among those who have observed normal pregnancy trophoblast in tissue culture pari passu non-tropho-

blast.³⁴ He describes as follows a tissue culture preparation of a normal rabbit embryo plus the contiguous trophoblast:

Maximov's description of the nutritive utilization by the trophoblast of somatic or embryonic tissue in vitro bears a striking parallelism to the following observation of Greenstein³⁵ on the nutritive behavior of the cancer cell:

"It is, indeed, astonishing that a tumor can thus attach itself to an organism already running downhill in negative nitrogen balance and subsequently grow at the host's further expense."

Parasitization is eloquently clear in the description given by Maximov and it is implicit in Greenstein's observation. Normal pregnancy trophoblast represents, of course, a parasitization of cells of one genetic constitution by those of another. If cancer is an unitarian and thereby a trophoblastic phenomenon, its parasitic behavior is very easy to understand.

Were pregnancy trophoblast in vivo or in situ to lack the humorally mediated checking influences that are lacking in vitro then such tissue would expectedly behave as it does in vitro and be exhibited in the fiercely malignant fashion of primary uterine chorionepithelioma.

Rather than pause here to review in further detail the points of identity between the cancer cell and the trophoblast cell, of which the senior author in a review of over 17,000 papers has been able to catalogue 43, let it suffice to say that we have been unable to find a single point of dissimilarity between the cancer cell and the trophoblast cell. The points of identity, of course, are those shared exclusively by the cancer cell and the trophoblast cell and not shared by any somatic cell.

If cancer is a truly unitarian phenomenon, then its cellular origin as well as its cellular nature are exemplified in the origin and nature of the most malignant exhibition of cancer---primary uterine chorionepithelioma.

Pregnancy trophoblast arises through the differentiation by meiosis of a diploid totipotent cell in response to organizer stimuli (afforded through the sex steroids). The meiosis of the diploid totipotent cell results in a haploid gametogenous cell whose only alternative to death is division (sexually or parthenogenetically induced) with the consequent production of trophoblast. The only cell from which the most primitive cell in the life-cycle, the trophoblast cell, can arise is the most undifferentiated or most potent cell in the life cycle: the diploid totipotent cell. It is this cell alone that is competent for meiosis. In fact, aside from the explanation of spontaneous generation, only two alternatives exist for the origin of the malignant cell. Like all other growth phenomena, it may arise as the result of the differentiation of an undifferentiated cell in response to organizer stimuli; alternatively, it may be ascribed to the ontogenetic "reversion" of normal cells to a primitive state. Even though the very notion of such reversion is a thermodynamic fantasy inadmissible by modern biology, if a normal cell could revert, the most primitive cell in the life cycle toward which such reversion could occur is still the trophoblast cell. Hence, aside from the errors of spontaneous generation or cellular reversion, only the phenomena of cellular differentiation are tenable in accounting for the origin of the cancer cell---though the stimulus to such differentiation may, of course, be diversely mediated.

It is thus a simple embryological fact that the malignant component of the most malignant of all exhibitions of cancer---primary uterine chorionepithelioma---represents the unchecked growth of normal trophoblast that has arisen through the differentiation of a diploid totipotent cell, by reduction division, and the division of the consequent haploid gametogenous cell to produce trophoblast. We have seen the proof of this in the fiercely malignant behavior of rabbit trophoblast removed from the checking influences of the maternal host and placed in tissue culture. This trophoblast, of course, came into being through processes normal to the production of all trophoblast in normal gestation. This is true also of the trophoblast of primary uterine chorionepithelioma.

It is necessary that we emphasize here the fact that our description of the origin of any trophoblast cells is merely a recapitulation of commonplace, universally accepted embryological data. We must not permit terminology to obscure this fact. Let us add that it has been experimentally established that in mammals the haploid gametogenous cell in either the male or the female may be nonsexually activated into division with the consequent and inevitable production of trophoblast.

Because the trophoblast cell of primary testicular chorionepithelioma is indistinguishable from that of the normal pregnancy trophoblast cell^{36, 37, 38} or a trophoblast cell of primary uterine chorionepithelioma,^{39, 40} the general consensus in pathology that chorionepitheliomas arise from the division of a gametogenous cell (non-sexually activated), derived through the normal meiosis of a diploid totipotent cell, is biologically and logically sound. It is likewise generally recognized that primary extra-genital chorionepitheliomas occurring in both sexes represent trophoblast that shares a common cellular origin with all other trophoblast; an origin from an haploid gametogenous cell (through fertilization or non-sexually) that has arisen through the meiosis of a diploid totipotent cell. This principle is congruent with the axiom that cells which are alike arise from pre-existing cells that are alike.

If cancer is an unitarian phenomenon in which all morphological exhibitions share, in varying degrees, the known malignant component of the chorionepitheliomas, then it follows (1) that the malignancy of a growth will vary directly with its concentration of trophoblast cells and inversely with its concentration of body or somatic cells; and (2) the trophoblast cells comprising a malignant lesion must possess the capacity for being morphologically masked or obscured by the tissue in which they primarily occur or to which they metastasize. Testicular chorionepitheliomas afford an interesting vantage point for the examination of these possibilities. In screening over 900 testicular cancers in the Army Institute of Pathology, Friedman and Moore (1946) reported, in part, as follows:⁴¹

Thus, not only may the trophoblast, when frankly exhibited as such in the primary site, metastasize to be morphologically masked in the secondary site, but the primary trophoblast itself may be morphologically masked by the soma and be frankly exhibited only when metastases occur into tissues of relatively lower reactivity in which the trophoblast is not morphologically masked but is frankly exhibited as such. The masking of the trophoblast by the reactivity of the somatic cells is a measure of the resistance of the host: the degree to which such somatic resistance against the ectopic trophoblast fails determines the malignancy with which the trophoblast is exhibited. Thus, the greater the incidence of a chorionepitheliomatous exhibition (trophoblast) in the metastases, the greater the degree of malignancy.

The origin of every new cell is the result of the apposition of a competent cell and an organizer stimulus. All new cells arise as the result of cellular differentiation, which is a process by which a new cell type of a higher degree of individualization and a lower degree of developmental competence is produced. There are no exceptions to this generalization---not even the cancer cell. While a differentiated cell may become plastically deformed or necrobiotic, it can never form a new cell type through any means except the forward-moving course of cellular differentiation. Cellular reversion is a thermodynamic impossibility; it has never occurred and can never occur. Water does not run uphill---not even in cancer. The cancerous cell is neither a deformed one nor a necrobiotic one. Its lethality resides in the very fact that intrinsically it is a normal cell---though its spatial and temporal relationship to the organism-as-a-whole is an abnormal one. The trophoblastic or unitarian thesis simply recognizes that: (1) the cancer cell is contained within the life-cycle and (2) that it is the most primitive cell in that life-cycle.

Though the diploid totipotent cells which give origin to trophoblast are known to be very abundant in the gonads, the question next arises as to their occurrence extra-genitally. Most modern pathologists ^{42, 43, 44, 45, 46} recognize the existence of so-called ectopic germ cells (diploid totipotent cells) and Bounoure ⁴⁷ has, in an extensive monograph, recently reviewed the conclusive observational and experimental evidence for the dispersion of such cells throughout the soma. Of course, embryologically, these cells are nothing more than totally undifferentiated cells that have not, as Arey phrased it,⁴⁸ participated in body building but have reserved their total potency or competency since the initial cleavage of the zygote. Cells of various degrees of undifferentiation exist within the soma as a reservoir from which tissue repair and regeneration occur. But only the totally undifferentiated cells of the soma are competent for meiosis; these cells are the diploid totipotent cells. Of course, all cells in the soma are diploid, but only those that are totally undifferentiated are totally potent or totipotent---hence competent for meiosis. That such cells exist as well as function in the soma is further proved by the occasional occurrence of primary extra-genital chorionepithelioma in the male in such regions of low tissue reactivity as the pineal gland^49,50 and the anterior mediastinum.^{51, 52, 53, 54} The frankly exhibited trophoblast cells are correctly attributed to the only progenitor of trophoblast: a diploid totipotent cell that has undergone reduction division or meiosis to form a haploid gametogenous cell that has trophoblast formation as the only alternative to death.

Carcinogenesis is thus seen to be a phenomenon involving a spatially anomalous differentiation in response to organizer stimuli. (Primary uterine chorionepithelioma---as well as normal pregnancy trophoblast---while involving precisely the same differentiation in its origin does not, of course, involve it anomalously.) The differentiation involves the phenomenon of meiosis with the consequent production of trophoblast, which, presented ectopically, is inevitably exhibited as cancer---the malignancy of which depends upon the extent to which such ectopic trophoblast is resisted. Thus in the unitarian thesis we see the malignant component in all exhibitions of cancer deriving from precisely the same cell type from which the chorionepitheliomas arise. We see all producing the same cell type---trophoblast. We see this cell doing ectopically precisely what it does in its normal canalization: eroding, infiltrating, and metastasizing.

"One of the most important problems in cancer research," Greenstein⁵⁵ points out, "is concerned with the question of why primary tumors metastasize." If cancer is trophoblastic, the problem of metastases is resolved: the normal pregnancy trophoblast is the only cell in the life-cycle that regularly metastasizes, doing so throughout the maternal host in the early months of pregnancy.^{56, 57}

The stimuli to malignant differentiation are exemplified in the sex steroids which induce the meiosis of diploid totipotent cells in their normal canalization. In view of the relatively specific organizer action of steroids, it is significant that practically all of the carcinogens are either steroids or, like diethylstilbestrol, possess the physiological properties of steroids. Though carcinogenesis may be mediated by highly diverse means, the ultimate common pathway involves the apposition of competent cell and organizer stimuli. The competent cell is always a totally undifferentiated cell (diploid totipotent cell) and the organizer stimulus ultimately involved appears to be a steroidal compound.

Agents producing a chronic inflammation can also prove indirectly carcinogenic, since chronic inflammatory sites have a marked capacity for localizing or concentrating steroidal sex hormones as well as other substances.⁵⁸ Certain chemicals may also prove indirectly carcinogenic through impairing the somatic detoxification mechanism for steroids.^{59, 60} That under special and very limited circumstances viruses may also contribute to the common pathway by which malignant differentiation is accomplished in birds^* and rodents is recognized. Virchow, however, pointed out 90 years ago that no stimulus can elicit from a tissue potencies not inherent within the tissue. The general consensus is that the role of the cancer virus is evocatory, eliciting from the organism an inherent potency; rather than creative, conferring de novo the cancer cell upon the organism.

Since the meiosis of normally canalized diploid totipotent cells is accomplished in both sexes through the organizer action of steroidal sex hormones, a review of the formidable literature on the carcinogenic properties of estrogen correlated with the unitarian thesis would be most pertinent to a complete elucidation of the thesis. Space will not permit this, and it must suffice to say that the normal estrogens bear as crucially a basic relationship to the origin of malignant cells, under ordinary circumstances, as chorionepithelioma bears to their cellular identity.

Since the virus theory is subsumed under the unitarian thesis---as a specialized contributory means^** of eliciting the malignant differentiation---the chief remaining theory is the somatic mutation hypothesis. This hypothesis explains nothing and is, in fact little more than a circular definition: cancer is due to a change; a change is a mutation. This change occurs in the body or soma; therefore, cancer is due to a somatic mutation. On the other hand, the trophoblastic or unitarian thesis does embrace a very definite genetic "mutation." This "mutation" is expressed as meiosis
-------
^* The phylogenic homologue of the trophoblast (extra-embryonic blastoderm) in birds is known to exhibit, under certain conditions, malignant properties: e.g., anidian formation⁶¹.
**Joseph Needham⁶² has cogently remarked: "It is an instructive exercise to read through the writings on the virus theory of cancer, substituting the words 'active agent' or 'active extract' for virus wherever it occurs. The results are illuminating."

whereby, with the division of the consequent gametogenous cell, the ectopic trophoblast (cancer) cell presented to the soma is, through the necessity of meiosis, of a genetic composition unique from the soma; and, therefore, in the most literal genetic sense a neoplasm.

Even were one uncritically to accept the somatic mutation hypothesis⁶³ or the virus theory of cancer,⁶⁴ it would be necessary either to seek their resolution in the unitarian or trophoblastic thesis or to turn to a non-unitarian explanation. In which case it would be necessary, then, to postulate an indefinitely large variety of unknown cancer viruses or a similar variety of unknown somatic mutations to account for the origin of the cancer cell. But not even these would suffice since neither hypothesis could account for the fiercely malignant behavior of normal trophoblast in vitro---nor for the fact that this cell has never been found in a non-pregnant organism except as cancer.

We have observed that the extra-genital dispersion of diploid totipotent cells is a commonplace fact. We have specifically ascribed the origin of all morphological exhibitions of cancer to the meiosis of one or more such diploid totipotent cells with the consequent production of a gametogenous cell whose only alternative to death is division with the resulting production of trophoblast.

In the normal reproductive canalization the only way in which trophoblast can arise is through the meiosis of a diploid totipotent cell and the consequent division (non-sexually or by fertilization) of the resulting gametogenous cell to produce trophoblast. Therefore, one question alone remains here: can the same diploid totipotent cell in an extragenital site undergo meiosis to eventuate in trophoblast production?

As early as 1879 Arnold observed gametoid (meiotic) mitosis in malignant tissue. About twenty years later Farmer, Moore and Walker reported the occurrence of meiosis (heterotypic mitosis) at the border of malignant tumors.⁶⁵ In 1929 Evans and Swezy described in inflamed somatic tissue changes "strikingly similar to those of meiotic mitosis."⁶⁶ In 1936 Hearne observed meiotic changes in tissues cultured with methylcholanthrene⁶⁷ and Molendorff made similar observations in 1939 with estrone.⁶⁸

Diploid totipotent cells are dispersed throughout the soma. Meiosis occurs within the soma. Frank trophoblast cells occur within the soma---though inevitably in a malignant exhibition. They can arise only through the division of a gametogenous cell produced by the meiosis of a diploid totipotent cell. Frank trophoblast cells have never been found in the soma except as the most malignant exhibition of cancer---with the exception of pregnancy.

Indeed, the difficulty is no longer one of accounting for the origin of the definitive malignant cell through the phenomena discussed, but rather one of seeking any explanation of how the meiosis of ectopic diploid totipotent cells, exposed to adequate organizer stimuli, could invariably be averted so as to preclude their normal differentiation to trophoblast, whose ectopic exhibition has never been known except in a malignant fashion. Frankly exhibited, such trophoblast comprises the most malignant exhibition of cancer possible, though when morphologically masked by the somatic response of the hostal cells the malignancy of such trophoblast is moderated.

The body of experimentally established facts comprising modern oncology is formidable. It is not possible for any explicitly defined thesis to stand unless it is congruent with, or at least not contradictory to, such facts. Only the unitarian thesis finds such congruence. To the unitarian thesis in general and in particular to the preceding data outlined for it, it is especially instructive to apply Herbert Spencer's criterion of truth---the inconceivability of the opposite. The thesis opposite or alternative to the unitarian one is that each morphological exhibition of cancer represents a biologically distinctive phenomenon, each with a malignant component different from all others. This would mean literally hundreds of basically different types of cancer cells---each type being normally unrepresented in the life-cycle; therefore, each being spontaneously created. Not only would it become necessary to postulate the existence of hundreds of distinct species of cancer cells, but also a postulate of an almost infinite number of subspecies of each type of cancer cell would be required to account for the varying degrees of malignancy exhibited by a given malignant lesion in the course of its evolution. Since a single chemical carcinogen can evoke practically any malignant exhibition, then it would become necessary---according to any non-unitarian concept---to conclude that causes which are alike produce effects that are unlike. On the same basis, the occurrence of the frankly exhibited trophoblast cells of extra-genital chorionepithelioma in the male (identical with those of the primary uterine form) would necessitate the unbiological conclusion that cells which are alike arise from cells that are unlike. The logical negation of any non-unitarian hypothesis is further apparent in the experimentally defined uniformity of cancer cells in every one of over twenty factors studied to date. (p.1)

In contrast to the alternative non-unitarian hypothesis, the unitarian thesis holds that the malignant component in all exhibitions of cancer is the same; that this component is not spontaneously created but represents the most primitive cell in the life-cycle; that this cell arises not through "reversion" but through differentiation; that the varying morphological exhibitions are simply conditioned by the nature and resistance of the tissue in which the ectopic trophoblast finds itself; and that the malignancy of the exhibition is, roughly, expressed in the degree of deformation of the somatic tissue by the ectopic trophoblast---and that this is reflected in the morphology from which histological diagnoses derive.

The unitarian thesis and the trophoblastic thesis are of logical necessity synonymous: the most malignant exhibition of cancer (chorionepithelioma) comprises cells intrinsically identical with pregnancy trophoblast cells.^* Then, if cancer is an unitarian phenomenon, the malignant component of the varying morphological types must be trophoblastic; for, two quantities equal to a third are equal to each other.

Finally, were we to set aside all else evidential of the unitarian or trophoblastic nature of cancer, and scrutinize but a single datum, we should find that neither experimental fact nor scientific reasoning can offer any alternative to the trophoblastic nature of cancer in explanation. This one datum is the fact that many authors over the past half-century have described frank trophoblast (chorionepithelioma) metastasizing from a primary site to appear at the secondary site in an adenocarcinomatous or other exhibition.^{69, 70, 71} And the converse has frequently been seen.⁷² Moreover, frankly exhibited trophoblast (chorionepithelioma) often has been described as merging by imperceptible degrees into an adenocarcinomatous or sarcomatous exhibition. In their comprehensive monograph on chorionepithelioma, Park and Lees (1950) write:

John Beard, a lecturer in embryology at the University of Edinburgh, first published on the trophoblastic thesis of cancer in June, 1902.⁷⁴ By February, 1905 he reported, on embryological grounds, the antithesis of the pancreatic enzymes to the trophoblast cell;⁷⁵ and, a few years later he specifically pointed out that the cancer or trophoblast cell protected itself against pancreatic enzymes through the production of specific antitryptic substances.⁷⁶ The occurrence of tryptic inhibitors in cancer sera has, during the past forty years, been described by at least fifteen different workers,^77-92 though not within the context of the trophoblastic thesis.

In 1947 Krebs, Krebs and Gurchot first pointed out the specific antithesis of chymotrypsin to the malignant (or trophoblastic) cell.⁹³ In 1948 Clark, Cliffton and Newton further confirmed the specific and antitryptic antithesis of the cancer cell and offered evidence for the diagnostic and prognostic utilization of the phenomenon. In 1949 West and Hilliard, in the study of sera of over 3,000 cancer patients, reported the specific antithesis of the malignant cell to chymotrypsin by showing that 15 grams of crystalline chymotrypsin would be necessary--in a single dose--to neutralize all of the average excess of chymotrypsin inhibitor in the serum of the advanced cancer patient. The latter workers proposed the utilization of the specific antichymotryptic titer of the serum for prognostic but not necessarily diagnostic purpose.^{88, 91}
-------
^*The malignant exhibition of the trophoblast of the placenta is the expression of a lack of extrinsic growth restraints against the trophoblast; this fact was demonstrated in the tissue culture of normal rabbit trophoblast.

It is noteworthy that West and Hilliard, as well as others, have described a quantitative relationship between the concentration of cancer cells and the titer of specific chymotrypsin inhibitor. This titer was observed to fall after the surgical removal of the malignant tumor and to rise linearly with its recurrence. Thus the data on the antitryptic properties of cancer sera are not only proof of the antithesis between the cancer cell and the pancreatic enzymes, but are further evidential of the unitarian--and thereby trophoblastic--nature of cancer.

Since the malignant cell is not spontaneously created but has its normal counterpart in the most primitive cell of the life-cycle, each organism in the span of its own gestation destroys the cellular counterpart of cancer. This destruction is accomplished through the pancreatic enzymes, notably chymotrypsin and amylase.

When the mammalian organism totally fails in this, the pregnancy trophoblast overgrows as chorionepithelioma.⁹⁴ A partial failure is reflected as a toxemic pregnancy⁹⁵ and/or a hydatidiform mole accompanied by an abnormally high excretion of chorionic (trophoblastic) gonadotrophin. For this reason hydatidiform moles are most frequently associated with toxemic pregnancies, while the risk of sequent chorionepithelioma is 2,000 to 4,000 times greater after hydatidiform mole than after normal pregnancy.⁹⁶ The reason for "the much higher curability rate of choriocarcinoma preceded by hydatidiform mole," as reported by Park and Lees,⁹⁶ is that the precedent hydatidiform mole represented at least a partially successful antithesis on the part of the maternal host to the trophoblast.^*

The reason why primary uterine chorionepithelioma can within a few weeks arise and kill the patient is that this most malignant tumor simply represents a hyperplasia of normal trophoblast cells freed from their extrinsic restraint---just as the in vitro culture of the rabbit trophoblast freed from the maternal environment yields a fiercely malignant exhibition.

It is well established* (1) that pregnant diabetics exhibit a greatly increased incidence of the pregnancy toxemias; (2) that the severity of such toxemias varies directly with the overgrowth of cellular trophoblast as reflected in the abnormally elevated excretion of chorionic gonadotrophin; (3) that the phenomenon involves a non-insulin deficiency of the pancreas gland; (4) that the predisposition to pregnancy toxemias is noted as early as five years^97,99 prior to the clinical onset of diabetes; (5) that the administration of steroidal sex hormones in such pregnancy toxemias frequently ameliorates the condition; and (6) that this amelioration is reflected in a proportionate depression in the urinary excretion of chorionic gonadotrophin.

Since such steroidal sex hormones as estrogen depress the proliferation of the cellular trophoblast both in normal and toxemic pregnancies, as reflected in a depression in the urinary excretion of chorionic (cytotrophoblastic) gonadotrophin, it is significant that Kullander (1948) found in primary uterine chorionepithelioma that the administration of stilbestrol resulted in a clinical improvement that paralleled the decline in the urinary excretion of chorionic gonadotrophin.¹⁰⁰ Though Kullander did not cure his patients, so long as stilbestrol controlled the excretion of chorionic gonadotrophin, they improved.

It is a commonplace observation that the administration of estrogen or testosterone during pregnancy will often depress the production of chorionic gonadotrophin sufficiently to cause the Ascheim-Zondek test or its Friedman modification to become negative.

In listing the criteria of malignancy, Oberling and Woglom write: "...Above all is the impudent independence called autonomy."¹⁰¹ Certainly, no other property is more characteristic of the cancer cell than autonomy; yet in the most malignant exhibition of cancer possible we find the trophoblast cells showing the same susceptibility to the checking influence of sex steroids as is found for the normal pregnancy trophoblast.

If cancer is trophoblastic, and as such an unitarian phenomenon, it would seem that the steroidal sex hormones should suppress the growth not only of pregnancy trophoblast and chorionepithelioma but all other exhibitions of cancer as well. That this would be the case were sufficient localization of the steroidal sex hormones possible at all malignant sites is shown in the fact that these hormones do act to suppress the growth of mammary cancer, prostatic cancer, and their metastases involving the skeletal system. Morphologically, the difference between a primary mammary cancer and a prostatic one is much less pronounced than the difference between either and a primary chorionepithelioma.

The placenta, the prostate, and the mammary gland are notably capable of the selective localization of steroids; hence, trophoblast in any of these areas will show a like response to the injection of steroidal sex hormones. In the case of prostatic and mammary growths the use of the physiologically antagonistic steroid is rational, since such causes the somatic elements in the growth to atrophy. That the palliative effect is dependent upon the ability of the somatic elements in the tumor to localize the steroids is shown in the fact that the skeletal metastases from the prostate as well as from the mammary gland are responsive specifically to estrogen and testosterone, respectively. Yet this amenability is lost as, with increasing malignancy, the original somatic elements in the skeletal metastases are lost. That such a loss is not directly due to the increasing malignancy but indirectly to the loss of the specific somatic cells responsible for the localization of the steroids is indicated by the fact that in the placenta, while the localizing somatic elements remain, the growth of the vastly more malignant chorionepitheliomatous exhibition is checked.

Thus we find the unitarian principle of cancer implicit in the sex hormone therapy of cancer, as in all other useful forms of cancer therapy. Moreover, in the unitarian principle the use of steroidal sex hormones in cancer finds its first rationale.

Since a non-insulin pancreatic deficiency has been identified with the overgrowth of pregnancy trophoblast, which overgrowth has been shown amenable to steroidal sex hormones, two questions arise: (1) what is the nature of the deficient pancreatic factor, and (2) is the deficiency of this factor associated with the overgrowth of all trophoblast? About half a century ago John Beard^102-119 found a concomitance between the commencing function of the fetal pancreas, as indicated by the appearance of zymogen granules in the gland, and the precipitate degeneration of the trophoblast or its phylogenetic homologue. Broad comparative studies confirmed his thesis that, in the span of normal gestation, the pancreatic enzymes are responsible for checking the growth and ultimately destroying the gestational trophoblast or its homologue. In fact, Beard's studies were so carefully performed that he was able to state half a century ago that in the 56th day in the span of human gestation the cellular trophoblast undergoes a sudden degeneration. Some 30 years after this work, the trophoblast cell-produced chorionic gonadotrophin was discovered, and only recently has the quantitative technic for the estimation of chorionic gonadotrophin been sufficiently perfected to show that a composite¹⁰² excretion curve for chorionic gonadotrophin made through the span of human gestation coincides¹²⁰ precisely with the curve predicted half a century ago by John Beard.

If the urinary excretion of chorionic gonadotrophin persists at the original level after the 56th to 70th day in the span of human gestation, the process is inevitably exhibited as chorionepithelioma. In fact, if the abnormal elevation of chorionic gonadotrophin found in pancreatic dysfunction in pregnancy exceeds a certain level, again the process is exhibited as chorionepithelioma.

If the urinary excretion of chorionic gonadotrophin persists at the original level after the 56th to 70th day in the span of human gestation, the process is inevitably exhibited as chorionepithelioma. In fact, if the abnormal elevation of chorionic gonadotrophin found in pancreatic dysfunction in pregnancy exceeds a certain level, again the process is exhibited as chorionepithelioma.

In view of the antithesis of the pancreatic proteases to the trophoblast cell, it is clear why both pregnancy and cancer are associated with high titers of trypsin and chymotrypsin inhibitors: antithesis is a two-way street, so to speak.

If the pancreatic enzymes are antithetic to the cancer cell, if they resist the cancer cell as the cancer cell is known to resist them (through the specific antitryptic inhibitors) why does cancer of the pancreas gland occur? Why is it that cancer is not only primary in this gland but that this gland itself may be subject to secondary growths through metastases or direct invasion?

The pancreatic proteases exist in the pancreas in the form of their inactive zymogens. These are not converted into the corresponding active enzymes until they are acted upon by the kinases of the blood or, especially, by those of the small intestine. In view of this, one may ask why the small intestine, then, is not practically immune to cancer. Woglom answers this question well in his commentary in an abstract of a paper by Raab:^120,122,123

It is noteworthy that the small intestine is not only practically immune to primary tumors but also to metastases. A fulminating malignant growth may exist in the pyloric end of the stomach a few millimeters from the immune small intestine, but, as William Boyd points out, "The duodenum is never invaded, the tumor stopping short at the pylorus. Spread to neighboring organs usually involves the liver or the pancreas."¹²⁴ The incidence of malignancy is, of course, high immediately distal to the ileocecal valve.

The pancreatic enzymes not only normally occur in the active state in the blood stream, which possesses an optimum pH for their action but the clinical determination of serum amylase and trypsin are standard procedures, especially in pancreatic diseases.

The fact that pregnancy occurs in the presence of a normal concentration of pancreatic enzymes indicates that trophoblast can exist for a while under such conditions. It must be remembered, however, that such trophoblast is: (1) held in check until the 56th day of gestation and almost completely destroyed shortly thereafter (with the commencing function of the fetal pancreas) and (2) that implantation occurs after the trophoblast has had about a four-day period of growth anatomically exterior to the host.

The trophoblast carries with it its own anti-tryptic enzymes against the pancreatic proteases. As we have seen, carcinogenesis involves ectopically precisely the same basic mechanisms involved in the production of canalized trophoblast. The prolonged exposure of a tissue to carcinogens results in a prolonged depression in its respiratory mechanisms.¹²⁵ This may result in the appearance and persistence of ectopic trophoblast in the exposed tissue. The trophoblast or cancer cell is autonomous of the hostal respiratory system and is obligatively anaerobic, undergoing [an]aerobic glycolysis even in the presence of a free oxygen supply.¹²⁶ The trophoblastic thesis explains the long-known identity of trophoblast cell metabolism with that of the cancer cell: ^{127, 128, 129} an obligative anaerobic system is obviously a necessity in a primitive parasitic cell like the trophoblast (or cancer) cell.

When cancer is elicited experimentally from a normal laboratory animal, the lesion usually does not metastasize, but attains a large size and is almost completely somatic. Herein reside the scientific limitations of artificially induced or transplanted animal tumors in the scientific study of chemotherapeutic agents. Such tumors are practically benign in the biological sense. Because the pregnancy trophoblast regularly and normally metastasizes in the early phase of gestation, we must expect metastases ultimately in any "full blown" cancer.

While a low-grade malignant growth (primarily somatic tumefaction) can be induced ultimately by sufficient carcinogenic stimuli in the presence of normal pancreatic function, a highly malignant exhibition is invariably accompanied by at least a relative pancreatic insufficiency implicit in the

correspondingly high serum titer of antitryptic and antichymotryptic enzymes.

That the induction of the ectopic trophoblast is usually accomplished against great difficulty---regardless of pancreatic adequacy---is indicated in the fact that non-chorionepitheliomatous exhibitions in man usually have a latent period of years, while a chorionepithelioma in pregnancy may arise from the preexisting trophoblast and destroy the host within a few weeks.

The extent to which the soma resists malignant involution is reflected in the fact that only two cellular differentiations---meiosis of the diploid totipotent cell and subsequent division of the resultant gametogenous cell---divide the malignant cell from the benign one. This explains the all-or-none suddenness classic to the malignant change---and the absence of true transitional cells.

The malignant lesion is a composite tissue comprising (1) trophoblast plus (2) somatic elements. The malignancy of a lesion varies directly with its concentration of trophoblast and inversely with its concentration of somatic elements. The normal placenta, too, represents a composite tissue; for, here the trophoblast cell finds its normal canalization in the life-cycle. Just as the malignancy of a placenta, in a chorionepitheliomatous exhibition, varies directly with the concentration of trophoblast cells, so in the ectopic presentation of trophoblast that comprises cancer the malignancy of the lesion varies with its concentration of trophoblast. The only fundamental difference is that in the latter the trophoblast cells are morphologically masked by the resisting soma---except in the most malignant of extra-genital tumors: chorionepithelioma.

A tissue can be malignant only by being a composite one. Malignancy is an antithetic relationship between cells and finds being by virtue of a thetic benignancy. In its simplest terms, then, a malignant tumor comprises somatic tumefaction plus a malignant component. It is for this reason that the greatest tumefaction is usually associated with the least malignant exhibitions and the least tumefaction often with the most malignant exhibitions. Since trophoblast normally metastasizes, tumors of the highest malignancy and lowest tumefaction tend to be the most metastatic. Thus the increase or decrease in the malignancy of a given tumor is not the result of a continuing spontaneous generation of an infinite variety of cancer cells, but merely the expression of the increase or decrease in the concentration of A CONSTANT MALIGNANT COMPONENT. As the antithesis of this component determines the malignancy of the lesion so that the soma determines its benignancy.

In the leukemias the constant malignant component (trophoblast) is present in the lymphopoietic or myelopoietic tissues. The reaction of such tissues to the malignant component results in the proliferation of somatic white blood cells of varying degrees of maturity. This is the counterpart of tumefaction in the sessile tumor. Thus the unitarian or trophoblastic thesis, different from the non-unitarian concept, finds no contradiction in the fact that often the most malignant phase of the leukemic process---the so-called aleukemic leukemia---actually involves a leukopenia. This phase is the most malignant because the somatic cells (leukopoietic tissue) have lost their ability to resist through virtue of the destruction of the leukopoietic tissue by ectopic trophoblast. For this reason the aleukemic or leukopenic stage is often terminal to a preceding highly leukemic or leukocytic phase.

The routine utilization of the trophoblastic hormone, chorionic gonadotrophin, is, of course, a clinical commonplace as a means of diagnosis as an index to therapeutic response in the case of the most malignant exhibitions of cancer---the chorionepitheliomas and certain other exhibitions of cancer. The excretion of this hormone varies directly with the malignancy of the tumor which, in turn, varies directly with the concentration of trophoblast cells.

In 1944 Roffo¹³¹ reported a similar gonadotrophin in all of 1,000 cancer patients examined, and none in the blood or urine of the control series---with the exception of pregnancy, of course. In 1946 Krebs and Gurchot¹³² reported the identification of Roffo's gonadotrophin as trophoblastic. In 1947 Beard, Halperin and Liebert published a confirmation of the prior papers and suggested a practical utilization of the phenomenon.¹³³ Prior to these studies numerous scattered reports of chorionic gonadotrophin in cancer serum and urine appeared in the literature but without the context of any unified theory. Zondek reported the hormone in the urine of 82 per cent of females afflicted with cancers of the genital organs and in 36 per cent of female patients suffering from extra-genital tumors.^134,135 Five years later Zondek was able to duplicate and extend his original findings,¹³⁶ which had been confirmed by others.^{137, 138, 139}

It is necessary to emphasize that the original work of Zondek as well as other workers was done on the erroneous assumption that the hormone was produced by the anterior pituitary gland. Even after tissue culture studies had proved the trophoblast-cell-origin of the hormone, its occasional identification in cancer urines, through the use of the Ascheim-Zondek or Friedman tests, was usually dismissed as an inexplicable datum of an inexplicable disease. Only within the context of the unitarian or trophoblastic thesis was sufficient theoretical justification found to concentrate and selectively extract the urines of the less malignant exhibitions of cancer specifically for the same hormones (chorionic gonadotrophin and syncytial steroids) always found by ordinary technics in the most malignant exhibitions.

Thus to the already established uniformities for 20 or more known factors among the various exhibitions of cancer, we now find an hormone (not only evidential of the unitarian thesis but of the specific trophoblastic nature of cancer as well) in the trophoblast cell-produced hormones. Like all other uniformities found in the malignant lesion, that for the trophoblastic hormones becomes increasingly apparent with the malignancy of the growth, so that frank chorionepitheliomas are found excreting as many as one million International Units of chorionic gonadotrophin every 24 hours, while the much less malignant exhibitions with no frank trophoblast cells excrete 50 or fewer units of the trophoblastic hormone.

There are only two fundamental kinds of cancer tests: (1) the indirect tests concerned with the detection of a substance produced by the soma as the result of the presence of cancer cells; and (2) the direct tests concerned with the detection of a substance produced by the cancer cells themselves. Though the incidence of a specific somatic change may bear a high correlation with the presence of an uniform stimulus, the correlation can never be a truly specific one, since obviously no somatic reaction is so specifically reserved for the presence of cancer or trophoblast cells that it can not be falsely elicited by other stimuli.

The limitations of the indirect tests have been well demonstrated in practice. The only reliable and generally accepted serum or urine tests for cancer are the direct ones, such as the Ascheim-Zondek test and its numerous modifications. Just as hundreds of indirect tests have been tried and discarded for pregnancy diagnosis, so have hundreds of indirect tests for cancer been tried and then discarded. The only tests for either pregnancy or cancer that have survived are those direct tests depending upon the identification of a substance unique to cancer and pregnancy: the hormone of the trophoblast cell. Since cancer is trophoblastic, its most malignant exhibition---chorionepithelioma---is highly amenable to the direct test. In fact, the possibility of either an indirect or direct general diagnostic test for cancer depends upon cancer being an unitarian phenomenon.

The efficient clinical implementation of the trophoblastic or unitarian thesis depends upon the development of a simple, reliable and highly accurate quantitative test for the specific products of the trophoblast cell.

While we have identified the presence of chorionic gonadotrophin in the urines of patients with all exhibitions of cancer, we have found the technological evolution of a quantitatively precise chorionic gonadotrophin test difficult for the less malignant exhibitions of cancer. When we consider that a chorionepitheliomatous exhibition of cancer in the male may yield over 1,000,000 I.U. of chorionic gonadotrophin while metastatic testicular cancers of a much lower malignancy---though biologically still more malignant than most extra-genital growths---may yield fewer than 50 I.U. for a like volume of urine, then the physical difficulties in the case of most of the extragenital tumors of still lower malignancy is obvious.

From the urines of patients with the common exhibitions of cancer, the authors have obtained highly active preparations of chorionic gonadotrophin, and are now engaged in the crystallization of chorionic gonadotrophin, by the method of Claeson, Hogberg and Westman (1948),¹⁴⁰ from pooled urines of various exhibitions of cancer. It is recognized that the specific steroidal hormones of the syncytial trophoblast also comprise a most important avenue to the development of a satisfactory diagnostic technic. However, these steroidal hormones have not been studied as intensely as chorionic gonadotrophin which is now characterized as a glucoprotein containing 18 per cent acetylglucosaminedigalactose polysaccharide.

Several cancer tests relying on the detection of trophoblastic hormones are now under study for the purpose of achieving a sufficiently practical quantitative test for general use.

As a composite tissue, cancer in its somatic component represents many diseases; in its constant malignant component, one disease; and, in its totality, a local manifestation of a general disease. Since the perspective of the clinician is necessarily anthropomorphic, he sees cancer primarily in its somatic phase as a series of many diseases. On the other hand, as Oberling and Woglom have so aptly phrased it, "To the experimentalist cancer is one disease and one disease only."

Both clinician and experimentalist are generally agreed that the somatic or anatomical changes produced by the malignant process are largely irreversible. Surgical extirpation or the primarily non-selective cautery of radiant energy may destroy the composite tissue of a primary tumor. But the vague hope for an agent that will cause the "reversion" of an organized malignant tumor to normal tissue is scientifically indefensible. Aside from the physical destruction of the tumor itself, one primary factor can contribute to the amelioration of the effect of the tumor on the host. This is the growth inhibition or destruction of the constant malignant component of the tumor. Selective ablation of the malignant component will not alter the already existing somatic dysplasia nor histologically change the architectonics of the tumor, except in highly malignant anaplastic exhibitions. Here the histological as well as the gross changes take an expected course: an histological increase in connective tissue elements with a palpable increase in fibrosity.

In the advanced and well organized lesion, the possible changes are not, as a rule, dramatic. Were the malignant component ablated, the somatic component would tend to persist largely unchanged, or even show a slight increase in benign tumefaction. Since none of the cells in a malignant tumor is per se a "diseased" or pathological cell, but rather a cell normal to the life-cycle, cancer does not itself produce any "toxic effects." Its lethality is eminently a physical matter involving the normal behavior of normal trophoblast in a spatially abnormal relationship. Above all, cancer is a natural phenomenon ultimately involving the soma in irreversible changes. To question the results expected from the selective ablation of the constant malignant component in a malignant lesion would be to suggest that, aside from actual tumor destruction, no malignant tumor has ever spontaneously regressed, that no highly anaplastic cancer has even spontaneously gone into a less malignant scirrhous exhibition, or that no patient has ever survived for five years or more after exhibiting an inoperable and highly malignant lesion. It is not necessary to review here an impressive literature on spontaneous regression. Much more important to a sound comprehension of the clinical implications of the trophoblastic or unitarian thesis are the thousands of cases of cancer in which the host is able to resist and to live with the cancer cells for years.

What are the factors---cells, tissues, organs, and their secretions---contributing to such resistance? What causes trophoblast in the pregnant diabetic to overgrow, despite a normal insulin supplement? Why do the specific inhibitors to pancreatic chymotrypsin and trypsin rise with the increasing malignancy of a growth and decline following its amelioration? Why is the small intestine practically immune not only to primary tumors, but to direct invasion and metastases as well? Why does the growth of the invasive, erosive and metastatic trophoblast of normal gestation cease and degeneration commence concomitant with the commencing function of the fetal pancreas gland? Why does the urinary excretion of chorionic gonadotrophin fall concomitantly with the degeneration of the trophoblast? After more than 99 per cent of the trophoblast has been removed from the placenta, why does its size remain unaffected though its invasive and erosive properties are entirely lost? Why are pregnancy trophoblast cells often indistinguishable histologically from the somatic cells in the uterine wall of the pregnant host? Why is it that the removal of normal pregnancy trophoblast to tissue culture will result in a fiercely malignant exhibition of such trophoblast toward all nontrophoblast cells?^*

Any attempt to implement clinically the trophoblastic or unitarian thesis should be made in the light of the answers to these questions.

Were malignant cells actually selectively susceptible to radiation, the most malignant exhibitions of cancer would be the most amenable to therapy, since they would, then, contain the highest concentration of radio-sensitive cells. Chorionepithelioma and malignant melanoma represent two of the most malignant exhibitions of cancer, yet they are radio-resistant. Glioblastoma multiforme and neurogenic sarcoma are also examples of highly malignant exhibitions of cancer that are radio-resistant.

We may generalize that the malignant component of a tumor is slightly less radio-resistant than the somatic connective tissue stroma but considerably more radio-resistant than the somatic parenchyma. This is why radiation often results in an increase in tumor fibrosity, which would be an excellent sign were this achieved at the cost of the radio-resistant malignant component (trophoblast) rather than at the cost of the somatic parenchyma. The so-called radio-sensitivity of a tumor is determined primarily by the radio-sensitivity of the somatic cells in which the constant malignant component happens to reside---not by the uniformly radio-resistant constant malignant component: the ectopic trophoblast.

The most commonly used radio-active element is that of iodine in the therapy of cancer of the thyroid. Rhoads^{141, 142} describes the limitations of this therapy as follows:

With an increase in the malignancy of the exhibition, there is necessarily an increase in the concentration of the definitively malignant cells (trophoblast) and a consequent decrease in somatic thyroid cells which are the only cells involved in the selective uptake of radio-active iodine. The decrease in tumefaction as a result of the uptake of radio-active iodine is an expression of the loss of functional somatic cells. This fact is further demonstrated in the successful use of this technic in toxic goiter.

The lower the concentration of trophoblast cells in a malignant lesion, the more amenable the lesion is to successful surgery. For this reason highly malignant growths like chorionepithelioma are generally inoperable.

The palliative use of the crystalline pancreatic enzymes in advanced human cancer rests entirely upon the validity of the unitarian or trophoblastic thesis of cancer.

Our own studies, too, appear to confirm the unitarian or trophoblastic thesis of cancer. The independently proved uniformities---which increase in degree of uniformity with the malignancy of the growth---of malignant lesions in the concentration of eight water-soluble vitamins; in vitamin C content; in water content; in cytochrome-c; in effect on liver catalase of the host; in Warburg's criteria of glycolysis; in lactic acid formation; in sugar content; in the respiratory response to added substrates; in a common means of induction; in antichymotryptic factors; in autonomy, invasiveness and erosiveness; in ability to metastasize; in amenability to universal therapeutic measures; in the general anticarcinogenic effect of

caloric restriction on the incidence of mammary tumors and leukemia alike in experimental animals; in heterotransplantability; in loss of specialized function as malignancy increases (in all tumors except chorionepithelioma); in departure from the histology of the site of origin (except in primary uterine chorionepitheliomas);^*; in numerous enzymes---all these uniformities, indeed, exclude any but an unitarian nature of cancer. Then as we examine the most malignant exhibition of cancer possible---chorionepithelioma---to find it comprised of trophoblast cells indistinguishable cytologically, endocrinologically or otherwise from those of normal pregnancy trophoblast, the fact becomes impelling that if cancer is, indeed, an unitarian phenomenon all of its properties must be exemplified in these most primitive of all cells in the life-cycle, the trophoblast cells. These cells in their normal canalization of pregnancy (as well as in vitro) exhibit every known property of malignant cells---though normally directed in pregnancy toward the physiological exploitation of the truly malignant process implicit in the embedding of the tissue of the conceptus into that of the mother.

Then, were all else evidential of the unitarian or trophoblastic nature of cancer set aside, and were there left for scrutiny but the single fact that primary exhibitions of trophoblast (chorionepithelioma) are not infrequently seen that metastasize to an adenocarcinomatous or sarcomatous exhibition, and vice versa, then reason would admit of only one explanation: the trophoblastic or unitarian fact of cancer.

Were the cellular counterpart of cancer not an inextricable component of the life-cycle, represented in the most primitive cell of that cycle, the processes of natural selection themselves would have precluded the survival of the spontaneously generated cells that any alternative to the trophoblastic fact of cancer necessitates.

The unitarian thesis is not a dogma inflexibly held by its proponents; it is merely the only explanation that finds total congruence with all established facts on cancer. While the unitarian or trophoblastic thesis seemingly admits of no alternative, it warrants the most corrosive scrutiny. For cancer either is or is not an unitarian phenomenon, and thereby it is either trophoblastic or not trophoblastic in nature. The definitive cancer cell is either the most primitive cell in the life-cycle or it is not the most primitive. It is either the result of the differentiation or meiosis (however spatially or temporally anomalous) of a cell or it is not the result of cellular differentiation. It either has its normal cellular counterpart in
-------
^* These are, indeed, instances in which the exception proves the rule; for, were cancer not trophoblastic, its most malignant exhibition---chorionepithelioma---would then show the greatest loss of function and the greatest deviation from the histology of the site of origin, instead of actually showing an accentuation in the normal function of trophoblast, as it does. Yet were one to attempt to ascribe to the malignant exhibition of trophoblast some intrinsic but subtle change from that of the non-malignantly exhibited trophoblast, such an attempt would be rendered nugatory by the fact that the most malignant exhibition of cancer possible in the male----chorionepithelioma---comprises trophoblast cells indistinguishable from those of pregnancy or chorionepithelioma in the female; yet, in the male chorionepithelioma represents the widest possible deviation in histology and function from the site of origin. The latter fact corroborates the proof of a rule previously proved by its exception.

the life-cycle, and thus is the result of cellular differentiation; or it has no cellular counterpart in the life-cycle, does not arise through cellular differentiation, and, therefore, is spontaneously created. The diploid totipotent cells within the soma, like their normally canalized daughter cells, can either undergo meiosis and subsequent trophoblast production, in response to sufficient organizer stimuli, or they can not. The occurrence of frank trophoblast cells within the soma (invariably as the most malignant exhibition of cancer) is either the result of the meiosis of a diploid totipotent cell or it is not; and, therefore, is the result of a spontaneous generation. The trophoblast or the cancer cell either produces specific inhibitors to pancreatic chymotrypsin and trypsin, or it does not (and the twenty or so independent workers how have so reported are all in error). A malignant tumor is either a composite tissue or it is not a composite tissue. The malignancy of a tumor is either determined by the concentration of a constant malignant component; or it is not so determined and depends, therefore, upon the successive spontaneous generation of a series of specific cells to account for the increasing malignant evolution of the tumor.

The trophoblastic or unitarian thesis holds the affirmative of all these propositions. It holds that any alternative to them will result in a reductio ad absurdum. The unitarian thesis recognizes the need for an orderly defined common ground of theory upon which all workers in cancer may at least meet, if not agree. It holds as reasonable the thesis that the more tenable of two distinctly opposed hypotheses should be given the greater credence in determining the direction of future research. It holds that in the intensive study of the peculiar metabolism of trophoblast both in pure cultures and in vivo, with the goal of the selective lysis of the trophoblast cell or the occlusion of its metabolism, the cancer problem may find practical resolution. It holds that the cancer problem need not offer amnesty to unbridled empiricism and negation to the most basic tenets of the rational process.

Above all else, the trophoblastic or unitarian thesis urges that the alternative non-trophoblastic or non-unitarian thesis, which is at present overwhelmingly the dominant hypothesis, be scrutinized in the light of whatever experimental evidence might exist in its support.^* Indeed, the evaluation of any alternative to the trophoblastic or unitarian thesis---within the context of experimental facts and scientific logic---by those who find the trophoblastic or unitarian thesis untenable or tenuous^{143, 144} should prove most instructive. For in cancer, as in all else, facts do not speak for themselves but must be spoken for.
-------
^*In reviewing over 17,000 papers on cancer and related biological subjects the senior author, in the course of his text on "The Biological Basis of Cancer," has not found a single valid contribution that fails to find congruence with, and illumination from the trophoblastic or unitarian thesis of cancer.

Ernst T. Krebs, Jr.
Reprinted from the Journal of Applied Nutrition, Volume 22, Numbers 3 and 4, 1970

Vitamin B-17 (nitriloside) is a designation proposed to include a large group of water-soluble, essentially non-toxic, sugary, compounds found in over 800 plants, many of which are edible. These factors are collectively known as Beta-cyanophoric glycosides. They comprise molecules made of sugar, hydrogen cyanide, a benzene ring or an acetone. Though the intact molecule is for all practical purposes completely non-toxic, it may be hydrolyzed by Beta-glycosidase to a sugar, free hydrogen cyanide, benzaldehyde or acetone.

We have proposed the collective generic term n-i-t-r-i-l-o-s-i-d-e for all such cyanophoric glycosides of dietary significance.

One of the most common nitrilosides is amygdalin. This nitriloside occurs in the kernels of seeds of practically all fruits. The seeds of apples, apricots, cherries, peaches, plums, nectarines, and the like carry this factor; often in the extraordinary concentration of 2 to 3 per cent. Since the seeds of fruits are possibly edible, it may be proper to designate the non-toxic water soluble accessory food factor or nitriloside that they contain as vitamin B-17. The presence of nitriloside in the diet produces specific physiologic effects and leaves as metabolites specific chemical compounds of a physiologically active nature. The production by a non-toxic, water-soluble accessory food factor of specific physiological effects as well as identifiable metabolites suggests the vitamin nature of the compound.

The ubiquity of the compound or its metabolites in plant and animal foods further corroborates its vitamin status. And the development of specific deficiency states as a result of its deficiency in or absence from the diet, and the correction of such pathologic deficiency states by supplying the factor confirm its vitamin status.

The diet of primitive man and most fruit-eating animals was very rich in nitrilosides. They regularly ate the seeds (and kernels) of all fruits, since these seeds are rich in protein, polyunsaturated fats, and other nutrients. Seeds also contain as much as 2 per cent or more nitriloside. There are scores of other major foods naturally, or normally, very rich in nitriloside. Let's consider now what happens when one eats the nitriloside-rich seeds of fruit.

In metabolism, nitriloside is hydrolyzed to free hydrogen cyanide, benzaldehyde or acetone and sugar. This occurs largely through the enzyme Beta-glucosidase produced by intestinal bacteria as well as by the body. The released HCN [hydrocyanide] is detoxified by the enzyme rhodanese to the relatively non-toxic thiocyanate molecule. The sugar is normally metabolized. The released benzaldehyde in the presence of oxygen is immediately oxidized to benzoic acid which is non-toxic. Thus this newly designated vitamin B-17 (nitriloside) could account for:

The thiocyanates in the body fluids--blood, urine, saliva, sweat, and tears;

For part of the benzoic acid (and subsequently hippuric acid); salicylic acid isomers;

For the HCN that goes to the production of cyanocobalamin from hydrocobalamin, or production of vitamin B₁₂ from provitamin B₁₂.

These are the physiological properties of the common nitriloside amygdalin. Before considering the possible antineoplastic activity of this vitamin B-17, let us recall that the benzoic acid arising from it has certain antirheumatic and antiseptic properties. It was rather widely used (in Germany and elsewhere) for rheumatic disease therapy prior to the advent of the ortho-hydroxy addition product of benzoic acid known as ortho-hydroxybenzoic acid or salicylic acid. It was originally obtained from beech-wood bark. As a matter of interest, the para- hydroxy isomer of benzoic acid occurs in the para hydroxybenzaldehyde aglycon (non-sugar) of the nitriloside found in the cereal millet. Millet was once more widely used in human nutrition than wheat. Wheat seed contains little or no nitriloside.

Recall now, that thiocyanate also was once widely used, in both Germany and American medicine, as an effective agent for hypertension. Used as such, as the simple chemical, the dosage was difficult to control. Obviously, this difficulty does not arise from the thiocyanate usually produced in the body through metabolizing vitamin B-17 (nitriloside). However, chronic hypotension has been reported in Nigerians who eat quantities of the nitriloside-containing manioc (cassava)--especially that of the bitter variety.

Let us pause to reflect upon this question: Might not the rheumatic diseases as well as certain aspects of hypertension be in some cases partially related to a dietary deficiency in nitrilosides? One can hardly deny that the ingestion of a sufficient quantity of nitriloside-containing foods will metabolically yield sufficient benzoic acid and/or salicylic acid isomers to palliate rheumatic disease and certainly to decrease, however temporarily, hypertension as well as to foster the nitrilosation of provitamin B-12 to active vitamin B-12: cyanocobalamin.

Despite all this, are we justified in suggesting that cancer itself might be another chronic metabolic disease that arises from a specific vitamin deficiency--a deficiency specifically in vitamin B-17 (nitriloside)?

Again, let us reflect for a moment. There are many chronic or metabolic diseases that challenge medicine. Many of these diseases have already been conquered. What proved to be their solution? By solution we mean both prevention and cure. What really cures really prevents. Let us think of some of these diseases that have found total prevention and hence cure. We are speaking of metabolic or non-transmissible diseases. At one time the metabolic disease known as scurvy killed hundreds of thousands of people, sometimes entire populations. This disease found total prevention and cure in the ascorbic acid or vitamin C component of fruits and vegetables. Similarly, the once fatal diseases so aptly called pernicious anemia, pellagra, beri beri, countless neuropathies, and the like, found complete cure and prevention in specific dietary factors, that is, essential nutrients in an adequate diet.

I can hear an objection of course. But let me remind you that all the solved or conquered chronic or metabolic diseases were found to be simple specific dietary diseases. Remember this: before these diseases were understood, before the means of total prevention and cure were discovered, it was widely believed that these dietary deficiency diseases were due to viruses, bacteria, bad air, "infection," or some such cause.

Now I ask you to name a single chronic or metabolic disease that has ever found total prevention and cure except by specific dietary factors and/or factors normal to adequate animal economy. I have never found anyone who has been able to suggest a single chronic or metabolic disease that has ever been totally prevented and cured except through a factor essential to adequate diet and/or to the animal economy.

Let's go a step further, almost to the border of dogmatism, to advance an axiom in medicine and biology:

No chronic or metabolic disease has ever found cure or prevention, that is, real cure and real prevention--except through factors essential to an adequate diet and/or normal to animal economy.

I would welcome a contradiction to this principle; but even an exception would "prove the rule."

Does it seem likely, therefore, that cancer will be the first exception to this generalization that to date has not had a single known exception? In my humble opinion, certainly not. But does it follow from this that vitamin B-17 (nitriloside) is the specific antineoplastic vitamin? Logically, by itself, alone, this conclusion that nitriloside is the specific antineoplastic vitamin does not follow. However, examine the brilliant laboratory studies of Dr. Dean Burk of the Department of Cytochemistry of the National Cancer Institute in Washington. I believe that in light of the experimental evidence that he has produced, you might agree that vitamin B-17 (nitriloside) is indeed the antineoplastic vitamin.*

One might ask, then, whether we suggest that vitamin B-17 (nitriloside) or Laetrile is an effective cancer drug. Our reply must be: it is not a drug; it is a

*Author's footnote: Dr. Dean Burk's paper was in the same program, also a report on the pharmacodynamics and clinical application of vitamin B-17 nitriloside (amygdalin) by Dr. Hans Nieper, a brilliant young man who combines an excellent ability in biochemistry with a genius in clinical medicine, in my opinion.

Page 78

vitamin. We feel certain that it will never be possible to speak of a true or effective "cancer drug," any more that it is possible to speak of a pellagra drug, a scurvy drug, a pernicious anemia drug, or the like. The U.S. Food & Drug Administration has just announced that the major drug (as contrasted to the normal animal product insulin) used in the palliation of diabetes--Orinase--is "no good." We know of no true drug that actually prevents or cures metabolic or chronic diseases--or really does any genuine good. We mean by "drug," of course, relatively toxic chemicals foreign to the body or foreign to the animal economy.

As already mentioned, vitamin B-17 (Laetrile) is totally non-toxic. Its lethal dose in mice and rats, by injection, is about 25,000 milligrams per kilogram of body weight. It is so nearly non-toxic that in some studies the water, used as a diluent, presents a greater toxicity than the vitamin. This applies for acute, subacute and chronic toxicity. By mouth in test animals it is less than 1/20 as toxic as aspirin. Speaking of aspirin, let us recall that this great German discovery, the acetylation product of ortho-hydroxy benzoic acid, and some salicylic acid isomers, as well as benzoic acid itself, are the normal metabolites of dietary nitrilosides found in the seeds of nearly all fruits and some cereals. For example, millet, mentioned above, once more widely used than wheat, yields the salicylic acid isomer para-hydroxybenzoic acid, which arises as the metabolic product of its nitriloside: p-hydroxymandelonitrile-B-glucoside. In this you can discern, however dimly, the dietary-therapeutic profile of the salicylates as a means of satisfying a dietary deficiency in benzoic acid and the related salicylic acid isomers.

Returning to the non-toxicity of nitriloside; it is no more toxic than dextrose or ascorbic acid--and to the diabetic less toxic than the former.

I have noticed that newspapers are carrying wire dispatches reporting the studies of Professor Roger Williams of the University of Texas. He is quoted on the "toxicity" of commercial white bread as sold in the United States. You will recall that Doctor Williams is the discoverer of vitamin B-1 or thiamine; and the first to synthesize it. Doctor Williams, in effect, showed that commercial white bread as sold in the United States is about 70 times more toxic than vitamin B-17. Doctor Williams fed four strains of white rats (noted for their vigor), nothing but commercial American white bread for three months. Seventy-five per cent of all the experimental animals so fed died of malnutrition before the experiment was complete. Those fed on whole wheat all survived. The commercial white bread was enriched by law with some crystalline vitamins, but not in a sufficient quantity and variety to prevent these rats being killed by the bread. So how about vitamin B-17 toxicity studies? White rats fed 70 times the normal human dose of vitamin B-17 (nitriloside) used in the palliation of human cancer were completely normal and healthy after 90 days. None of them died. There were some "physiological side reactions" to vitamin B-17--greater weight and appetite. After all they were receiving nourishment; a vitamin, not a vitamin-deficient ration or a drug.

The rats that died from eating commercial white bread--all 75 per cent of them--died as a direct result of a deficiency in vitamins found in the whole grain of wheat. There was the deficiency in vitamin E as a result of the missing germ or seed of the wheat, a deficiency of choline, vitamin B-15 (pangamic acid), vitamin B-6, biotin and other factors as a result of the missing bran taken from highly refined bleached white flour. Recall that the natural whole grain of wheat is composed of the starchy endosperm or bulk of the grain as well as the germ or the seed which carries the oils in which are dissolved the tocopherols or vitamin E; and the bran which contains an abundance of the B vitamins.

Those rats died from a vitamin deficiency produced by eating less than the whole grain, the whole food. When civilized man eats less than the whole fruit, for example, by discarding the seed or kernel he experiences a specific and total deficiency not only in oils and proteins but in minerals and such vitamins as vitamin B-17 (nitriloside) which is found only in the seed, not in the flesh of the fruit. By discarding the seed or kernel, man experiences a specific and total deficiency in vitamin B-17 so far as that fruit is concerned. Let me remind you that were man by circumstance limited to no source of food but apricots, peaches, plums, cherries and the like and ate only their fruit without their seeds he would in a short time develop a fatal deficiency in proteins and fats not to mention vitamins. He would die from this deficiency just as the white rats died from the deficiency produced by eating only the starch of wheat without the seed germ and bran. But if he ate the seeds or kernels with the fruit flesh, he would get proteins, fats and other nutrients essential to health.

Vitamin B-17 (nitriloside) is also found in great abundance in a very wide variety of vegetable foods once eaten in great abundance by man, and the natural fodder of animals is similarly rich in the factor. In a paper which I hope to publish soon, I have listed over 62 plant foods eaten by man and over 70 common fodder plants that are very rich in vitamin B-17 (nitriloside). Their concentration of this vitamin compares favorably with that of vitamin C (ascorbic acid) so far as quantity and ubiquity are concerned. As in the case of many other vegetables, sprouts may contain 10 to 30 times as much vitamin B-17 as mature plants. It is not practicable to furnish here the several hundred references of the basic research on nitrilosides nor to list extensive tables showing the occurrence of this new vitamin in a wide range of foods. It would not be germane to explain the reasons why and how "modern diet" has been almost totally stripped of nitrilosides. Suffice it to say that the factors that made commercial white bread lethal to rats and gave the world the empty calories of refined white sugar also have served to produce a fulminating deficiency in vitamin B-17 (nitriloside) in the diet of so called civilized man.

So much for the specific nutritional aspect of vitamin B-17 (nitriloside). How can a compound that is totally non-toxic be relevant to a disease as serious as cancer, a disease perhaps as lethal as pernicious anemia once was? Would we not expect that very powerful cytotoxic compounds would be required to destroy cancer cells? Would these not be compounds like the nitrogen mustards, the antimetabolites, the cyclophosphoramides, methotrexate, 5-fluoruracil, 6-chloropurine, 6-mercaptopurine, azaserine, triethlyenphosphramide, the nitrosoguanidines, and countless other compounds so toxic that some kill almost 25 per cent of the patients treated directly or indirectly through toxicity alone?

It is true that neoplastic cells are destroyed by cytotoxins. The cytotoxins used so far, the ones I have mentioned, are more toxic to body or somatic cells than specifically to cancer cells. This is obvious. Otherwise we would be able to administer these cytotoxins until they killed all cancer cells and left the host alive. But they almost always, if not always, kill the host before killing the neoplastic cells. In the problem of neoplastic therapy we have in drugs an almost insoluble paradox. For an agent to be effective it must be both non-toxic to somatic cells and yet present powerful cytotoxins to neoplastic cells--cytotoxins like the cyanides and benzaldehyde.

Vitamin B-17 (nitriloside) releases a specific and powerful cytotoxin, probably the most powerful one known. This is hydrogen cyanide. Our formulation of Laetrile also releases an equimolar quantity of benzaldehyde which, before oxidation to benzoic acid, is a very powerful cytotoxin. We have here two very powerful cytotoxins. Doctor Dean Burk of the National Cancer Institutue has brilliantly demonstrated, largely through utilization of the technics and manometer of Otto Warburg, that the benzaldehyde released by the hydrolysis of nitriloside or Laetrile is not only in itself a powerful cytotoxin but that it multiplies through a very powerful synergy the cytotoxic effects of both--cyanide and benzaldehyde--to an extent many, many times greater than the arithmetic sum of their separate effects.

These two compounds in synergy are more powerful cytotoxins than any of those that I have already mentioned above.

Why isn't the equimolecular quantity of benzaldehyde oxidized immediately by the cancer cells to harmless benzoic acid as occurs in body or somatic cells, and why isn't the equimolecular quantity of cyanide converted immediately to thiocyanate as it is in body or somatic cells? Recall that Otto Warburg himself received one Nobel Prize for proving the suboxidative activity of cancer cells. They ferment--fermentative metabolism rather than respiratory metabolism plays a large role in cancer. This metabolism utilizes less oxygen (in the free state); therefore, oxidation of benzaldehyde occurs much more slowly. Unoxidized benzaldehyde lags, as it were, in the neoplastic cell. This cell also lacks a very important enzyme possessed by body or somatic cells. This enzyme is rhodanese or thiosulfate transulfurase. It convert cyanide to the harmless thiocyanate. With the selective lag of both undetoxified cyanide as well as unoxidized benzaldehyde in the neoplastic cell, and the multiplication of cytotoxicity that the combination affords, the neoplastic cells suffer a lethal cytotoxicity while the hostal or somatic cells are totally unaffected--except possibly in a beneficial or physiological manner. We are dealing with a vitamin, remember.

Pause again to reflect. Is it possible that this described cytotoxic synergy arising from the hydrolysis product of vitamin B-17 (nitriloside), is a coincidental or fortuitous phenomenon--a synergy totally ungrounded in any other biological experience, a pure accident? Or does this synergy represent the end product of the enduring effects of a process of natural selection between plants and animals through which a specific antineoplastic vitamin, vitamin B-17, has evolved in a natural environment once as abundantly rich in nitrilosides as in ascorbic acid?

There is no controversy, of course, on the fact that equimolecular quantities of benzaldehyde and cyanide resulting from the hydrolysis of vitamin B-17 will selectively kill cancer cells. The cytotoxicity of these chemicals against neoplastic cells is known, but the margin of safety for these raw chemicals is very little greater than the most powerful cytotoxins--except that different from the latter there is no residual, cumulative or chronic toxicity from them. Contrast this to the utter non-toxicity of these same chemicals bound in the white sugary nitriloside molecule.

Wherein, then, is there a controversy over this vitamin in therapy? Though the major and practically sole controversy is and has always been a political one, if we were to try to pin-point a specific scientific criticism it would probably be this: what real or experimental proof is there that the nitriloside molecule is selectively hydrolysed or broken down to free cyanide, benzaldehyde and sugar at and by the neoplastic lesion? It is, of course, a commonplace-now almost a century old--that the nitriloside is split to its 3 major components by the enzyme Beta-glucosidase. It is also known that the malignant lesion contains a high concentration of certain Beta-glycosidases (e.g., Beta glucuronidase). The proponents of vitamin B-17 for the prevention and palliation of cancer have long argued inferentially for the presence of specific Beta-glucosidase activity in the malignant lesion, which would account or its selective lysis here with the release of the admittedly highly cytotoxic HCN and benzaldehyde in synergy.

The opponents of vitamin B-17 in cancer therapy have rather myopically, (I believe), argued that there is no proof that selective hydrolysis of the nitriloside occurs in the neoplastic cell. They reject all existing clinical evidence, however impressive, for this effect. Thus it is an extraordinarily important finding that Doctor Dean Burk reports on his observation of the effect of the incubation of C3H mouse mammary cancer with vitamin B-17 in the Warburg manometer. He reports that the malignant mammary tissue selectively hydrolyzes the added nitriloside to free cyanide, benzaldehyde and sugar with a highly effective cytotoxicity; and that this does not occur in benign or somatic control mammary tissue! This experimental observation means, of course, that the neoplastic tissue carries a specific Beta-glucosidase activity that normal or somatic tissue lacks, which lack here is obvious in view of the total non-toxicity of the material toward normal tissue. This very crucial experiment will, of course, be repeated and checked and rechecked in many laboratories.

Let us in summary simplify all this in terms of vitamin action. When vitamin B-17 enters the body (in foods, for example), it is hydrolyzed only to a very slight degree by body or somatic cells. This is obvious from the non-toxicity shown by B-17. But even if some of the B-17 is hydrolyzed by body or somatic cells, the very high concentration of the enzyme rhodanese in these cells converts the HCN immediately to relatively non-toxic thiocyanate. (This accounts largely for the thiocyanate that you find in blood, urine, saliva, etc., as stated above).

How different it is with the neoplastic cell! It contains great quantities of Beta-glycosidase. Fischman and many others in America have independently shown this in the case of Beta-glucuronidase. Sometimes there is over 1,000 times as much of this Beta-glycosidase as in the contiguous normal or body cell. The neoplastic cell is almost completely deficient in the enzyme rhodanese. Recalll that when B-17 reaches the cancer cell the Beta-glycosidase there hydrolyzes it with the release of extremely large quantities of cyanide (relative to the situation in normal body cells). This selective effect occurs in a cell that is almost totally deficient in the enzyme rhodanese, which in normal body cells is present to detoxify cyanide to thiocyanate. Thus the end result of the presence of one enzyme that causes the selective release of hydrogen cyanide in cancer cells, plus an oxidative deficiency (fermentative metabolism) that causes a lag in benzaldehyde oxidation to benzoic acid, result in the selective persistence of free or undetoxified cyanide plus free or unoxidized benzaldehyde which synergistically exert their selective antineoplastic effect.

A discussion of the clinical details of vitamin B-17, nitriloside in animal and human cancer is best left to our clinical students of the subject. They are faced with the fact that today more people per 100,000 of the population are developing cancer and dying from it at an earlier age than any other time in recorded history of the human race. At least one in three of the population develops clinical cancer and probably all develop subclinical neoplasms in the course of a lifetime. The situation, in our opinion, almost identifies itself in terms of a fulminating deficiency disease a priori. As our veterinary friends tell us, even our cats and dogs are showing an incidence of cancer parallel to that of their "civilized" owners. Observe how quickly these animals when released from an apartment or kennel will single out (and eat) such nitriloside-rich grasses as Johnson grass, Tunis grass or Sudan grass as a supplement to their diet. Some of these grasses contain as much as 17,000 mg of nitriloside per kilogram of dry weight!

In this presentation we have attempted to touch a vast and relatively unexplored area. But before closing let me introduce a little Yankee humor. It may be sick humor: judge for yourselves. We know of the white bread that will kill 75 per cent of hearty rats in 90 days, of calorie-free white sugar, of cola drinks, of fulminating vitamin deficiencies, and the like. But in the United States there is one "school of nutritional thought" that, despite all this, sought to append the following statement to the labels of all bottles of vitamins:

"Vitamins and minerals are supplied in abundant amounts by the foods we eat. The Food and Nutrition Board of the National Research Council recommends that dietary needs be satisfied by foods. Except for persons with special needs, there is no scientific basis for recommending routine use of dietary supplements."

The lethal commercial white bread is by law supplemented, but not supplemented enough not to kill the rats. It is argued, of course, that this won't hurt man too much unless he relies almost solely on this staff of life and is no tougher than the rats!

Lest this new vitamin B-17 or nitriloside still be a less concrete reality in your mind than ascorbic acid, thiamine, niacin or the like, let me leave you with an example of a daily ration or diet remarkably rich in nitriloside or vitamin B-17. For breakfast we start with buckwheat, millet and flax-seed gruel; all three cereals are very rich in nitriloside. On our millet bread toast we put some nitriloside rich elderberry jelly. The stewed apricots we eat carry the nitriloside-rich seeds, which we detect through their delicious almond-like flavor. At lunch we have nitriloside-rich lima beans or possibly a succotash containing nitriloside-rich chick peas. Our millet rolls may be spread with plum jam carrying the nitriloside-rich seeds that add so much to the flavor of the jam. We may choose some nitriloside-rich elderberry wine. For dinner we may have a salad with some nitriloside-rich bean sprouts and nitriloside-rich millet sprouts. Our dinner rolls may be made of nitriloside-rich buckwheat and nitriloside-rich millet and sweetened with nitriloside-rich sorghum molasses extracted from sorghum cane--almost all of the foregoing are very rich in nitrilosides. For our meat course we may have rabbet that fed on nitriloside-rich clover and as a result carries 5 to 10 times more thiocyanate and nitriloside than animals not so fed. If the milk we drink came from cows that ate fodder rich in nitrilosides this milk will contain as much as 7 times more nitriloside than a cow living on nitriloside-deficient fodder. At the end of the dinner we may choose a nitriloside-rich apricot, peach, cherry, or plum brandy originally prepared from crushing the entire or whole fruit. We may also choose a number of wild berries very rich in nitrilosides--all members of the raspberry family. We may nibble on some nitriloside-rich macadamia nuts or chew nitriloside-rich bamboo sprouts.

In such a menu of three meals in the course of a day we should ingest over 300 mg of nitriloside or vitamin B-17 in our foods--every one of which contained nitriloside. The quantities of the vitamin B-17 in the described foods have been very carefully determined by independent workers over the years. Because of our cultural antipathy to cyanide, our food technology has made every conceivable effort through processing, hybridizing, distilling, etc., to remove every trace of derivable cyanide from foods for man and animals. It is good that this irrationality has not to date, at least, completely removed the cyanide-containing vitamin B-12 or cyanocobalamin.

Finally, let me conclude with this. In nitriloside or vitamin B-17 we have a new vitamin in which all of us are severely deficient. This fact is beyond question. As to the clinical application of vitamin B-17 (nitriloside) in human and animal cancer, we feel that every case is morally entitled to whatever vitamin B-17 can offer, just as every being stricken with scurvy, pellagra, or pernicious anemia is morally entitled, respectively, to vitamin C, niacin, vitamin B-12 and folic acid. Indeed, the matter goes far beyond clinical cancer itself. Mankind can not afford any longer a human and animal population deficient in vitamin C, vitamin B-12, vitamin B-15, vitamin B-17 or any other vitamin essential to animal or human nutrition.

However, the capacity of political power for stupidity is truly infinite. We can not predict how long the orderly clinical study of crystalline vitamin B-17 will be delayed. But take some comfort in this. Were vitamin B-12 and folic acid completely proscribed tomorrow, liver would still offer complete salvation in pernicious anemia. Similarly, one gram of defatted apricot seed or kernel carries about 30 milligrams of nitriloside. Six or seven teaspoonful will supply what our clinical investigators consider an adequate oral dose--one gram. It is best that the B-glucosidase enzyme be completely heat inactivated in such material.

So far as other parts of the world may be concerned, I fear no such described obstruction. In Germany I was very happy to find from four to five proprietary and ethical brands of vitamin B-15 (pangamic acid), or its DIPA analogue, and I look forward to seeing a similar distribution of vitamin B-17 (nitriloside) very soon. In visiting the great museum in Hanover I was pleased to find in a display of food-stuffs recovered from Stone Age digging in Europe that of eight food plants shown, three of them are heavy nitriloside-producers. One was Himbeere (Rubus idaeus), another Brombeere (Rubus fruiticosus) and Schwarzer Hollunder (Sambucus niger) or the common elderberry (from which the nitriloside sambunigrin was originally isolated). In the United States the Lovelock Caves in Nevada have yielded petrified animal and human faeces (fecoliths) that through carbon-dating have been found to go back many years. They showed numerous remnants of nitriloside-bearing plants.

Just as the German chemists Huber and Weidel in 1873 first synthesized niacin through the oxidation of nicotine about forty years after Wohler and Liebig in your country first isolated and identified the first nitriloside, amygdalin, and just as niacin was destined half a century later to be identified and defined as the factor that prevents and cures pellagra in man, so we find that the nitriloside isolated and identified over a century ago in Germany likewise is now achieving the status of a vitamin--vitamin B-17. Let us hope that like niacin it has at least left the chemical museum to serve the impelling needs of improved nutrition.

A noted biochemist, Ernst Krebs, Jr. took his student work at Hahnemann Medical College in Philadelphia 1938-41. He received his AB at the University of Illinois in 1942; he did graduate work at the University of California during 1943-45, researching in pharmacology during the periods of 1942-45. He is science director of the John Beard Memorial Foundation, having held this position since 1946. He is the author of "Unitarian or Trophoblastic Thesis of Cancer" (1950); co-discoverer of pangamic acid (1948), the role of pancreatic enzymes in human cancer (1948-50), and the relevance of the nitrilosides (Vitamin B-17) to animal and human nutrition.

This paper is a summary of remarks presented in German before a congress of the International Medical Society for Blood and Tumor Disease, Nov. 7, 1970, in Baden-Baden, West Germany. On this occasion, the author received an award honoring his discovery and research on vitamin B-15 (pangamic acid) and vitamin B-17 (nitriloside).

Charles Gurchot, Ph.D.

Oral doses of Vitamin B-17 seem not to much affected by the action of the acid medium of the stomach, but pass into the intestine where the substance is acted upon by bacterial enzymes.

In the intestine the enzyme complex Emulsin containing the enzymes Beta-glucosidase, Benzocyanase, and others, degrades the Amygdalin into four components: Hydrocyanic acid, Benzaldehyde, Prunasin, and Mandelonitrile, which are absorbed into the lymph and portal circulations.

Cyanide is converted to thiocyanate probably in the blood circulation, and certainly in the liver by the enzyme rhodanese in the presence of sulfur-bearing compounds.^1,2 The circulating thiocyanate exerts certain physiological effects on blood pressure and thyroid action, and is not excreted rapidly. (In the absence of the enzyme or sulfur, the cyanide may form cyano-hemoglobin.)

In cancer patients some thiocyanate finds its way to the site of the cancer lesion.

The benzaldehyde formed in the intestine probably has no important function, but in the circulation forms benzoic acid and is excreted as benzaldehyde hippurate.

Prunasin (the mono-glucoside of Mandelonitrile) can circulate in the body and reach the malignant lesion, and as such hydrolyse to liberate hydrocyanic acid, benzaldehyde, and one glucose molecule.

Prunasin may also be changed in the liver to Mandelonitrile glucuronoside. This conversion to the glucuoronoside may take place in two different ways: 1) by combining with glucuronic acid, which would remove one sugar molecule; 2) by oxidation of the terminal alcohol group of the prunasin glucose molecule.

The mandelonitrile is absorbed from the intestine, going directly to the liver where it is converted by the detoxification mechanism of joining it to glucuronic acid. It may then be excreted as the glucuronide or find its way to the site of a malignant lesion.

Glucosidic enzymes at the lesion may hydrolyse prunasin into its components cyanide, benzaldehyde, and a glucose molecule, to interfere with tissue respiration. In the process of enzyme hydrolysis pure mandelonitrile, as an intermediate step, may be released.

Mandelonitrile of itself may undergo spontaneous hydrolysis to HCN and benzaldehyde or enzymatic decomposition by benzocyanase present in the emulsin complex.

Mandelonitrile glucuronide may be hydrolysed at the tumor site by Beta-glucuronidase to yield HCN, benzaldehyde and glucuronic acid.

Benzaldehyde released through these processes at the site of the malignant lesion may be reduced to benzyl alcohol, and combine with the thiocyanate to form benzo thiocyanate. This compound is further reduced to a thio-alcohol, benzo mercaptain, and hydrocyanic acid. In this manner HCN reappears and may continue to do so in a cyclic manner until the intracellular conditions that permit the reaction involved in the cycle are no longer operative.

These phenomena would explain the synergistic effect of benzaldehyde and cyanide in depressing the metabolism of mouse tumor slices in the Warburg apparatus (Dean Burk³).

In the absense of rhodanese the cyanide probably exerts its lethal effects on cell respiration, which is relatively small in cancer cells, by interferance with the cytochrome oxidase enzymes.

Cyanide, either as such, or as mandelonitrile, may combine with glucose to form cyanoglucose, which, on hydrolysis, forms a glucuronide heptose analogous to gluconic acid, which would be excreted, or dehydrogenated to heptose, which also would be excreted. The conditions for this transformation exist in cancer tissue and would constitute anti-gluconeogenesis.

[From Physicians Handbook of Vitamin B-17 Therapy, McNaughton Foundation, Published by: Science Press International, 1973]