Enzyme Therapy: Back to the Beginnings
The roots of our work with cancer and other degenerative diseases go back to the turn of the century and the brilliant Scottish biologist, John Beard. Beard, who taught at the University of Edinburgh until his death in 1923, was not a physician but a research biologist whose main interest was the placenta. This is the anchor, the point of attachment between the developing fetus in mammals and the mother’s uterus. Importantly it is the point where the blood supply of the mother, carrying nutrients and oxygen, connects with the blood supply of the embryo, saturated with the end products of metabolism such as carbon dioxide. Here the fetal blood can absorb needed nutrition in a perfectly predigested form and transfer its wastes. Without the placenta in utero development would be impossible.
The placenta is a complex structure, shaped at full term like a disk, perhaps two inches thick and ten inches in diameter, weighing about 500 grams (one-half pound). Its formation begins within days of conception, after the primitive fetus—called at this point a blastocyst—makes its way into the uterine cavity. At that point the growing blastocyst consists of several dozen indistinct ameboid-like cells shaped into a microscopic ball. Several of these primitive cells begin secreting powerful enzymes that enable the embryo to imbed into the uterus. At that critical juncture a thin, single layer of cells on the surface of the blastocyst, reacting to signals from the cells lining the uterine cavity, form what scientists call trophoblast cells, the cells that ultimately become the life sustaining placenta. These very invasive cells quickly establish a firm foothold in the uterine tissue.
Beard was especially fascinated by the microscopic appearance of early placental cells, the trophoblastic layer of tissue that so effectively attaches to the uterine wall. Early in his studies Beard made a simple but extraordinary observation; he noticed that these trophoblast cells were very similar in their appearance microscopically to cancer cells. Although by today’s standards we may look back at the 19th century and early 20th century as primitive times in terms of modern molecular biology, the development of microscopy during the 19th century had already opened the way for a generation of pathologists to catalogue the differences between normal and cancer cells. Scientists such as Beard knew what cancer cells looked like.
Under the microscope cancer cells differ from normal tissues primarily by a lessening of what scientists call differentiation. All cells of all tissues in all organisms have a distinctive appearance that is unmistakable, unique for the tissue of origin, that reflects the particular function of that cell. The cells lining the small intestine look like, and only like, cells lining the small intestine; nerve cells look like nerves cells, pancreas cells look like pancreas cells, muscle cells look like muscle cells. Even cells types within an organ can vary greatly, depending on their specific function. For example, the pancreatic cells that secrete insulin are far different than their neighbors in the pancreas that secrete the pancreatic digestive enzymes such as trypsin.
Cancer cells lose this specificity, this quality known as differentiation; cancer cells may resemble somewhat cells from the organ in which they develop but as the cancer cells become more aggressive, the resemblance becomes less pronounced. In fact, pathologists define certain aggressive tumors as "poorly differentiated," and such cells can be so primitive and indistinct in appearance that an experienced pathologist, unless he knows the history of the specimen, often cannot identify the tissues of origin.
Placental cells not only look like cancer cells under the microscope, Beard realized, but even more significantly, the trophoblastic cells behave like cancer cells. Even during Beard’s time, cancer biologists had identified the behavioral characteristics of cancer cells that distinguished them from the normal tissues. First, cancer cells are invasive; such cells produce a host of enzymes that enable them to break down tissue barriers and spread through normal tissue with deadly efficacy. Second, cancer cells and malignant tissues develop their own blood supply—through the process known as angiogenesis—allowing the tumor to grow effectively wherever it chooses to grow. And third, cancer cells and tumors, unlike normal tissues and organs, grow without restraint or inhibition; normal tissues grow as needed and when needed but only as appropriate. For example, the lining of the large intestine is sloughed off every five days or so and is completely replaced from precursor cells in the intestinal lining. If a surgeon removes a kidney, the remaining kidney can double in size and actually increase its function to compensate for the loss. If a portion of the liver, in fact up to 80 percent, is surgically excised, the remaining liver cells start reproducing until the missing liver completely regenerates. But the growth stops, usually on signal, just at the right time. Cancer cells, however, grow without restriction and without regard for boundaries, until the tumor jeopardizes the life of the host organism.
Indeed, as Beard discovered, trophoblastic cells do effectively invade the uterus, just as a tumor might; the placenta, just like a tumor early on in its growth, begins generating its own complex blood supply, allowing for its growth and continued invasion of the maternal uterus. However, while early on, the placenta aggressively invades the placenta; generally this growth slows and stops. I say generally, because even a hundred years ago physicians knew that occasionally the placenta, just like a tumor, does not stop growing as it should and instead becomes a very aggressive cancer called choriocarcinoma. Choriocarcinoma is a cancer of uncontrolled placental growth that in Beard’s day would kill usually within months. Today this particular malignancy can be controlled quite effectively with chemotherapy and represents one of the few successes in the drug war against cancer.
Beard knew that that during its development the placenta changed from an aggressive, invading tissue, to a non-invasive, rather tame and stable organ. In his research Beard uncovered a fundamental truth about the nature of trophoblastic growth: in every species of mammal that he studied, he learned that the placenta stops growing at a very specific point in embryological development that is unique for each species. In the human he proposed that the placenta changes from its aggressive to non-invasive form on day 56 after conception. Today, a hundred years later, this milestone in fetal-placental development holds true.
Beard realized that something was happening on day 56 that turned a tumor-like tissue into a mature essential organ. And he then made a leap of faith: he assumed that if he could understand what turned the aggressive, invasive, poorly differentiated trophoblastic tissue into a non-aggressive differentiated tissue, he would have the answer to cancer.
Beard devoted years of his life trying to unravel the signal that turned the trophoblast, in most instances, into a non-life-threatening, life-sustaining organ. He realized the signal could be coming from the mother or from the fetus and he systematically analyzed, at least with the scientific tools available to him at that time, the various possibilities. He investigated the development of the fetal nervous system and the endocrine system of both the embryo and the mother (at least the endocrine system as understood at that time). He thought about blood supply and immune function. The pathologist Virchow had already uncovered the underlying concepts of modern immunology and Beard probably had some knowledge of Virchow’s pioneering work.
But nothing seemed to make sense, no clue provided a definitive answer in Beard’s mind until he considered the embryonic pancreas. The pancreas sits in the back of the upper abdominal cavity, behind the stomach, in what anatomists call the retroperitoneal space. It is a complex organ that is really two organs in one, both an endocrine and exocrine organ. Endocrine organs secrete hormones into the blood system that act on distant tissues and the endocrine pancreas secretes glucagon and insulin, used to regulate blood sugar levels. The exocrine pancreas, the bulk of the pancreas, manufactures the various digestive enzymes which are secreted into the small intestine during and after a meal. Scientists identify three main classes of pancreatic enzymes: the proteolytic enzymes such as trypsin and chymotrypsin which digest proteins, the lipases which break down fats and the amylases which digest starches. Even in Beard’s day the major classes of pancreatic enzymes and their respective functions, were well known.
After his years of research and his many false starts, Beard had come to a pivotal conclusion. He believed that the very day the placenta stopped growing, stopped invading and metamorphosed from an aggressive tumor-like tissue to a life-sustaining organ, was the very day the fetal pancreas became activated. This is an astonishing phenomena to have uncovered, when one considers the somewhat primitive tools that were available to Beard at that time. But the more he studied the problem of placental growth in animal models, the more convinced he was that some product from the fetal pancreas ultimately signaled the placenta to slow and eventually stop its growth. Based on further animal studies, Beard concluded that the primary signaling factor must be the proteolytic, protein-digesting enzymes—particularly trypsin and chymotrypsin.
Recent embryological research confirms that the fetal pancreas does begin manufacturing and secreting digestive enzymes very early on in development. This is an interesting finding in itself because theoretically the fetus has no need for an activated pancreas nor for pancreatic enzymes, until it takes its first meal the day of its birth—nine months after conception. The fetus receives all the nutrients it needs for growth in a perfectly predigested form from the blood supply of the mother; the growing embryo really has no need for digestive enzymes. Yet they are being produced, and produced in a not insignificant amount, early in fetal development, beginning at approximately two months of a nine-month gestation.
Beard was the first to suspect and document that the fetal pancreas produced enzymes early in development. He hypothesized that the fetus produced enzymes for one primary, life-essential reason, to control the placenta and to prevent its uncontrolled growth, which could kill the mother and in turn the baby itself. And if indeed the proteolytic pancreatic enzymes did control placental growth, Beard assumed then that these same enzymes should be able to control cancer—since he believed increasingly that cancer was nothing more than placenta-like cells growing without the controlling influence of adequate pancreatic enzymes.
Early in his research Beard used analogies; trophoblastic cells behaved like cancer cells, the placenta was like a tumor. But as his knowledge base increased he began to believe that the connection between cancer and trophoblastic cells was even more direct and goes to the very origin of cancer itself.
After a hundred years of study, there is still debate as to the origin of cancer cells. Cancer researchers still ponder the process by which mature differentiated cells performing their normal function in an organ—say the cells lining the large intestine or the cells lining the pancreatic ducts—somehow mutate, through genetic alterations, and become less differentiated, more primitive, capable of invasion, angiogenesis (blood vessel formation) and uncontrolled growth. Such a process requires that mature cells become less mature, less specialized.
When I studied pathology in medical school in 1980 my textbook of pathology, written by the famous Dr. Stanley L. Robbins, suggested that cancer cells might arise through quite a different mechanism involving uncontrolled growth of stem cells. In recent years stem cells have been the subject of intensive research around the world. Stem cells are primitive, undifferentiated cells found in every organ. Upon proper signaling, stem cells start dividing and ultimately can form mature, functional tissues of the organ. For example, as mentioned above, every five days the lining of the large intestine sloughs off and needs to be replaced. Throughout the lining of the large intestine are microscopic indentations, known as crypts, that harbor nests of these primitive stem cells. These precursor cells are continually migrating to the surface of the intestine and as they migrate they change from ameboid-like cells, with no distinctive appearance or functional capability, into the very specialized lining cells of the large intestine. The growth, development and differentiation of these stem cells of the large intestine is a very carefully orchestrated, very carefully controlled process. Should these stem cells, during their migration to the surface of the large intestine, not differentiate into mature lining cells, they remain primitive, develop the ability to invade and will grow without restriction. Such cells, unless controlled, can become deadly cancers. We know further, from our understanding of stem cells, that during the process of differentiation, during the process when the primitive stem cells become adult, mature cells, they lose their ability to grow uncontrollably. With differentiation comes control of growth.
Stem cells are necessary for life; they are necessary for normal physiological replacement of tissues that turn over rapidly, such as the tissues lining the intestinal tract. Stem cells are necessary for repair of damaged tissue, such as a liver that has been reduced by surgery, or skin that must heal after a wound. Histologists have now identified stem cells in each tissue of each organ of the body, from the brain to the skin of the big toe, available as needed to provide for tissue replacement or tissue healing. We know that there are a variety of signals—hormonal, neurological, peptide, for example—that can stimulate the stem cells into action.
However, it is possible that it is these same undifferentiated stem cells, so necessary for life, in the absence of proper signaling, can grow unrestrained, without proper differentiation, into cancer cells and ultimately into tumors. Stem cell research is one of the most productive areas of study in medicine today, not only in terms of cancer but also in terms of organ regeneration and tissue healing.
Beard may have been the first to recognize what we today call stem cells, though he didn’t use that term. In many respects one of Dr. Beard’s greatest achievements was his recognition that each tissue in every species that he studied contained nests of primitive undifferentiated cells. Beard evidently was quite skilled in microscopy and in his writings argues convincingly that such cells exist—in every tissue. He further proposed that these primitive undifferentiated cells—which to his eye resembled none other than the primitive trophoblastic cells, were actually residual placental cells left over from early fetal development. Beard claimed these cells migrated from the primitive yolk sac of the developing mammalian fetus and ended up in every tissue of the body. He wasn’t sure why these cells were present but he found them wherever he looked.
Beard claimed further that contrary to what researchers believed at that time—and what many still believe today—cancer tumors did not arise through some process of de-differentiation whereby mature, specialized cells suddenly changed into primitive, immature, aggressive, dividing, uncontrolled tissues. Instead he maintained that all tumors, whether originating in the brain or the skin of the foot, arose from these misplaced placental cells, which had been deprived of proper control. In the final summation of his life’s work he said that this ultimate controlling signal, this factor that determined the behavior of these misplaced placental cells, were the enzymes from the pancreas. Beard thought finally that all cancer—not just the well-documented choriocarcinoma—developed from placental cells left over from our embryonic stage and that these cells would normally be kept under control by circulating pancreatic enzymes. However, these cells could quickly grow out of control should the pancreas fail to manufacture or release adequate amounts of the proteolytic digestive enzymes.
When Beard presented his theories in a series of lectures and papers during the period 1902–1915, his ideas were greeted largely with scorn, ridicule, derision and hostility. Few could accept his theories about placental growth, the similarity of the placenta to cancer, its intricate growth regulation and the correlation of growth control with fetal pancreatic activation. No one but Beard at the time could find these primitive undifferentiated "placental cells" he claimed to see in every mammalian tissue. Unfortunately Beard was 100 years ahead of his time; 80 years would pass before other scientists would prove the fetal pancreas became active early in embryonic life. Decades would pass before histologists and molecular biologists would identify primitive stem cells—Beard’s misplaced placental cells—in every tissue in every organ. Nearly 100 years would pass before these primitive cells, that Beard saw so clearly, would be seen increasingly as the cell line which, if not properly controlled, could develop into malignancy.
When I read Beard’s crowning achievement, his book The Enzyme Treatment of Cancer published in 1911 and summarizing his life’s work, I realize how frustrated he was by the disregard given his work by the orthodox research establishment. To Beard, the greatest frustration was that there was no mystery to cancer at all; it was a question of misplaced placental cells, growing without restraint because of inadequate pancreatic enzyme production.
Beard’s work has come full circle I hope. With the publication of our first clinical trial in 1999, documenting significant improvement in survival in patients suffering inoperable pancreatic cancer treated with high-dose pancreatic enzyme therapy, we have taken a first step toward testing and documenting his thesis. With our current NCI-NIH funded clinical trial, currently up and running at Columbia University, we hope to demonstrate, finally, the validity of this pioneering and too long ignored scientist.