By Nicholas Gonzalez, M.D. and Linda Isaacs, M.D.
The roots of our work with cancer and other degenerative disease
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, and weighing
about 500 grams (one 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 uterus, 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 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, thought 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 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.
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