The

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Medicine a nd So cie t y
Debra Malina, Ph.D., Editor

Why Does the Weeping Willow Weep? Reconceptualizing

Oncogenesis in Breast Cancer
Michael Baum, M.B., Ch.B.
Why is my flat-fronted, early-19th-century Georgian cottage considered so desirable in my part
of northwest London, even though it lacks decoration or even a brightly painted front door? Its
attraction, unlike that of Baroque or Victorian
architecture, has nothing to do with elaborate
stucco or stained glass windows; rather, its related to something integral in the proportions.
The ratio between the height and width of a
Georgian town house is replicated in the proportions of the door and the windows and again
at a smaller scale in the panels on the door and
the individual windowpanes. For reasons that
are obscure, the ratio of height to width of 1.62
called the golden ratio is intrinsically
beautiful both in art and in nature. Is it possible
that there is an evolutionary advantage of beauty,
or is the ratio the common currency of health in
the animal and plant kingdoms that has found
expression in architecture and design since ancient times? Of course this is a circular argument
like the chicken-and-egg paradox.
If you look at the weeping willow tree in my
front yard and measure its branches and feathery hanging leaf clusters by extending your arm,
holding up a pencil, and squinting one eye, you
will find that the ratio between the lengths of
proximal and distal branches at each bifurcation
is the same as that of the length of the trunk to
the length of the first branches approximately 1.62. That ratio also holds for second-,
third-, and fourth-order branches. If you look
closely, you can see that even the terminal leaf
complexes repeat this beautiful symmetry. This
sequence of a constant ratio is known as fractal
geometry. It is but a small leap of imagination
from botanical beauty to the idealized beauty of
the human face. The ratio of length to breadth
of an almond is a repeat of the golden ratio, and

we might extol the beauty of the celebrated portrait head of Nefertiti by describing her eyes as
almond shaped.
But what interests me more than surface
beauty is the aesthetics of the internal anatomy
of the human body both in sickness and in
health. The obvious place to start is the aptly
named bronchial tree, where once again we see
perfect fractal geometry and golden ratios. The
same applies to the vascular trees supplying most
of the organs and the collecting systems of excretory or secretory glands. So what happens to
this ubiquitous symmetry in disease?
It is hard to convey a surgeons enthusiasm
for the study of pathology. Certainly I, and I suspect others, take an aesthetic as much as a scientific interest in the subject. The aesthetics can
be appreciated in the exquisite microscopic
anatomy and molecular biology of the normal
breast before we examine the malignant transformation that turns this transcendental beauty
into life-threatening ugliness.
Broccoli, as well as resembling the bronchial
tree, offers an almost perfect representation of
the mammary ducts and glands at the time of
lactation. The main difference, of course, is that
the branches of the mammary gland are tubular.
Imagine a treelike tubular structure and then
imagine taking transverse or random oblique cut
sections and magnifying them. If the structure
is perfectly symmetric and the cuts are perfectly
horizontal, you will see a plane scattered with
symmetrically positioned circular structures. Of
course, in real life the organs are not perfectly
symmetric and the pathologists cut is not perfectly horizontal to the central tubes of the
system. In fact, when you examine the breast
carefully, you will find as many as 12 ducts opening at the nipple. Each of these is the mouth of

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a treelike system for gathering milk at lactation

from the glandular elements at the terminal ends
of the system that look a little like the florets on
the surface of broccoli. You can now picture what
normal breast tissue looks like under the microscope it appears as a collection of circles of
various diameters or as ellipses where the tubule
has been cut obliquely. You will also see clusters
of tightly packed cells representing the glandular
elements that secrete milk. Sometimes you will
even spot a tiny terminal tubule emerging from
the lobule itself.
If you increase the magnification, you can see
the detail of the individual tubular structures. In
health they are quite banal one layer of simple
cuboidal duct epithelial cells surrounded by a
single layer of spindle-shaped myoepithelial
cells. If you increase the power of the simple
light microscope to its highest magnification,
you will start seeing something of the extraordinary internal organization of these simplelooking cells. Just as many people become giddy
when contemplating the magnitude of outer
space and the expanding universe, I feel giddy
when considering the miniaturization at the other
extreme of the cosmic spectrum. The cell is enclosed by a membrane that looks like simplicity
itself until you begin envisaging the comings
and goings of molecules and the recognitions of
chemical signals by specific receptors on the cell
surface that alert the interior mechanisms to
speed up or slow down. Beyond all that, and
even beyond the highest magnification of the
electron microscope, we can try to imagine
whats going on at the molecular level. The fact
that such a complex and beautiful system retains
its integrity is a miracle; the fact that some
trivial molecular mismanagement can cause the
whole system to crash in spite of the robust
repair mechanisms and immune response to diseased tissues that exist in health and lead to
the death of its host should not be a surprise.
What is remarkable is the near-perfect fidelity of
these complex structures, retained through thousands of divisions of their cellular units and the
sharing out of the genome between the two
daughter cells at each event.
Surgeons and pathologists often describe
breast cancers under the microscope as uglylooking lesions. When they are distorted by this
ugliness, the duct and lobular epithelium lose
their fractal geometry. When we grade these
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cancers, the severity of the patients prognosis is

directly proportionate to the ugliness of what we
see. Could it possibly be that one of the first
steps in malignant transformation is a mutation
in the genes that control fractal geometry? In
other words, external symmetry might be a surrogate marker for internal symmetry, which is
no doubt determined by sequences on the human
genome that control fractal geometry. Loss of
fractal geometry is associated with malignant
transformation, but what is the direction of causality? Is the ugliness the cause or consequence
of the malignant change, or is one a necessary
but insufficient trigger for the other?
As a young clinical scientist and surgeon, I was
taught that the natural history of breast cancer
is unpredictable, like the weather. As I matured
in my chosen field, I rebelled at what seemed to
me a nihilistic attitude. Furthermore, the weather
is not so unpredictable now that meteorologists
use chaos theory to refine their weather-forecasting precision.
Some 20 years ago, I saw one of the first
performances of Tom Stoppards Arcadia at the
National Theatre in London. In the third scene,
set in a Georgian country house in 1809, Thomasina, a very precocious 16-year-old, asks her tutor,
Gods truth, Septimus, if there is an equation
for a curve like a bell, there must be an equation
for one like a bluebell, and if a bluebell, why not
a rose? Do we believe nature is written in numbers? Perhaps Thomasina would have gone on
to discover chaos theory if only the computer had
been invented. As the story unfolded, I experienced a eureka moment it suddenly seemed
clear to me that the natural history of breast
cancer was unpredictable because wed been using the wrong mathematics all this time. I soon
recruited Mark Chaplain, an exponent of chaos
theory, and together with three Ph.D. students
we set to work to try to explain the extraordinary
unpredictable pattern of recurrence of breast
cancer after surgery.
In 1999, our group published an article that
challenged the linear mathematics conventionally
used to describe the natural history of breast cancer and offered the heretical suggestion that the
initial peak of relapse occurrence between 2 and
3 years after surgery was actually provoked by the
act of surgery itself and that this pattern could
only be modeled by using chaos theory.1 We then
wrote a series of articles that strengthened that

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hypothesis and ultimately suggested that the inflammatory response to surgery provoked the
outgrowth of latent foci of residual disease and
that this phenomenon might be inhibited by the
administration of antiinflammatory drugs in the
perioperative phase.2,3 Included in the first article
was a formula developed by Chaplain and Anderson that if iterated and reiterated on a powerful
computer could produce remarkable animated
images of angiogenesis and how it might be
perturbed by one or two simulated mutations,
as a result of which the blood supply to the breast
tissue lost its beautiful fractal geometry.
Since then, Ive speculated that loss of fractal
geometry of the blood supply to human tissues
might be an early step in oncogenesis, and perhaps many of the mutations we see in cancers
might be the results rather than the cause of this
early phenomenon. It has already been suggested that tissue hypoxia leads to loss of cell polarity, instability of the genome, and uncontrolled
cell proliferation.4,5
In the front yard of my house are two ornamental trees. One is Salix caprea pendula, the weeping willow described above, but the other is Salix
matsudana tortuosa, the corkscrew willow. The former has beautiful fractal geometry, whereas the
latter is a complete mess and reminds me of the
vascular system of a cancer as generated by the
ChaplainAnderson model. Searching the botanical literature, I found an interesting article suggesting that the mutant corkscrew phenotype was
related to a dominant allele at a single locus and
that this mutation is associated with vascular

cell collapse within the trees structure.6 If similar mutations occur in the animal kingdom, perhaps we might start a new line of inquiry. It
should not be beyond the wit of humans or even
molecular biologists to search for similar genes
to help us understand the geometry of normal
tissue and their malignant phenotypes. This approach may lead to new insights about the treatment of cancer aimed at restoring both beauty
and function to a diseased organ.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
I thank Lilian and Robert Slowe for having the foresight to
plant the two willow trees 15 years ago.
From the Department of Surgery, University College London,
and the Clinical Trials Group, Royal Free and University College
School of Medicine both in London.
1. Baum M, Chaplain MA, Anderson AR, Douek M, Vaidya JS.
Does breast cancer exist in a state of chaos? Eur J Cancer 1999;
35:886-91.
2. Baum M, Demicheli R, Hrushesky W, Retsky M. Does surgery unfavourably perturb the natural history of early breast
cancer by accelerating the appearance of distant metastases? Eur
J Cancer 2005;41:508-15.
3. Retsky M, Demicheli R, Hrushesky WJ, et al. Reduction of
breast cancer relapses with perioperative non-steroidal antiinflammatory drugs: new findings and a review. Curr Med
Chem 2013;20:4163-76.
4. Schwartz L. Cancer between glycolysis and physical constraint. New York:Springer, 2004.
5. Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-
induced genetic instability a calculated mechanism underlying tumor progression. J Mol Med (Berl) 2007;85:139-48.
6. Lin J, Gunter LE, Harding SA, et al. Development of AFLP
and RAPD markers linked to a locus associated with twisted
growth in corkscrew willow (Salix matsudana Tortuosa). Tree
Physiol 2007;27:1575-83.
DOI: 10.1056/NEJMms1505722
Copyright 2015 Massachusetts Medical Society.

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