A Most Challenging Problem

A Most Challenging Problem
“None of the [advances of the 20th century medicine] depend on a
deep knowledge of cellular processes or on any discoveries of
molecular biology.
Cancer is still treated by gross
physical and chemical assaults on
the offending tissue.
Cardiovascular Disease is treated by
surgery whose anatomical bases go
back to the 19th century … Of course,
intimate knowledge of the living cell
and of basic molecular processes
may be useful eventually.”
Lewontin (1991)
10 years later…
“A decade later, molecular biology can claim very few successes
for drugs in clinical use that were designed ab initio to control a
specific component of a pathway linked to disease: these include
the monoclonal antibody Herceptin, and the kinase inhibitor
Reik, Gregory and Urnov (2002)
Herceptin Antibody
Imatinib (Gleevac)
We now have
The Human
Frontiers of Complexity
Baruch Blumberg (19252011)
Nobel Laureate in Medicine (1976)
My experience is that, in medicine, where observational science is crucial,
the complexities of a phenomenon can be understood, at least in part, by
repeated observations of a whole organism or a population of organisms
under a wide range of circumstances; all the variables are retained and as
many as possible are examined. For example, in studies of disease, it is
possible to build up a knowledge of effects of a large number of variables
on the host, genetic susceptibilities to the diseases, and outside factors
which interact with each other, the host, and the environment. By
contrast, in the reductionist approach, traditionally found in physics,
chemistry, and molecular biology, experiments are designed to simplify
the study of a natural phenomenon by the elimination of all but a few
variables, and explanation is in terms of the most fundamental units.
The study of hepatitis B virus (HBV) and its
interactions can be used as an example of
observational science. HBV causes primary
cancer of the liver, one of the most common
cancers in the world. But not everyone who is
exposed to HBV becomes chronically infected and
not all infected persons develop cancer. The
internal and external factors that determine
infection and outcome are interactive and time
HBV life cycle
dependent. There are interactions between HBV
and other viruses which attach the liver, the AIDS
virus, malaria, and probably other micro-organisms which influence
both the probability of infection and the outcome. Genes, gender, and
age have a significant effect. In addition, environmental agents such as
aflatoxin—a carcinogen which is elaborated by fungi that contaminate
foodstuffs—iron, arsenic, and probably others increase the risk of cancer
and chronic disease. As a further complication, the environmental
effects are influenced by products of the host genes.
The virus has developed remarkably clever strategies to maximize its
persistence without killing the host prematurely, in order to be
transmitted, primarily through sexual intercourse and by passage from
mother to child during childbirth and infancy. Its strategies for the
evasion of the human immune protective system are particularly clever;
they include “smoke screens” of surface antigen produced in excess to
befuddle the immune response; the development of tolerance to an
antigen of the virus which allows it to reside for years within the liver cells
of its host, replicating and spreading, but not immediately disabling its
innocent bearer; and many other “intelligent” schemes.
All this data cries out for a model that will reveal the complex and timedependent interactions of known and unknown variables. But
conventional model makers find it difficult to deal with such complexity
since so many assumptions must be made.
…Traditional science, particularly the Greek ideal, worships simplicity,
harmony, symmetry, and other attributes of pure beauty. In some
interpretations, Plato taught that the observed world was not as real as its
essence which may be concealed by the complexities that cloud it, and it
is this essence we should desire to know. Experimental science attempts
to approach this essence by creating a world inferred from experience but
with a minimum of complications. …In interventional science, such as
medicine, it may be the complexities themselves that provide the key to
the problem. In a biological system gone wrong—due to disease—the
more complexity we are aware of, the more numerous are the sites where
intervention can take place. It is valuable to know the “real” cause of a
disease, that is the one essential element that is causative, but this is often
not knowable and may be a fiction of the investigator’s desire to have
simple answers to complex problems. But, as you read, successful
engineers and other applied scientists are practical and don’t allow the
perfect to drive away the good.
… study of complexity, even if it does not provide totally satisfactory
solutions, should make reductionist science aware that no matter how
many details are uncovered, no matter how comprehensive
understanding may be, there will always be unknowns beyond the sum of
current knowledge. Each time an experiment is performed to test a
hypothesis, more questions are revealed; there is no limit to the mysteries
of nature and to our desire to understand them. … an opportunity to
stand back and consider the global interactions of fundamental units—
atoms, elementary particles, genes—to create a synthesis that crosses the
borders of scientific disciplines, to see a grand vision of nature.
The key concept