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Changing Fashions in Medical Research: Experience-Based Lessons in Adapting and Surviving

The recent book The Immortal Life of Henrietta Lacks, by Rebecca Skloot, has become a “must read” bestseller among scientists and non-scientists (Science, vol. 327, 26 February 2010 p. 1081).  When I read this book and heard Skloot speak at length about the “HeLa experience,” it led me to think about the role these cells had on my own career and the subsequent lessons I learned related to them.   

When HeLa cells became available in the 1950s, I was an undergraduate biology major in need of a project for my honors thesis.  My older brother, a medical student in the Baltimore area, alerted me that I could obtain a unique immortal line of cancer cells, the HeLa cells, to use as a basis for my project.  I got caught up in the excitement among researchers and in the lay press about the fact that this cell line was the successful culmination of decades of effort to keep cancer cells alive outside of the body.  In Skloot’s words, “cell culture was going to save the world from disease and make man immortal.”

I spent months getting the necessary funding,  supplies, and equipment,
and more than a year learning the very basic techniques necessary for
carrying out my simple experiment: to study the effect of increasingly
dilute concentrations of cyanide on HeLa cells.

My results
(unpublished, but in the archives of Franklin and Marshall College) were
an early proof of hormesis, demonstrating that tiny amounts of a poison
result in effects opposite to what you see at higher doses  (Science
vol. 327 29 January 2010).  The real importance of this work to me,
however, was twofold:
1)    I had mastered an important and, at
that time, difficult technique and had it available to call upon again
and again throughout my career — such as when I established the
earliest continuous cell lines of retinoblastoma and ocular melanoma.

2)    It focused and inspired me on a career involving cancer research.
forward to the end of my medical education:  Tissue culture was no
longer the cutting edge of biological science, although it remained an
important technique.  What was hot was electron microscopy (EM). 
Suddenly, all the structural secrets within cells were laid bare by
transmission electron microscopy.  You could see not only bacteria but
virus particles, and you could explore the surfaces of cells and tissues
with scanning EM.  Again we were told this was a technique that was
“going to save the world from disease and make man immortal.” 

my residency in ophthalmology, I spent 3 years of postdoctoral work at
the National Institutes of Health and the Armed Forces of Pathology
(AFIP) where I learned how to cut thin sections of cells, stain them,
and align an electron microscope and change its filament.  Like hundreds
of other researchers around the world, I compared the structure of
previously invisible components of cancer cells to the normal cells they
were derived from, seeking clues to what was different and what had
gone wrong.  My focus this time was on eye tumors.  I took advantage of
cell culture and made interesting and, I hope, significant
contributions, but cancer and other diseases were largely unconquered
and man remained mortal.

Fast forward again. A decade passed and
EM, although still a useful technique, was no longer at the cutting edge
of science.  The hot topic in medical research was immunology. 
Advances in immunology impacted and progressed in all the basic
biological and clinical disciplines and improved our understanding of
cancer and its treatment.  By the end of the 20th century, 20
immunologists had received Nobel prizes, again leading some to speculate
that this body of knowledge would “save the world from disease and make
man immortal.”  Raising antibodies for particular proteins, tagging
them, and using them as markers were techniques that were essential to
progress and successful competition in the field of cancer research. 

when my first sabbatical came due, I was off to the University of
London to spend a year becoming well versed in the fundamentals and
hands-on techniques of immunology, and, indeed, this effort helped
provide some answers and proved useful in the years subsequent to that

By the late 1980s, in the constellation of “cutting
edge” disciplines and high-powered techniques, immunology had been
replaced by genetics as the means by which we would “save the world from
disease and make man immortal.”  We progressed from understanding the
nature and structure of DNA to the mechanism of DNA replication, with
new techniques for sequencing the multiple variations of each gene and
identifying and mapping the 20,000-25,0000 genes of the human genome
from both a physical and functional standpoint.  With these
discoveries,  new avenues for dramatic advances in biotechnology and
medicine were opened to cancer researchers and the prospect of “designer
drugs” targeted to specific gene abnormalities seemed possible. 

1983, the powerful polymerase chain reaction (PCR) was developed and
the technique to amplify DNA across many orders of magnitude was
paramount.  These techniques were more difficult to master and
collaboration became increasingly necessary.  Nevertheless, I was able
to participate in a meaningful way in the cloning of the retinoblastoma
gene, the first cancer-inhibiting gene to be discovered, and to develop
transgenic models of this tumor — the first transgenic mice with solid
tumors — and contribute to progress at the beginning of an exciting era
of biological discovery.

Today, with the promises of genetic
therapy still in its infant stages, we find ourselves in the era of the
stem cell.  And indeed, we hear new talk of stem cells “saving the world
from disease and making man immortal.”  These cells have the remarkable
ability to develop into many different cell types in the body and serve
as an internal repair mechanism, dividing without limit to replace and
replenish other cells as long as the person or animal lives.  The
methods and techniques of stem cell research reveal knowledge about how
an organism develops from a single cell.  And for medical science, stem
cell research will hopefully inform us of how healthy cells will replace
damaged or diseased cells in adult tissues.  As the tools of stem cell
research are packaged and simplified and the lines themselves become
available to the rank and file of medical researchers, stem cell
research holds sway for many as the most fascinating area of
contemporary biology and an attractive area for researchers in the
biological sciences.

Thus, in my own professional lifetime, I
have witnessed and participated in the scientific progression from the
HeLa cell and tissue culture research to the flourishing of electron
microscopy, immunology, genetics, and, now, stem cell research.  Gained
from my experiences, here are the lessons I have learned about what’s
important to doing successful research and staying competitive for
research funding:

•    Pick a challenging and basic question or
topic for your research career, one you are passionate about, and
maintain your focus.

•    As relevant disciplines are born or
mature, make sure you are knowledgeable about them and can access their
associated technology and apply it to your focus of research.

•    Don’t become fixated or so enamored of a technology that you stop using it as a tool and make it an end in itself.

 Be skeptical that any given discipline or technology will be the
ultimate one that will “save the world from disease and make man

•    Rest assured that another fascinating
breakthrough and cutting edge area of biology will soon emerge to be
mastered, incorporated, and valued, and when it comes, figure out how
you can use it to advance your own corner of science. 

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