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Science Careers Blog

April 22, 2010

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My results (unpublished, but in the archives of Franklin and Marshall College) were an early proof of hormesis, demonstrating that tiny amounts of a poison result in effects opposite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.
 
Fast 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." 

After 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. 

Therefore, 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 sabbatical.

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. 

In 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 immortal."

•    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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