Sunday, July 28, 2013


The Germans have a word for it - Festschrift - and it is something that we should probably do more often -honoring a respected person during their lifetime.  Memorials are nice, but I have often thought that it would be great if the person who passed away could have heard the many nice words said in their honor.  A Festschrift is usually honoring an academic, and the one below is something that I wrote IN 1993 that appeared in a special issue of the International Journal of Developmental Biology, with numerous articles honoring Dr. G. Barry Pierce.  I am hoping to write more festschrift posts here about good friends and colleagues, to honor them whilst they are still with us!


Douglas E. Swartzendruber
Department of Biology, University of Colorado at Colorado
Springs, Colorado Springs

It is a privilege to participate in this Festschrift honoring the career of Dr. G. Barry Pierce. Throughout the past 25 years, there are innumerable examples of the impact that Dr. Pierce has had on my career. However. I would like to use two descriptors that characterize many of our professional and personal interactions: serendipity and mentoring.  Serendipity means -finding valuable things not sought for, and a mentor is -a close, trusted, and experienced counselor or guide.

First - serendipity. In the Spring of 1968, I graduated from Goshen College (IN) with a Bachelor's degree in natural sciences. A college classmate, Marlin Nofziger. had graduated at semester and had found a research technician position in a pathology laboratory at the University of Michigan. Marlin told me that there would be other positions available because the laboratory was moving to the University of Colorado. I traveled to Ann Arbor for an interview and, in the Fall of 1968, moved to Denver to join the research laboratories of Drs. Pierce and Nakane. It was through this set of fortuitous circumstances that I came to know Dr. Pierce, first as an employer, then as the Chairman of the Department in which I pursued my graduate studies, and finally as a mentor and member of my Dissertation Committee.

Second - mentoring. During my years at the University of Colorado Health Sciences Center, Dr. Pierce provided encouragement, guidance, and scientific insight, and was always quick with a thoughtful question or a challenging comment. His weekly research meetings were an important learning forum for research assistants, graduate students, residents and faculty. Results were discussed, new experiments were designed, and strategies were planned for answering specific questions. And most importantly, Dr. Pierce would discuss how the research pieces fit into the bigger topic of the biology of cancer.

I began my graduate research project in the laboratory of Dr. John M. Lehman in 1972. Dr. Lehman and Dr. Pierce had begun a collaborative project to combine Dr. Lehman's SV40 experimental system with the mouse teratocarcinoma system of Dr. Pierce. The goal was fairly straightforward: infection of teratocarcinoma stem cells with SV40 would provide well-character;zed genes and gene products that could be readily followed as the malignant stem cells gave rise to well-differentiated. and often benign, progeny. The first task was to establish the teratocarcinoma in vitro, and to characterize growth and developmental potentials. Dr. Lehman. Dr. Wendell C. Speers (a pathology resident working in the lab) and I successfully established several cell lines and demonstrated that their in vitro growth and differentiation closely mimicked in vivo development (Lehman, et af., 1974). We determined that frequent subculture would greatly enrich for stem cells whereas long-term nutrient feeding without subculture would promote differentiation to a widevariety of cell types. 

Once teratocarcinoma cultures were established, my task was to infect the stem cells with SV40 and then assess the regulation of expression of SV40 genes, such as T antigen, as the stem cells differentiated. Even though I was convinced that all of the experimental procedures had been carried out correctly, numerous attempts to infect the stem cells failed. Since SV40 is nonpermissive in mouse cells,infection with a permissive virus (polyoma) was also attempted, without success. However, I noted that if any differentiated cells developed in the culture. they were susceptible to infection with both SV40 and polyoma. When these results were discussed at the research meetings. serendipity and mentoring again were both evident. Something very unique was occurring in that the stem cells were innately resistant to infection, but upon differentiation, the progeny became susceptible in typical mouse. system fashion. Thus, the emphasis of my thesis research shifted to focus on the resistance of the stem cells to infection with small, DNA viruses (Lehman et al.1975: Swartzendruber and Lehman. 1975; Swartzendruber et al. 1977). Interestingly. the teratocarcinoma system again mimicked normal developmental biology in that stem cells of the very early mouse embryo also resist such viral infections. I was fortunate to encounter such a unique set of experimental findings. These initial findings have been greatly expanded and investigated in depth by students and fellows in Dr. Lehman's laboratory, as well as in other laboratories.

In 1974, I moved to the Los Alamos National Laboratory to begin a postdoctoral fellowship. As I began to develop my own experimental investigations of the biology of tumors, and even today as I do the same, there are several key guiding insights that Dr. Pierce made very clear: i) a tumor is a tissue: ii) all tissues including tumors are innately heterogeneous, from molecular genetic properties tophenotypic characteristics to differentiation potential to growth kinetics: and iii) tumors are often caricatures of tissue renewal. At Los Alamos, it became clear to me that flow cytometry was a powerful tool for quantitative analysis of tumor heterogeneity in the teratocarcinoma system as well as in other experimental and clinical neoplasias. High-speed single cell analysis provides the means to analyze single cells isolated from tumor tissue. to quantitatively assess a wide variety of genotypic and phenotypic characteristics of individual cells. and to determine population distributions of such characteristics. As a fellow and a staff member at Los Alamos, I utilized single- and multiparameter flow cytometry to quantitate in vitro differentiation of teratocarcinoma cells (Swartzendruber. 1976: Swartzendruberet al. 1976. 1979: Hoffman and Swartzendruber .1979).1 also developed several flowcytometric techniques to assess tumor cell heterogeneity. including discrimination of cycling cells from noncycling ce1ls (Swartzendruber. 1977a.b) and kinetic assessment of enzyme activities in individual cells (Martin and Swartzendruber. 1980). These techniques were used to assess both spontaneous and induced differentiation of teratocarcinoma stem cells. (Swartzendruber et al..1980a,b). Thus flow cytometric techniques provided quantitative information concerning attempts to direct the differentiation of malignant stem cells.

Many of the types of studies carried out in my laboratory in New Mexico were extended to human neoplasia while I was in the Department of Developmental Therapeutics at the M.D. Anderson Hospital in Houston. In collaboration with Dr. Bart Barlogie and his co-workers. quantitative flow cytometric analyses of cell cycle kinetics and other genotypic and phenotypic characteristics of human malignancies were carried out in an attempt to develop rational approaches to chemotherapy (summarized in Barlogie et al.. 1983).

As my interest in human cancer increased, the principles of tumor biology put forth by Dr. Pierce continued to be central to my studies: that is, neoplasia is a problem in developmental biology, cancers arise via abnormal stem cell development, and understanding the innate heterogeneity of tumors is key to developing effective treatments. During the past several years, much of my research in tumor biology has been toward understanding the growth kinetics of human breast cancer. Breast cancer tissue. like any normal renewing tissue is characterized by heterogeneity. The cells within the tissue often display a variety of morphologies, differentiated functions, proliferative capabilities. genotypes and metastatic potentials. This innate heterogeneity has confounded the understanding of the biology of breast cancer and has obfuscated the search for effective treatments. Specifically, adjuvant chemotherapy and hormona! therapy extend disease-free survival. but are not curative for the majority of patients.

In collaboration with Dr. Michael Retsky and co-workers, a computer model has been developed that simulates the biological characteristics of breast cancer. including growth kinetics. Although most standard chemotherapy is based on constant. exponential (or Gompertzian), regular (homogeneous) growth kinetics, our studies show that like many characteristics of cancer tissue  growth kinetics are also heterogeneous (Retsky et al.. 1987. 1989). Computer modelling  has reemphasized the need for an appreciation of the complex nature of  cancerous tissue, challenged the old paradigm of breast cancer growth  and treatment, and provided the basis for a new paradigm 
(Retsky et al., 1990, 1993).

Throughout the years since I graduated from the Pathology Department at Denver, Barry Pierce's work has influenced my own. His mentoring extended beyond the research laboratory to the classroom, to informal discussions with peers and students and to explanations of cancer to nonscientists. I am fortunate to have Barry as a mentor, colleague and friend.


SWARTZENDRUBER, D.E. GOHDE. W. and FREIREICH, E.J. (1983). Cytometry in
clinical cancer research. Cancer Res. 43: 3982-3997.

HOFFMAN R,.A.and SWARTZENDRUBER D.E .(1979). Electrical impedance analysis
of single murine teratocarcinoma cells. Exp. Cell Res. 122: 426-429
LEHMAN,J.M., SPEERS, w.e. and SWARTZENDRUBER, D.E. (1975). Differentiative
and virologic studies of teratocarcinoma in vitro. In Cell Biology and Tumor
Immunology Vol. 1. E:-.cerpta Medica International Congress Series 349: 176-

Neoplastic differentiation: characteristics of cell lines established from a murine
teratocarcinoma. J, Cell. Physiol. 84: 13.28.

MARTIN J.M. and SWARTZENDRUBER DE. (1980). Time: a new parameter for flow
cytometry. Science 207: 199-201.

Med. Hypotheses 33: 95-106
Proceedings of the Fourth International Symposium on Adjuvant Therapy of Primary
Breast Cancer. In Recent Results in Cancer Research. Springer-Verlag, Heidelberg.

V. (1989). Larry Norton: a gompertzian model of human breast cancer growth.
Cancer Res. 49: 6443.6444.

(1987). Prospective computerized evaluation of breast cancer: comparison of
computer predictions with nine sets of biological and clinical data. Cancer Res. 4 7:

SWARTZENDRUBER, D.E. (1976). Squamous cell differentiation in a clonal
teratocarcinoma cell line. Differentiation 7: 7-12.

SWARTZENDRUBER, D.E. (1977a). Microfluorometric analysis of cellular DNA after
incorporation of bromodeoxyuridine. J. Cell. Physiol. 90: 445.454.

SWARTZENDRUBEDR.D.E. (1977b). A bromodeoxyuridine-mithramycinfor detecting
cycling and noncyclingcells byflow microfluorometry. Exp. Cell Res. 109: 439-443.

SWARTZENDRUBER, D.E. and LEHMAN. J.M. (1975). Neoplastic differentiation:
interaction of polyoma virus and SV40 with murine teratocarcinoma cells in vitro.
1. Cell. Physiol. 85: 179-188.

SWARTZENDRUBER, D.E.,COX,K.Z.and WILDER, M.E.(1980a). Flowcytoenzymology
of the early differentiation of mouse embryonal carcinoma cells. Differentiation 16:

SWARTZENDRUBER, D.E., CRAM, L.S. and LEHMAN .J.M. (1976). Micro-fluorometric
analysis of DNAcontent changes in a murine teratocarcinoma. Cancer Res. 36:

SWARTZENDRUBER, D.E.,FRIEDRICH,.TJ. and LEHMAN J.M. (1977). Resistance of
teratocarcinoma stem cells to infection with SV40: early events. J. Cell. Physiol. 93:

SWARTZENDRUBER D..E., PRICE, B.J. and RALL, L.B. (1979). Multiangle lightscattering
analysis of murine teratocarcinoma cells. J. Histochem. Cytochem. 27:

SWARTZENDRUBER D.E. .,TRAVIS G, .L.and WILDER, M.E.(1980b). Flow cytometric
analysis of the effect of 5'bromodeoxyuridine on mouse teratocarcinoma cells.
Cytometry 1: 238-244.


Bizzy Brain said...

Quite an impressive list of references!

Douglas E said...

I suppose that it is all relative Bizzy - my total numbers might be about 'average' for someone in my career path, but it really is fairly hard to quantify. Good enough to get tenure, make full professor, etc. :-) Regardless - thanks!

Douglas E said...

Just got this word from a colleague:

"I wanted to pass along some news I just heard from Bob Low. Barry Pierce passed away this morning at age 90, of a stroke. Bob said Barry was still fairly coherent up until the end. He also told me that Barry’s wife, Donna, passed away a few years ago.

"I remember G Barry Pierce as the best of people and as the worst of people – he was an amazingly intelligent scientist with an ability to put together many discrepant data and form hypotheses when others could not. He could also be incredibly mean and attack when you weren’t expecting it. I hope he found peace with himself after he left here."

I would generally agree with the sentiment expressed, and thankfully I was never on the receiving end of Dr. Pierce's attacks. I do believe that he mellowed as the years went by, and am thankful that he did not suffer a long down-hill decline before passing away. -doug-

David A. Rives said...

Lot to talk about, re Barry Pierce. Could you call me: 800 648-2737?
David Rives
LSA, '65

David A. Rives said...

Great talking with you yesterday, Doug.
As mentioned: in my senior year at Michigan, majoring in Cellular Biology, about to enter Michigan Medical School, my instructor in Cell Physiology lab came up to me one day and said, "Barry Pierce is giving a lecture this afternoon. Wanna go?", to which I answered "Sure."
Sat through the hour-long lecture -- on teratocarcinoma, naturally -- then, the next day, went to visit Dr. Pierce in his office in the Path Dept. "basement" (i.e., ground floor).
"Can I help you?" he said.
"Yes. My name is David Rives. I'm majoring in Cell Biology. I've taken a lot of biology classes, and chemistry classes, and physics classes and math classes."
"Also, I'm a pretty smart guy."
"Well, I sat through your entire lecture yesterday, on teratocarcinoma--?"
"And...well...I didn't understand a word you said!"
"So, therefore, I will have to go to work for you this Summer -- if for no other reason than to do whatever it takes to, in fact, understand what the hell you said!"
(continued in next post)

David A. Rives said...

To which the great doctor smiled and shook his head. "Well, I've never had anyone ask for a job that way, so I guess I'll have to hire you! What day do you graduate?"
"May 5th."
"Fine, then you'll start the following Monday."
Which I did.
As it happens, in addition to Michigan Med, I had also been accepted to Washington University in St. Louis, and the UC Med School in San Francisco. However, all I'd ever wanted to do with my medical education was: cure cancer. Which I was now about to do -- working for one of this country's three ACS Lifetime Professors!
Which meant I no longer "needed" Wash U or UC. So, I told both of them what they could do with my acceptance.

Well, I start work in Dr. Pierce's lab. Naturally, my first question, to one of my labmates is: "So, where, exactly, is the 'Cancer Cure' department in this rather extensive laboratory?"
"Oh, he says,"you don't know?"
"Know what?"
"We don't do that anymore."
"Excuse me?!"
"I said--"
"No, I heard that. But what do you mean, 'you don't do that anymore'?"
"Exactly what I said: We don't do that anymore. We do 'basement membrane' instead."
"'Basement membrane'?"
"That's right: Dr. Pierce is looking for a way to alter basement membrane."
"What the hell for?!"
"Oh, because he thinks we might be able to cure kidney disease that way -- you know, glomerulonephritis and the like."

So, there I stood, chafing at the bit to cure cancer, figuring I had accidentally stumbled on the best way to do that (I mean, the guy had his OWN ELECTRON MICROSCOPE, for God's sake, and was thinking of ordering another, at a time when the entire Michigan Biology Dept. was trying to figure out how to get their FIRST!); having told two other pretty good medical schools -- that featured curricula I'd DROOLED over -- to "kiss off; I've got what I was looking for," with the full knowledge that the medical school I WOULD be going to -- the University of Michigan -- was among the worst, education-wise, in the country, no matter what "reputation" they may have garnered outside Ann Arbor -- there I stood, with all of that going on, only to be told, "Oh, we don't do that anymore"(?!)
Are you with me here: an entire LIFETIME changed because of a misunderstanding; because "we don't do that anymore" which no one bothered to tell me, ahead of time, was the case in the Pierce lab(!)
(continued in next post)

David A. Rives said...

So, what did this semi-cum laude graduate of the University of Michigan wind up doing in that lab that summer?
Just this: killing mice, by breaking their necks, then cutting off their tails, holding the "body end" of the tail in one hand, a pair of pliers in the other, grabbing the distal end of the tail with the pliers, then pulling out strands of pure collagen from the interior of the tail, so the guys in the lab down the hall could analyze it and compare it with basement membrane. That's it.
Oh, Barry did "throw me a bone" now and then -- once, by letting me chop up a cancer he had come across and implant bits of it in some mice spleens, to see if they would grow there (some actually did).
And I got to use his ultracentrifuge once or twice, to spin down some RNA, to see if it would have any effect on the resulting tumors (it didn't). But that was essentially it for the summer.
In the Fall, I started Michigan Medical School and, as I had been forewarned, it turned out to be one of the worst educational experiences a human being could go through.
Luckily for the Medical School, most of the class had their eyes so firmly planted on the MONEY doctors made/make that the LAST thing they would be doing was complaining about the curriculum. "Oh no," their attitude was, "just let me suffer through this crap, so I can come out the other end a rich man!"
To humor me, I guess, the school stuck me in the Honors program, but that was little more than a "frying-pan-to-fire" arabesque.

In the end (i.e., after two years), I simply left the school, after starting to ask the "wrong questions:" 1) "Excuse me, professors, is there anything we can actually CURE?!" "Uh, nothing that comes to mind." 2) "Well, since we can't 'cure' anything, what about -- oh, I don't know -- PREVENTING disease! How does THAT grab you?"
"'Prevent disease'?! Are you crazy?! You want to put us out of business?! Get out of here!"
So, I did.
Moved to the West Coast and eventually began doing what I had wanted to do via Medical School: prevent disease, with my books "Walk Yourself Thin" and "Dying for a Smoke."

Anyway, that's my (Barry Pierce) story and I'm "sticking to it!"
Glad I had the chance to share it with those who knew the man.