G. BARRY PIERCE - MENTOR

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!

 

G. BARRY PIERCE - MENTOR

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.

References

BAR LOGIE, B.. RABER. M.N., SCHUMANN. J.. JOHNSON. T.S.. DREW\NKO. B.,
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-
177.

LEHMAN, J.M., SPEERS.w.e.. SWARTZENDRUBER D.E. and PIERCE, G.B. (1974).
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.

RETSKY, M.W., SWARTZENDRUBER D.E,WARDWELL, R.H. and BAME P, .D.(1990).
Med. Hypotheses 33: 95-106
.
RETSKY, M.W.. SWARTZENDRUBEDR.E, .,WARDWELRL,.H.and BAMEP, .D. (1993).
Proceedings of the Fourth International Symposium on Adjuvant Therapy of Primary
Breast Cancer. In Recent Results in Cancer Research. Springer-Verlag, Heidelberg.


RETSKY, M.W., SWARTZENDRUBER.D.E., WARDWELL,R.H., BAME,P.D. and PETROSKY,
V. (1989). Larry Norton: a gompertzian model of human breast cancer growth.
Cancer Res. 49: 6443.6444.

RETSKY, M.W., WARDWELL, R.H., SWARTZENDRUBER, D.E. and HEADLEY ,D.L.
(1987). Prospective computerized evaluation of breast cancer: comparison of
computer predictions with nine sets of biological and clinical data. Cancer Res. 4 7:
4982-4987.

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:
23-30.

SWARTZENDRUBER, D.E., CRAM, L.S. and LEHMAN .J.M. (1976). Micro-fluorometric
analysis of DNAcontent changes in a murine teratocarcinoma. Cancer Res. 36:
1894-1899.

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:
25-30.

SWARTZENDRUBER D..E., PRICE, B.J. and RALL, L.B. (1979). Multiangle lightscattering
analysis of murine teratocarcinoma cells. J. Histochem. Cytochem. 27:
366-370.

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.

PLANET PEPPERDINE

Well if Planet Boulder is 25 square miles surrounded by reality, Planet Pepperdine is life in a beautiful bubble.  There is much to like about Pepperdine University, not the least of which is its beauty.  Others agree, as noted in a recent Huffington Post article found here.  Visit this link to take in a virtual tour of the campus.  Enjoy.

 

Remodeled Science Center - My office was on the left, past the arched doorway.

"Livin' the Dream"  -  CrossFit Scott

WILLEMS FAMILY & COUSIN REUNION

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TWINKIES ARE BACK

Another great cartoon from Gary Varvel:

H/T Essenhausmann

SPIRITS OF ST. LOUIS & THE SILNA BROTHERS

 

When we lived in Malibu, I learned that Ozzie Silna was also a Malibu resident.  I knew that Ozzie and his brother, owners of the Spirits of St. Louis ABA team, had pulled off one of the best deals in the history of professional basketball, and the NY Times article below lays out the details.  I had the opportunity to chat with Ozzie one time at a Malibu restaurant, and he was congenial and fairly low key about how well things turned out for him. 

No Team, No Ticket Sales, but Plenty of Cash

By RICHARD SANDOMIR

For years, it was an underappreciated wrinkle in the historic deal that merged the established National Basketball Association and the upstart American Basketball Association in 1976. The owners of the Spirits of St. Louis agreed to be paid a small fraction of the N.B.A.’s television money to comfort them for being cut out of joining the older league.

Their piece amounted to a sliver of the modest amount that CBS was paying the N.B.A. in those days. But if the share was small then, one particular term of the arrangement was attractive: the owners, Ozzie and Daniel Silna, would be paid the money every year in perpetuity, or as long as the N.B.A. existed. 

The Spirits became a distant memory, even for people in St. Louis. But the N.B.A. has continued to exist quite nicely, meaning the Silnas’ haul has been substantial: $255 million and counting. But as sweet as the deal has been, the Silnas want more, and they have gone to court to get it.

In Manhattan federal court on Thursday, lawyers for the Silna brothers and the league argued over whether the men are owed money beyond what they get from the N.B.A.’s national broadcast and cable television contracts. They want to tap into the money the league gets from international broadcasts, NBA TV, the league’s cable network, and other lucrative deals that could not have been imagined in the three network television universe of 1976.

If Federal District Judge Loretta A. Preska agrees, the Silna brothers — Ozzie, 79, and living in Malibu, Calif., and Daniel, 68, and living in Saddle River, N.J. — stand to receive millions more, all without having assembled a team or used an arena for more than three decades. 

“This issue has been a nuisance as long as I’ve been associated with the league,” said Ed Desser, the former president of NBA Television and new media ventures who now runs his own media consulting firm. “It was never enough to be a serious distraction. It’s one of those accidents of history.” 

Four of the A.B.A.’s seven teams merged with the N.B.A. in 1976, but the Virginia Squires were a financial wreck and the Kentucky Colonels were placated with a $3.3 million payment. But if the Spirits couldn’t join the N.B.A., the Silna brothers wanted to share in what the A.B.A. didn’t have: national TV revenue. They settled with one-seventh of the television money generated annually by each of the four surviving A.B.A. teams — the Nets, the San Antonio Spurs, the Indiana Pacers and the Denver Nuggets.

The arrangement began to get public attention as the size of the league’s network TV deals swelled. The four surviving teams have tried to extricate themselves from the arrangement, but have not found a way.

In the early 1980s, the teams discussed buying out the Silnas for $5 million to $6 million but did not pursue it. They offered substantially more in the late 1990s, but the Silnas rejected the offer.

Donnie Walsh, the president of the Indiana Pacers, said in 2003 that discussing the Silnas’ deal “puts a dagger in my heart,” reminding him of losing that one-seventh share of TV money each season. On Thursday, he said he preferred not to talk about it.

In 1980-81, the first year the Silnas were eligible to get their share of TV money, they received $521,749, according to court documents filed by the N.B.A. For the 2010-11 season, they received $17,450,000. The N.B.A.’s latest TV deal, with ESPN and TNT, is worth $7.4 billion over eight years. Soon, the Silnas’ total take will hit $300 million.

The A.B.A. was already seven years old when the Silnas — the owners of a New Jersey textiles business that specialized in making polyester — bought the Carolina Cougars and moved them to St. Louis in 1974. Formed to challenge the N.B.A., the A.B.A. wanted nothing more than to join the N.B.A. 

The A.B.A. instigated a salary war. It discarded the traditional orange ball for a red-white-and-blue one. It implemented the 3-point line and juiced up its All-Star Game with a slam dunk contest. Stars like Julius Erving, Connie Hawkins and George Gervin played a freewheeling game that reflected a counterculture sensibility that contrasted with the N.B.A. squares. 

Still, one team was owned by the prototypical square, Pat Boone. Yet another had Morton Downey Jr. as its general manager well before he became known as a coarse, chain-smoking talk show host.

Teams left cities as if attached to moving vans. Their names changed regularly. Into this unrest came the Silnas. 

“They spent a lot of money to get a good team as quickly as they could,” said Rod Thorn, who was fired as the Spirits’ coach 47 games into the 1975-76 season. “Ozzie was the main guy. They were really involved, big fans and came to a lot of games.” 

Michael Goldberg, who was the A.B.A.’s general counsel, recalled the Silnas as passionate owners who took a risk by buying into a shaky, undercapitalized league.

“They fell in love with the idea of owning a team,” he said. “Dan was a little less focused on the team. Ozzie reminded me of a schoolyard player who got picked eighth in the game but still loved it.” 

The team’s announcer, fresh from Syracuse University, was Bob Costas. The Spirits were lucky to draw a few thousand fans to home games and once announced a crowd of 848, said Costas, who believed the number was closer to 400. The zenith of the Spirits’ history was defeating the defending champion Nets in the 1975 playoffs before losing to Kentucky in the next round. 

“It was like winning a championship,” Costas said. “I remember Ozzie and Danny running through the locker room and into the showers, just like a couple of kids on a frolic.” 

Nearly four decades later, the Silnas are recalled for a savvy deal that continues to enrich them. But not all of their business moves have been so lucrative. They were victims of Bernard L. Madoff’s massive fraud. Daniel Silna told Forbes last year that they lost all that they had invested with Madoff, but would not say how much. In lawsuits against the Silnas, the trustee for the victims of Madoff’s Ponzi scheme have said that the Silnas, relatives, family trusts and two corporate entities collected $24 million in fictitious profits

.

After the hearing Thursday, a lawyer for the Silnas declined to comment or allow his clients to be interviewed

Daniel Silna and Donald C. Schupak, the lawyer who negotiated the TV deal with the old A.B.A. teams, had listened to arguments over whether two 36-year-old documents contained language that would let the Silnas collect even more money from TV sources not yet created in 1976. 

They showed little emotion as Preska, the judge, sparred with a lawyer for the N.B.A. She gave the league more time to make its case and urged both sides to settle. But her comments seemed to indicate that she was inclined to side with the Silnas, two brothers who might be the savviest owners the N.B.A. never had.

 

50K

No, I did not recently run 31.1 miles [although I did run at least 5K this morning]; rather, you may have noted that the counter on the right side of this page recently went past 50,000.  Yes, I know that some folks get 50,000 visits per day - but they usually write about interesting or controversial stuff!!  And yes, I know that some of those 50,000 visits were from spammers, before I put the kibosh on that by requiring a word verification before making a comment.  Also, this will be the 431st post, so it won't be a real long time until that hits 500.  Remember that you can aggregate posts by clicking on the category labels - I sometimes use it to watch/listen to music.  And speaking of music, I will throw one in here - not particularly relevant other than some folks think blogging is crazy :-)

I remember when, I remember I remember when I lost my mind
There was something so pleasant about that place  
Even your emotions have an echo in so much space
And when you're out there without care  
Yeah, I was out of touch  
But it wasn't because I didn't know enough  
I just knew too much
Does that make me crazy?  
Does that make me crazy?  
Does that make me crazy?
Possibly
And I hope that you are  
Having the time of your life  
But think twice  
That's my only advice
Come on now, who do you  
Who do you, who do you, who do you think you are?
 Ha ha ha, bless your soul
You really think you're in control?
Well, I think you're crazy  
I think you're crazy  
I think you're crazy  
Just like me
My heroes had the heart  
To lose their lives out on a limb  
And all I remember Is thinking, 
I want to be like them
Ever since I was little  
Ever since I was little It looked like fun  
And it's no coincidence I've come  
And I can die when I'm done
But maybe I'm crazy  
Maybe you're crazy  
Maybe we're crazy  
Probably

GIANT HERBIVOROUS FISH!!

Discovered near Sunshine Creek, about 100 yards from our place.  Initially it seemed obvious that it is a Steelhead, but then I noted that it looked more like a 20 foot Muskie.  We  need some exert opinion here - I asked evolutionary biologist Jerry Coyne to weigh in, since this is obviously intelligently designed and is a special creation!  Additional opinions welcome.....

IT'S ALL ABOUT ME

Now that I have your attention, I am copying below Our Monthly Featured Runner for March, 2013, on the Evart, Michigan 4th of July 5K Race website.  This year was the second annual Walk/Run, and once again I finished second in my age group - need to train harder for next year.  Probably should more precisely say that I need to train for next year - I have been battling a bit of plantar fasciitis for a few months and did not really get to prepare properly for the race.  Of course the good news is that there are not too many runners in my age group!!

Our Featured Runner for March is Doug Swartzendruber.  At the 2012 Evart 4th of July 5k Doug was 66 years old and finished second in the 60 and over age group in a time of 29:47.  As a semi-retired college teacher, Doug is either traveling the world for Pepperdine University or at home in Boulder, Colorado where he trains at high altitude.  As one of the fittest cities in the United States, and one of the main centers of running activity in the country, Boulder offers Doug plenty of opportunity to stay in shape.

Doug began running “a little over 30 years ago,” but his primary sport has always been basketball. When he was in high school Doug played for the New Paris (Indiana) Cubs, a school about the same size as the school in the movie HOOSIERS.  Doug took up running as an activity in itself because of a bet with his brother-in-law.   “While recovering from a holiday meal, my brother-in-law and I thought we had better go for a run.  We were not particularly successful and decided that a challenge was in order.  My brother-in-law took it seriously and quickly became one of the top runners in the region, and I pretty much kept playing basketball.”  Doug has continued to run off and on as his schedule permits and has maintained his fitness level so well over the years that he still plays basketball regularly and holds his own against players 30 years younger.

Doug credits running as the activity that has helped him control the weight gain that naturally occurs with advancing age.  He has not had to change his diet much in order to accomplish this.  Doug says that his extended family has quite a few heavy folks and that he consciously tries not to go down that path.  At this time Doug runs several days a week and walks on most of the other days.  Though Boulder is blessed with many, many runners, Doug usually runs alone.  He doesn’t “mind running alone” but has, in different situations, routinely run with a small group of close friends.  Running on trails is Doug’s favorite workout.  He particularly enjoys running on the Barr Trail (Pikes Peak), the Garden of the Gods in Colorado Springs, or on Mt. Sanitas in Boulder, describing these runs as a combination of a “good workout and an adventure.”

Doug’s personal record for 5k is 18:49 and for 10k “just under 40:00.”  Doug has run several marathons.  He has run the incredibly tough Pikes Peak Marathon where the Ascent (half marathon) is considered to be about equal in time to a regular marathon.  His best Ascent time is 3:42.  Doug also did the round trip on Pikes Peak in slightly under 7 hours, and has also run the Las Vegas Marathon and Grandma’s Marathon in Duluth, Minnesota, both in the 3:50’s. 

Doug plans to make the journey from Colorado to Evart again next 4th of July to run our race. He says that Evart is “a great place to visit and the 4th of July 5k is one of the most enjoyable” events he has done,” even though “it was a tad hot” last year.