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Discusses discoveries and trends in natural product pharmacology (botanical supplements, OTCs, and prescription drugs), drug safety, and academic career development in the biomedical sciences.
David J Kroll
21 posts
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- December 2, 2008
- 08:08 AM
- 1,828 views
Chris Patil (ouroboros) on the Campisi lab's new PLoS Biology paper: cellular senescence, protein secretion, and the aging/cancer paradox
by David J Kroll in Terra Sigillata
I've kept a passing interest in senescence (cellular, not personal) over the last 20 years or so because I've always felt that attempts to increase longevity in a multicellular organism would also increase the risk of cancer (more seasoned readers may recognize this as the Hayflick phenomenon of replicative cellular senescence first identified in 1965). As a newly-minted PhD looking for postdoc fellowship, including in a yeast lab focused on aging, I thought that harnessing the senescence pathway might be a valuable strategy for treating cancer.
Yesterday's PLoS Biology paper from Coppé et al., builds on a newly-described cellular response that throws a wrench in that simplistic idea. Cells induced to undergo senescence with DNA-damaging agents exhibit a secretory phenotype, termed the senescence-associated secretory phenotype (SASP), whereby molecules involved in inflammation and metastasis are released into the local environment. In younger individuals, this mechanism could prevent the development of cancer but in older individuals could increase the risk of cancer. In cancer, for example, therapies that causes cellular growth arrest and senescence may be of limited utility unless those senescent cells are removed. My takehome message from this paper is that we may have to rethink the benefit of cancer therapies that are cytostatic. Read the rest of this post... | Read the comments on this post...... Read more »
Jean-Philippe Coppé, Christopher K. Patil, Francis Rodier, Yu Sun, Denise P. Muñoz, Joshua Goldstein, Peter S. Nelson, Pierre-Yves Desprez, & Judith Campisi. (2008) Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biology, 6(12). DOI: 10.1371/journal.pbio.0060301
- January 29, 2008
- 08:01 AM
- 1,698 views
Male dietary supplement for bodybuilding and sexual performance associated with metastatic prostate cancer cases
by David J Kroll in Terra Sigillata
If you read nothing else: Men with prostate cancer should avoid any dietary supplement containing testosterone (or anything that sounds like it) or that offers claims of increased virility, sexual performance, or increased muscle mass.
Consumption of a herbal/hormone dietary supplement has been linked to two cases of aggressive prostate cancer as reported in a paper in the 15 January issue of Clinical Cancer Research (abstract free; full paper paywalled) . The observations and follow-up studies were conducted by urologists at the University of Texas Southwestern Medical School and... Read more »
S Shariat, D J Lamb, R G Iyengar, C G Roehrborn, & K M Slawin. (2008) Herbal/Hormonal Dietary Supplement Possibly Associated with Prostate Cancer Progression. Clinical Cancer Research, 14(2), 607-611. DOI: 10.1158/1078-0432.CCR-07-1576
- October 24, 2008
- 03:55 PM
- 1,657 views
Missed opportunity: how many of the placebos "prescribed" were herbal or non-botanical dietary supplements?
by David J Kroll in Terra Sigillata
"Prescribing 'placebo treatments': results of national survey of US internists and rheumatologists," is the title of a newly-published article in the 23 October issue of BMJ (British Medical Journal). The full text article and PDF are available for free at the time of this posting.
In this study of 679 US physicians, Tilbert et al. reveal that 46-58% of those responding report regularly using some sort of placebo in their practice. The reason for the range is that questions were asked in a manner that did not use the word, "placebo," but instead took into account:
"Placebo treatment" is an unclear and complicated concept that lacks a standard definition. Placebo treatments include "inert" agents that have little or no pharmacological activity, such as sugar pills and saline injections given to promote positive expectation, and physiologically active agents, such as vitamins or antibiotics, that the physician prescribes solely or primarily to promote positive psychological effects
Dr Jake Young at Pure Pedantry does a superb job covering the article and I encourage you to read his take. Janet Stemwedel, house ethicist, takes me by surprise a bit by suggesting a scenario whereby use of a placebo might be considered ethical.
Since these bloggers wrote about the ethical issues, I am more interested in what kinds of things were suggested by doctors as placebo treatments in that the study was funded in part by the NIH National Center for Complementary and Alternative Medicine (NCCAM). moreover, one of the authors is a relatively well-known, Harvard-affiliated doctor of oriental medicine. Read the rest of this post... | Read the comments on this post...... Read more »
J. C Tilburt, E. J Emanuel, T. J Kaptchuk, F. A Curlin, & F. G Miller. (2008) Prescribing "placebo treatments": results of national survey of US internists and rheumatologists. BMJ, 337(Oct 23 (2)). DOI: 10.1136/bmj.a1938
- February 23, 2009
- 12:02 PM
- 1,652 views
Entheogen and hallucinogen, N,N'-dimethyltryptamine (DMT), identified as endogenous ligand for sigma-1 receptors
by David J Kroll in Terra Sigillata
Thanks to Dave Munger & Co's ResearchBlogging.org, I just found a fabulous neuroscience grad student blogger from Emory University: Laura E Mariani at Neurotypical?
Doctor-to-be Mariani blogged last Monday about a paper in Science where the endogenous ligand of the orphan sigma-1 receptor was identified as the hallucinogen, N,N'-dimethyltryptamine, or DMT. The work originated with the group of Arnold Ruoho and colleagues at the University of Wisconsin's Depts of Pharmacology and Physiology, together with a collaborator at the Isfahan University of Technology in Iran.
As an aside, what blows me away is that the first author on this publication, Dominique Fontanilla, is a graduate student in the UW Molecular and Cellular Pharmacology training program. The funding acknowledgment suggests that she was on an NIH institutional training grant and then scored her own individual predoctoral NRSA from the National Institute on Drug Abuse. It appears that she also has a background in synthetic chemistry that extends back to her Sigma Xi-recognized undergraduate work at Carleton College in Minnesota. If anyone is looking for a stellar postdoc candidate in this field (*cough* DrugMonkey), you'd better get in line now.
Anyway, as a neuroscientist, Laura tells the story far better than I can so you should go to her post to read the details.
Where a natural products cancer pharmacologist gets interested in this story is its intersection with plant-derived medicines - 25% of today's pharmaceuticals can be traced to natural sources, I recognize that the history of my discipline lies in the ethnobotany of indigenous cultures and their religious and ritual use of plant compounds with hallucinogenic effects of other activities in modulating the central nervous system. Hallucinogens used culturally in religious rituals are often called entheogens (loosely translated as "creating god within"). Read the rest of this post... | Read the comments on this post...... Read more »
D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, & A. E. Ruoho. (2009) The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator. Science, 323(5916), 934-937. DOI: 10.1126/science.1166127
- February 2, 2008
- 04:01 PM
- 1,648 views
More on medical geophagy in chimps: montmorillonite clay and the origins of life
by David J Kroll in Terra Sigillata
Readers and colleagues often ask why scientists care to blog, especially given increasing time demands and decreasing research funding. For me, the blog is an opportunity to have discussions with colleagues from diverse research areas all around the world. Quite often, I learn something quite new that I would not normally encounter in my chosen field of cancer pharmacology.
A case in point stems from a reader comment by Dr Italo MR Guedes, a Brazilian soil scientist who writes the blog, Geófagos (Google Translate works well enough unless, of course, you are already fluent i... Read more »
James Ferris, & Gozem Ertem. (1992) Oligomerization of Ribonucleotides on Montmorillonite: Reaction of the 5'-Phosphorimidazolide of Adenosine. Science, 1387-1389. info:PMID/1529338
M Hanczyc. (2003) Experimental Models of Primitive Cellular Compartments: Encapsulation, Growth, and Division. Science, 302(5645), 618-622. DOI: 10.1126/science.1089904
James Ferris. (2006) Montmorillonite-catalysed formation of RNA oligomers: the possible role of catalysis in the origins of life. Philosophical Transactions of the Royal Society B: Biological Sciences, 361(1474), 1777-1786. DOI: 10.1098/rstb.2006.1903
- June 14, 2009
- 11:41 AM
- 1,642 views
Sage advice?: NC to join 13 states in outlawing Salvia divinorum
by David J Kroll in Terra Sigillata
Salvia divinorum (Salvia, Magic Mint) is a plant used for entheogenic purposes by the Mazatec people of Mexico. A relative of the common garden plant "scarlet sage" (Salvia splendens), S. divinorum contains several hallucinogens that include salvinorin A, the first non-nitrogenous agonist known for kappa opioid receptors (KOR).
I had known of salvinorin A since a highly-cited 2002 Proceedings of the National Academy of Sciences paper by Bryan Roth, Richard Rothman and colleagues (full text here). At that time, I had read several anecdotal reports (that I cannot locate now) that the hallucinations rendered by Salvia ingestion or smoking were so bizarre and disturbing that 8 of 10 first-time users declared they would not use it again. Hence, I never really thought that Salvia would become much of a public health problem or be embraced by recreational hallucinogen enthusiasts.
However, just Google "Salvia" and take a gander at the ads on the right sidebar.
I'm still not certain if Salvia is enough of a public health problem to warrant legislation but we just learned this week that North Carolina will join 13 other US states in criminalizing possession and use of the plant or extracts made thereof:
A bill that would outlaw the psychoactive herb Salvia divinorum has passed the state Senate, prompting consumers to rush to buy it legally.
Senate Bill 138, sponsored by Sen. Bill Purcell, D-Laurinburg, would prohibit the "manufacture, sale, delivery, or possession" of Salvia divinorum. The law calls for a fine for the first two offenses and misdemeanor charges for subsequent offenses. Purcell stressed that North Carolina's law would not be as strict as those of 13 states, which made Salvia divinorum a drug on par with heroin. Read the rest of this post... | Read the comments on this post...... Read more »
Roth, B. (2002) Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences, 99(18), 11934-11939. DOI: 10.1073/pnas.182234399
- August 13, 2008
- 09:02 AM
- 1,632 views
Methadone for cancer (no) and cancer pain (yes)
by David J Kroll in Terra Sigillata
Most people know of methadone as a long-term substitution therapy for people addicted to heroin, morphine, or other similar drugs called opiates or opioids. A good, free full-text description of methadone maintenance therapy (MMT) can be found in the 15 June 2001 issue of American Family Physician.
Now, in the 1 August 2008 issue of Cancer Research, Claudia Friesen and colleagues at the University of Ulm report that methadone can kill leukemia cells in culture and reverse acquired resistance to other drugs like doxorubicin (Adriamycin). Press reports to this effect appeared at the beginning of the month in ScienceDaily and Scientific American online.
However, Karl Schwartz of Patients Against Lymphoma and Lymphomation.org dialed us up for comment on the most complete description of this paper that appeared in ScienceNOW Daily News in an article by Rachel Zelkowitz entitled, "Relief from Rehab?"
Karl wrote primarily because a contributor to one of his patient discussion boards said that methadone would never be developed as a cancer drug because:
Methadone joins a long list of molecules that have shown activity in the lab but will never see the light of day as drugs as either they were not patentable in the first place (naturally occuring molecules) or their patient has expired.
Here was my response to Karl to pass along to his commenter: Read the rest of this post... | Read the comments on this post...... Read more »
C Friesen, M Roscher, A Alt, & E Miltner. (2008) Methadone, Commonly Used as Maintenance Medication for Outpatient Treatment of Opioid Dependence, Kills Leukemia Cells and Overcomes Chemoresistance. Cancer Research, 68(15), 6059-6064. DOI: 10.1158/0008-5472.CAN-08-1227
- April 12, 2008
- 11:01 AM
- 1,627 views
"You got lead in my marijuana. . ."
by David J Kroll in Terra Sigillata
". . .you got marijuana in my lead."
Two great tastes that do not go great together.
A concise but fascinating medical detective story appears in the letters of this week's (10 Apr 2008) issue of the New England Journal of Medicine (free full text at the time of this posting.).
An astute group of physicians at Leipzig Hospital in Germany noted a local surge of young people presenting with classic symptoms of lead poisoning - 29 patients aged 16 to 33 over the course of 3-4 months. Patients exhibited symptoms ranging from abdominal cramps, nausea, and "Burton's lin... Read more »
Franziska Busse, Leyla Omidi, Alexander Leichtle, Michael Windgassen, Eyleen Kluge, & Michael Stumvoll. (2008) Lead Poisoning Due to Adulterated Marijuana. New England Journal of Medicine, 358(15), 1641-1642. http://content.nejm.org/cgi/content/full/358/15/1641
- October 19, 2009
- 01:43 PM
- 1,471 views
Dietary supplement adulteration with prescription drugs: Is it really a problem of DSHEA?
by David J Kroll in Terra Sigillata
Rebecca Skloot, journalist, University of Memphis writing professor, and author of the upcoming book, The Immortal Life of Henrietta Lacks (pre-order here), just brought to my attention this commentary by Dr Pieter Cohen in the New England Journal of Medicine entitled, "American Roulette -- Contaminated Dietary Supplements."
In the commentary, Dr Cohen remarks upon the epidemic of adulteration of herbal and non-herbal dietary supplements with undeclared prescription drugs or unapproved drugs:
In July 2009, the FDA expanded its alert to include 75 tainted weight-loss products that contain undeclared medications. Analyses by the FDA have found the stimulant sibutramine in weight-loss supplements at levels amounting to three times the maximum recommended daily dose. Several of the unapproved anorectic ingredients detected in dietary supplements have been linked to serious adverse events: rimonabant to suicide and fenproporex to both addiction and suicide. The inclusion of furosemide and other diuretics in some of these supplements may result in dehydration and hypokalemia; other contaminants, such as benzodiazepines and antidepressants, mask the side effects of stimulants while conferring an increased risk of dependence. Some weight-loss pills, including many from Brazil, combine multiple medications in a single formulation. . .
. . .Recently, unscrupulous manufacturers have made it more difficult for the FDA to detect undeclared ingredients by incorporating pharmaceutical analogues into their products. Analogues are created by modifying the original chemical structure of a compound -- for example, by adding a hydroxyl group. It is suspected that these analogues are developed to evade detection by the FDA, making the products more difficult to regulate, and to reduce the risk of patent-infringement lawsuits. A recent analysis showed that more than half of 26 supplements marketed for the enhancement of sexual function contained analogues of phosphodiesterase type 5 inhibitors. Read the rest of this post... | Read the comments on this post...... Read more »
Cohen, P. (2009) American Roulette -- Contaminated Dietary Supplements. New England Journal of Medicine, 361(16), 1523-1525. DOI: 10.1056/NEJMp0904768
- October 2, 2009
- 07:02 PM
- 1,371 views
Destigmatizing depression among medical (and graduate) trainees
by David J Kroll in Terra Sigillata
The Clinical and Translational Science Network (CTSciNet) section of Science Careers has just published a superb article by Karyn Hede on the issues of depression precipitated during the rigors of medical education. Hede is a freelance writer in Chapel Hill and has contributed before to Science Careers, particularly with this article on the challenges of women MD-PhDs and another on why so many of us have crappy interpersonal and lab management skills.
The current article focuses primarily on the medical profession given its placement in the clinical/translational section but these issues are true for PhD trainees as well:
Depression among medical trainees is well-documented. A recent large-scale survey of medical students and residents at six major medical schools revealed that one in five have mild to severe depression, a rate 15% to 30% higher than the general public. One out of every 17 even said they had thought about suicide. The study, reported in the journal Academic Medicine in February, brought to the fore the problem of depression among students immersed in the rigors of medical training.
"Certainly, medical school, residency, Ph.D. training, all those kinds of advanced degrees are set up with a lot of expectations, and by and large the people that are doing them are driven," says Deborah Goebert, a psychiatrist at the University of Hawaii, Manoa, and lead investigator of the study. These stressors, along with lack of sleep, financial concerns, and family pressures, can push people into an episode of clinical depression, she says. Read the rest of this post... | Read the comments on this post...... Read more »
Hede, K. (2009) Destigmatizing Depression. Science. DOI: 10.1126/science.caredit.a0900118
- December 4, 2009
- 06:02 PM
- 1,239 views
How to report in vitro cancer studies: maitake mushroom extract doesn't "fight cancer"
by David J Kroll in Terra Sigillata
Earlier this week, I saw one of the best treatments of a misinterpreted story that has me thinking about how all news outlets should report in vitro laboratory studies.
Only thing is that it didn't come from a news outlet.
It came a brainwashing site run by those medical socialist types - I am, of course, speaking of the UK National Health Service and their excellent patient education website, NHS Choices.
You may recall reading in the popular dead-tree or online press that investigators from New York Medical College in Valhalla published in British Journal of Urology International about maitake mushroom extract killing bladder cancer cells. The most widely cited reports came from the UK Daily Mail by Tamara Cohen entitled, "Mushroom 'shrinks cancer tumours by 75 percent,'" and "Cancer Cure: Mushrooms Can Shrink Tumors," by Jo Willey of the UK Daily Express.
Well, NHS Choices took a look at the study and detailed how the mushroom extract was only used on bladder cells in culture. Throughout their review and in the conclusion that follows, they specifically took to task the story in the Daily Express: Read the rest of this post... | Read the comments on this post...... Read more »
Louie, B., Rajamahanty, S., Won, J., Choudhury, M., & Konno, S. (2009) Synergistic potentiation of interferon activity with maitake mushroom d-fraction on bladder cancer cells. BJU International. DOI: 10.1111/j.1464-410X.2009.08870.x
- February 9, 2010
- 09:02 PM
- 1,167 views
What's the buzz?: Synthetic marijuana, K2, Spice, JWH-018
by David J Kroll in Terra Sigillata
My field of natural products pharmacology was founded by indigenous cultures who recognized that plants and fungi contain compounds that produce altered states of consciousness, leading to their most common use in religious ceremonies. While we may most often associate these naturally-occurring drugs with hallucinogens, the arguably most common natural product in use today is marijuana or Cannabis sativa. Indigenous to India and China, Cannabis has been the subject of increasing decriminalization worldwide due in part to its clinical, medicinal effects in multiple sclerosis, cancer, and AIDS.
Over the last few months, I've seen reports of a so-called "synthetic marijuana" being sold on the internet with stories most commonly coming from England and Germany and, in the US, from Kansas, Missouri, and Arizona. In fact, the St. Louis Post-Dispatch reports today that a bill has been brought before the Missouri House Public Safety Committee seeking to add this product to the state's list of illegal drugs.
I became intrigued as to why anyone would go through the trouble of making a synthetic marijuana when it is so readily cultivated worldwide.
So what is it? Read the rest of this post... | Read the comments on this post...... Read more »
Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, & Martin BR. (2000) Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. Drug and alcohol dependence, 60(2), 133-40. PMID: 10940540
- June 18, 2010
- 09:02 AM
- 1,008 views
HBCU medical schools at Morehouse, Meharry, and Howard lead "social mission" metric - Annals of Internal Medicine
by David J Kroll in Terra Sigillata
Reuters Health Executive Editor and proprietor of the excellent Embargo Watch blog, Ivan Oransky, was kind to alert me to this topical paper that appeared in Monday's issue of Annals of Internal Medicine entitled, The Social Mission of Medical Education: Ranking the Schools.
To the credit of the Annals, the full text of the primary article is currently free. An accompanying editorial is behind the subscription wall.
The study was conducted led by Fitzhugh Mullan with Candice Chen, MD, Gretchen Kolsky, and Michael Spagnola from the Department of Health Policy at the George Washington University and Stephen Petterson, PhD from The Robert Graham Center was supported with funding from the Josiah Macy Foundation.
The authors developed a metric called "social mission" to rate US medical schools on their responsiveness to three major issues they cite as facing medical schools and policymakers: "an insufficient number of primary care physicians, geographic maldistribution of physicians, and the lack of a representative number of racial and ethnic minorities in medical schools and in practice." Attempts to increase physician distribution to underserved populations and/or geographical areas have had mixed success. My anecdotal experience is a typical case: a program to recruit high school students from rural areas to medical schools gave me a chance to work while a postdoc with an exceedingly bright high school student from a sheep ranching family in rural northwestern Colorado. She went to the University of Colorado Medical School and did a vascular surgery fellowship at Emory University, finally returning to Denver. In her case, it's not just that a country kid got a taste for the big city; she told me long ago that she couldn't be a doc in her rural town because the one that was there hardly ever got a chance to take a day off or vacation. So - yes - being a vascular surgeon in the city gives her more flexibility than being a primary care physician in the country.
And with all of the baited breath that awaits annual magazine rankings of all educational institutions, this passage in the Introduction notes that such rankings fail to take into account these major issues that impact underserved communities:
"Medical schools, however, are the only institutions in our society that can produce physicians; yet assessments of medical schools, such as the well-known U.S. News & World Report ranking system, often value research funding, school reputation, and student selectivity factors over the actual educational output of each school, particularly regarding the number of graduates who enter primary care, practice in underserved areas, and are underrepresented minorities."
To evaluate the "social mission" rating of US medical schools, the authors developed a metric based on three criteria: percentage of graduates who become primary care physicians, work in health professional shortage areas (HPSAs) as defined by the Health Resources and Services Administration, and are underrepresented minorities based on an Association of American Medical Colleges (AAMC) definition (African-American, Hispanic, and Native-American).
These criteria were then used to rank medical schools based on following the career path of 60,043 physicians in active practice who graduated during 1999 to 2001 using data from the American Medical Association Masterfile.
The three historically Black medical colleges obviously skewed the data for the underrepresented minority score so the authors, "normalize[d] the skewed distribution, we calculated the standardized scores without these 3 schools, then reincluded them by using the calculated mean value and SD."
Still, these three schools - Morehouse in Atlanta, Meharry in Nashville, and Howard in Washington, DC - ranked as the top three schools in social mission. Perhaps not surprisingly is that the major top-tier USN&WR medical schools in the northeastern US ranked in the bottom 20 of the rankings, with Duke, Stanford, and Johns Hopkins the bottom three - the only time you will ever see these schools at the bottom of any ranking.
You can view Table 1 for yourself to see if there are any surprises to you. I was pleasantly surprised to see Kansas, Michigan State, Iowa, and Oregon Health & Sciences among the top 20. Conversely, I was surprised to see Texas A&M in the bottom 20.
The key point of my post here, and perhaps the primary reason Ivan Oransky referred the article to me knowing of my interests, is that we see here a specific and essential role of historically Black colleges and universities. HBCUs not only education underrepresented populations, but they then served underrepresented communities - not just with regard to race but also with regard to, in this case, providing primary care to areas with a shortage of health professionals.
Of course, not everyone is happy with a social mission in medicine. The first commenter on the paper, William S. Aronstein, in a screed entitled, Fundamentally Wrongheaded, seems to state that medicine is above this and responsiveness to diverse and underserved populations is more the realm of public health. Beginning with, "This is one of the most disturbing articles I have ever seen in the Annals," it's worth a read if for nothing else than this gem taking a swipe at the corresponding author:
To a large degree, I suspect that the folk-marxist ethos in which from his other voluminous writings at least Fitzhugh Mullan appears to operate may account for the article's emphasis on population-based public health rather than the actual practice of medicine.
Any wagers as to whether he graduated from one of the bottom 20 schools?
Mullan F, Chen C, Petterson S, Kolsky G, & Spagnola M (2010). The social mission of medical education: ranking the schools. Annals of internal medicine, 152 (12), 804-11 PMID: 20547907... Read more »
Mullan F, Chen C, Petterson S, Kolsky G, & Spagnola M. (2010) The social mission of medical education: ranking the schools. Annals of internal medicine, 152(12), 804-11. PMID: 20547907
- March 16, 2010
- 11:02 PM
- 975 views
What's the difference between HeLa and HeLa S3 cells? Part III: Theodore "Ted" Puck, MD, and the first clonal isolation of human tumor cells
by David J Kroll in Terra Sigillata
This post is the third in a series on the origin and history of HeLa S3 cells. The first post details how I came about to ask this question when launching my independent research laboratory. The second post details the life and careers of the legendary physician-scientist pioneer, Dr. Florence Rena Sabin.
Today, we take up a discussion where we will finally learn the origin of HeLa S3 cells, complete with original literature citations.
A recap
We left our previous discussion with the final and still-productive years of Dr. Florence Rena Sabin. After graduating from Johns Hopkins Medical School in 1900, Dr. Sabin embarked on a nearly 40-year career at Hopkins and now-Rockefeller University, elucidating the developmental origin of the lymphatics and antibody responses to tuberculosis and training a generation of physician-scientists. She was truly a pioneer, becoming the first woman to be appointed to faculty at Johns Hopkins, their first female full professor, the first female full member (full prof-equivalent) at Rockefeller, and the first woman invited to join the National Academy of Sciences.
Upon her retirement in 1938, she returned to her native Colorado to join her sister, Mary. Near the end of World War II, she was tapped by the Colorado governor to lead a committee that would address existing public health issues in the state that would have to be solved while absorbing a large number of men and women returning from the war to civilian life. Although in her 70s, Sabin was highly effective and shared the 1950 Lasker Award for Public Service. In 1951, the University of Colorado School of Medicine honored her with the dedication of the Florence R. Sabin Research Building for Cellular Biology.
That same fall was a sharp contrast for the Virginia-born tobacco farmer, Henrietta Lacks. She, too, was spending time at Johns Hopkins. But in this case, it was because her life was being cut short at age 31 from an aggressive case of cervical cancer.
In the months before her death on October 4, 1951, cells derived from her tumor had been successfully cultured in the Hopkins laboratory of Dr. George Gey. These cells were called HeLa, so named for the first two letters of Henrietta Lacks's names, and took a place in history as the first human cell line to be continually propagated in culture. They would live on in laboratories not only at Hopkins but around the world, including that of Colorado geneticist, Dr. Theodore "Ted" Puck.
From bacteria and bacteriophage to human genetics
Ted Puck came to Colorado a few years earlier. His 1994 autobiography in the American Journal of Medical Genetics tells you far more than I can here. Here he shares his situation before the Sabin Building became available:
On my arrival in Denver in 1948, I first became aware of the magnitude of the responsibility which I had undertaken. The total contribution of the medical school to the budget of the Department of Biophysics was $5,000 per year. All the rest was to come from grant funds. I was the only faculty member in the newly formed department which was required to present a major course to the medical students, to institute graduate training leading to the Ph.D. degree in biophysics, to conduct a post-doctoral training program for
M.D.'s and Ph.D's, to conduct a significant research program in biophysical science, and to raise the necessary grant funds for those activities. An old unused lumber room in the basement of the medical school was cleaned out, painted, and transformed into offices and a laboratory for the department. A native of Chicago, Dr. Puck did both his undergraduate (1937) and graduate training (1940) at the University of Chicago. His doctoral mentor in Physical Chemistry was Dr. James Franck, a physicist who had shared the 1925 Nobel Prize in Physics. Puck's PhD work focused on the atomic transitions in chlorophyll necessary for photosynthesis.
At the end of his PhD, World War II had begun and Puck remained at Chicago as a research associate to work with Dr. O.H. Robertson on the potential of polyethylene vapor to kill airborne microorganisms for the Commission on Airborne Infections of the Office of the Surgeon General of the Army. The relevance of this project during wartime was exemplified by Puck publishing five papers in Science and six papers in J Exp Med on this work. While on this project, he worked with Phil Marcus, a master's student who would later join him in Colorado.
After the war, Puck did formal postdoctoral work on the genetics and kinetics of bacteriophage interactions with bacteria at the California Institute of Technology with Max Delbrück, who later shared the 1969 Nobel Prize in Physiology or Medicine with Alfred Hershey and Salvador Luria (yes, Luria broth). Delbrück was originally a physicist and obviously contributed to Puck's early enthusiasm for "applying physicochemical approaches to problems of biology."
Clonal populations of mammalian cells
Puck's work with phage impressed upon him that studying human genetics would require that similar techniques be developed to manipulate human cells. Because HeLa cells were taken from the tumor of Henrietta Lacks, they contained several populations of cancer cells. Puck and his then-graduate student Phil Marcus and Steven Cieciura were trying to figure out how to grow clonal populations from single cells.
Establishing "clones," or colonies that grew from a single cell, was first accomplished with mouse L929 cells in 1948 by Katherine Sanford and Gwendolyn Likely in the laboratory of Wilton Earle at the National Cancer Institute (JNCI 1948; 9:229). Earle is credited with the isolation and propagation of the first continuously cultured cell line, mouse L cells. This heterogeneous population was originally isolated in October 1940 as an outgrowth of subcutaneous connective tissue from mammary fat pads excised from a 100-day-old C3H/An mouse (JNCI 1943: 4:165). The cells acquired a malignant phenotype in culture and could produce sarcomas when injected back into mice.
Just as an aside, Earle's group acknowledged the cell culture work of Lewis (Science 1935; 81:545) and Fischer and Davidsohn (Nature 1939; 143:436). The 1935 paper from Warren H. Lewis was his presidential address to the American Association of Anatomists where he reported the continuous culture of rat sarcoma cells for 2-4 years, although no photographs or formal data were shown. Albert Fischer and Fanja Davidsohn reported carrying mouse adenocarcinoma cells for up to 12 years. But while both Lewis and Fischer had lengthy careers, I'm unable to find any follow-up literature on these respective cell lines. Hence, the most continually documented work of Earle's group is most deserving of the "first" designation.
Recognizing that L cells came from a heterogeneous cell population, the Earle group worked on isolating single cells and propagating clonal cultures from those cells. At the time, the composition of cell culture medium was not fully refined and attempts at growing out cells from small populations were unsuccessful. Earle's group recognized that using medium "conditioned" by growing cells produced diffusible factors that encouraged growth of small cell populations. To produce single clones, Earle's group painstakingly transferred single L cells to small capillary tubes together with a small amount of conditioned medium, producing the first clonal cultures of immortalized mammalian cells. The most widely studied of these is clone 929, known more properly as NCTC L-929 cells, the first immortal mammalian cell line offered by ATCC, appropriately as CCL-1.
The capillary approach to cloning seemed too cumbersome to Puck and he wanted to develop a method that was more analogous to isolating clonal bacteria cultures from distinct colonies that had grown from individual cells. Moreover, quantitative assessment of cellular sensitivity to drugs or radiation would not be possible using the capillary method. Because he was interested in human genetics, he decided to work with HeLa cells. As cited below in references 1 and 2, he obtained his original HeLa culture from the George Washington Carver Foundation of historically black institution, Tuskegee University in Alabama, rather than from George Gey at Hopkins who had originally isolated the cells.
From Hopkins to Minnesota to Alabama to Colorado
The role of Tuskegee in the polio treatment and vaccination effort ... Read more »
Puck TT and Marcus PI. (1955) A rapid method for viable cell titration and clone production with HeLa cells in tissue culture: the use of X-irradiated cells to supply conditioning factors. Proceedings of the National Academy of Sciences, 41(7), 432-437. DOI: 10.1073/pnas.41.7.432
Puck TT, Marcus PI, and Cieciura SJ. (1956) Clonal growth of mammalian cells in vitro: growth characteristics of colonies from single HeLa cells with and without a "feeder" layer. Journal of Experimental Medicine, 103(2), 273-284. DOI: 10.1084/jem.103.2.273
Puck TT, & Fisher HW. (1956) Genetics of somatic mammalian cells: I. Demonstration of the existence of mutants with different growth requirements in a human cancer cell strain HeLa. Journal of Experimental Medicine, 104(3), 427-434. PMID: 19867118
Sato G, Fisher HW, and Puck TT. (1957) Molecular growth requirements of single mammalian cells. Science, 126(3280), 961-964. DOI: 10.1126/science.126.3280.961
- February 12, 2008
- 05:01 PM
- 893 views
Beware of alternative medicine sites offering breast cancer advice
by David J Kroll in Terra Sigillata
There are responsible ways to present medical information and irresponsible ways. I will say at the outset that I have no ethical issues with discussing complementary and alternative medicine with cancer patients, as long as the information presented is based in fact.
So it was no surprise to me and actually quite alarming to read a recent report suggesting that while only 1 in 20 breast cancer websites offer incorrect information, CAM-focused websites were 15 times more likely to contain inaccurate or incorrect information. The study to which I refer will appear in the 15 March i... Read more »
Elmer Bernstam, Muhammad F Walji, Smitha Sagaram, Deepak Sagaram, Craig W Johnson, & Funda Meric-Bernstam. (2008) Commonly cited website quality criteria are not effective at identifying inaccurate online information about breast cancer. Cancer. DOI: 10.1002/cncr.23308
- March 21, 2011
- 07:56 AM
- 832 views
Molecular Target for Thunder God Vine
by David J Kroll in Terra Sigillata
This post appeared originally last Friday for my monthly gig at Science-Based Medicine. Thunder god vine may not be a useful herbal medicine but the compounds isolated from it are fascinating – if not as medicines, then most certainly as laboratory tools. Nature Chemical Biology recently published an article where a research team from Johns [...]... Read more »
Titov, D., Gilman, B., He, Q., Bhat, S., Low, W., Dang, Y., Smeaton, M., Demain, A., Miller, P., Kugel, J.... (2011) XPB, a subunit of TFIIH, is a target of the natural product triptolide. Nature Chemical Biology, 7(3), 182-188. DOI: 10.1038/nchembio.522
- May 11, 2011
- 08:02 AM
- 674 views
Fingolimod (Gilenya; Novartis) for Multiple Sclerosis
by David J Kroll in Terra Sigillata
A very well-written review of an orally-active drug for multiple sclerosis has just appeared in the April 25th issue of the Journal of Natural Products, a publication of ACS in conjunction with the American Society of Pharmacognosy. The review, Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite, is co-authored [...]... Read more »
Strader, C., Pearce, C., & Oberlies, N. (2011) Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite. Journal of Natural Products, 74(4), 900-907. DOI: 10.1021/np2000528
- December 12, 2010
- 10:41 PM
- 665 views
Not Miley Cyrus: A small human trial of salvinorin A
by David J Kroll in Terra Sigillata
Some interesting news came out last week regarding Salvia divinorum, the hallucinogenic mint plant, whose primary active constituent, salvinorin A, is a highly selective kappa opioid receptor agonist that is remarkable as a nonnitrogenous psychoactive compound. However, my interest had nothing to do with the widely-discussed video at TMZ.com showing actress and singer-songwriter Miley Cyrus doing a [...]... Read more »
Johnson MW, Maclean KA, Reissig CR, Prisinzano TE, & Griffiths RR. (2010) Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum. Drug and alcohol dependence. PMID: 21131142
- October 14, 2010
- 08:14 AM
- 591 views
BMJ meta-analysis: Reboxetine “an ineffective and potentially harmful antidepressant”
by David J Kroll in Terra Sigillata
Thanks to Ben Goldacre and Vaughan Bell, I learned this morning of an interesting paper in British Medical Journal that analyzed substantial unpublished data from Pfizer on their norephinephrine reuptake inhibitor antidepressant, reboxetine. Sold in Europe as a pair of enantiomers under the trade name Edronax, reboxetine’s US application was rejected by the FDA in [...]... Read more »
Wieseler, B., McGauran, N., & Kaiser, T. (2010) Finding studies on reboxetine: a tale of hide and seek. BMJ, 341(oct12 1). DOI: 10.1136/bmj.c4942
- September 7, 2010
- 07:06 AM
- 549 views
What’s the buzz?: Synthetic marijuana, K2, Spice, JWH-018
by David J Kroll in Terra Sigillata
The topic of one of our most popular posts of all time has been the synthetic marijuana products containing JWH compounds, naphthoylindole cannabimimetics synthesized in the 1990s in the Clemson University laboratory of John Huffman. This post first appeared at the ScienceBlogs home of Terra Sigillata on 9 Feb 2010 and gives you some background [...]... Read more »
Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, & Martin BR. (2000) Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. Drug and alcohol dependence, 60(2), 133-40. PMID: 10940540
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