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A natural product of his environment

I’m delighted to have the opportunity to join this outstanding group of medical professional bloggers in adding my natural products angle to the application of science-based medicine.  With the exception of Dr. Gorski, who holds MD and PhD degrees, I believe I am the first “only a PhD” to be invited to SBM.  However, I have spent much of my career training, and training with, physician-scientists; so enthusiastic am I about the special qualities of the physician-scientist that I married one (or, rather, she chose to marry me, truth be told.).  Conversely, I view the invitation to write here as a responsibility in representing what my fellow basic scientists bring to bear on discussions of the scientific arguments for and against modalities classified broadly as complementary and alternative medicine or integrative medicine.

Why write about herbal medicines and natural products?

I have long been interested in bringing objective scientific information to the public, perhaps as early as my college years in bars while visiting my working-class hometown of Wallington, NJ, or while shooting darts with Philadelphia cops across from my undergrad apartment.  Any chat I’d have with an old buddy or bartender about drugs, cancer, or drugs and cancer would invariably draw some interest from fellow patrons overhearing my discussions.  These were usually followed by, “Hey, aren’t you Frankie Kroll’s boy?,” or “I’ve heard the government is hiding the cure for cancer – do you have any inside dope on that?”

Why I mention this story on a somewhat more scholarly blog than which I am accustomed is because I am convinced that regular people without letters after their names are starved for authentic scientific and medical information that affects their lives.  But all too often, people other than health professionals are the ones providing that information, many of whom are trying to hawk some dubious health and wellness product.  This is why I write for the public and have been engaged in public science education since my first faculty appointment at the University of Colorado School of Pharmacy in 1992.

But let’s step back a moment and introduce ourselves properly: I am a PhD cancer pharmacologist who has been studying chemotherapeutic drugs derived from natural sources since beginning graduate school in 1985.  Cancer chemotherapy is particularly rich in the application of natural products to therapeutics.  Plants have given us the microtubule polymerization inhibitor, vincristine, as well as the microtubule depolymerization inhibitor, Taxol/paclitaxel. Marine organisms have given us the precursor to cytosine arabinoside, or ara-C, to treat leukemias.  The underappreciated world of microorganisms has been an exceptionally rich source of chemotherapeutics including doxorubicin and daunorubicin, bleomycin, mitomycin C, and even the antileukemic asparagine-degrading enzyme, L-asparaginase.  These naturally-occurring compounds have then in many cases been subjected to medicinal chemistry manipulations to produce semi-synthetic derivatives with improved potency and selectivity, longer duration of action, lack of tumor cell cross-resistance with similar compounds, and better solubility for parenteral dosing.

With this background, I came into medical and pharmacy education with a deep appreciation of nature as a source of chemical diversity for targets not just in cancer, but in other therapeutic areas as well. But in 1994-1995, my pharmacy students became notably more vocal in asking questions in our Pharmacology & Therapeutics class about these herbal medicines that were increasingly marketed in retail pharmacies where many were doing their internships.  Since I already knew a bit about naturally-sourced prescription pharmaceuticals, they asked if I could start adding some lecture content on this topic.  Unappreciated by me at the time was the fact that these requests coincided with passage of the 1994 Dietary Supplement Health and Education Act (DSHEA) which many of you know permits herbal supplements to be sold in the U.S. without proof of safety or efficacy as long as direct disease treatment claims were not made.  Pharmacoeconomics colleagues told me that herbal medicines and non-botanical dietary supplements were the biggest product growth area in retail pharmacy during those mid-1990s.

How does a conventionally-trained scientist become versed in herbal medicines?

I certainly knew about natural products outside of cancer and one can usually kick off a lively lecture of natural products talking with young college students about CNS-active recreational plants like marijuana, hallucinogenic mushrooms, and the art and practice of toad-licking.  But herbal medicines were a bit out of my bailiwick although I was in fact hired in place of Colorado’s then recently-retired herbal medicine and pharmacology professor, Dr. Glenn Appelt, who together with his wife, Jennifer, authored several treatises on the Hispanic folk medicines of the San Luis Valley in the southcentral part of the state.

So as not to trouble the Appelts in their retirement to the Alabama Gulf Coast, I was lucky to be able to turn Dr. Ara DerMarderosian, Professor of Pharmacognosy, at my alma mater, the then-Philadelphia College of Pharmacy and Science.  Dr. DerMarderosian has been studying herbal medicines for over four decades and joined the PCP&S faculty during the year of my birth.  His pharmacognosy course never fit into my curriculum when I was there but when I contacted him, he was extremely generous with articles, books, and other resources.  Hence, I began my self-education on the pharmacology of herbal medicines: the fact and fiction behind the therapeutic potential of complex plant mixtures.

Do we wish to turn back the clock 200 years?

Readers should keep in mind that herbal medicines take us back to a scientific period that precedes the 1800s.   Most physicians are well-aware of the story of British doctor and botanist, William Withering, who adopted a country remedy for dropsy (pulmonary edema due to congestive heart failure)  composed of 20 herbs including the foxglove, Digitalis purpurea and other species.  Depending on the time of year that foxglove was harvested, it could act as a remedy or induce significant nausea and vomiting.  We now know the plant contains the cardiac glycosides, digoxin and digitoxin, whose abundance varies under growth conditions and time of harvest.  Pure digitoxin was not isolated until about 1875 by the German scientist, Oswald Schmiedeberg, regarded as the father of pharmacology and mentor of John Jacob Abel, the so-called American father of pharmacology.

However, the concept of reproducible and predictable treatment with an herbal medicine really began in 1805 when the German pharmacist and chemist, Friedrich Wilhelm Sertürner, made similar observations about opium extract from the poppy, Papaver somniferum. Sertürner believed that the “active principle” could be isolated from the crude latex of ripe flower heads and was the first to isolate the alkaloid he called morphine, after Morpheus, the Greek god of sleep.  Opium extract also contains other active compounds such as codeine and papaverine.

I mention all of this background not because I am simply an enthusiast of the history of my discipline.  Instead, I wish to stress that today’s practice and marketing of herbal medicine takes us backwards over 200 years.  When plant medicines were all we had, underdosing and overdosing were common because we had not yet achieved the scientific skills or knowledge to effectively isolate known quantities of physiologically-active constituents.

Today’s herbalists and purveyors of alternative medicines will frequently argue that 1) whole herbs possess a synergy that is missing when one isolates and uses pure constituents, or that 2) the mixture is safer than pure compounds because one compound can reduce the side effects of another without compromising its therapeutic efficacy.  In the former case, synergy has actually be described in the scientific literature but the cases are extremely rare.  These few cases are scientifically fascinating and worthy of discussion in future SBM posts.  The safety attributed to herbal mixtures is more likely due to the fact that any active constituent lacks the abundance or oral bioavailability to have any effect, pharmacological or toxicological.  I have yet to see any convincing peer-reviewed publication that convincingly demonstrates efficacy and reduced side effects in the same herbal mixture.

In fact, as I learned more about herbal medicines as used today, I became increasingly disappointed that so few of them were actually backed up by clinical trials.  But among these disappointments are a few gems that hold promise for therapeutics that I will discuss in future posts.

From newbie to expert?

But what I was not prepared for was the rapidity with which I became an “expert” in herbal medicines once I began teaching this information to my pharmacy and medical students in 1995.  Offers for speaking engagements came in from around the state and then around the country for pharmacy, nursing, and medical continuing education; media requests began to pile up from local radio to national television.  I was taken aback because I had spent at least ten years in my area of cancer research without being even mistaken for an expert.  Yet within two years of teaching about herbal medicines I was suddenly a widely sought speaker and commentator.  Because I did not trust even myself with the title of “expert,” I developed a degree of mistrust for, or at least a cautious eye toward, anyone the media considers a medical expert.  In fact, these experiences and concerns seeded my current interests and involvement with the University of North Carolina at Chapel Hill’s MS Program in Medical & Science Journalism.

I’ve since worked quite hard to develop and refine my interests in herbal medicine education and have even progressed to the point of including this work in my NIH-funded research.  I’ll speak more later about my subsequent experiences in other posts but I was fortunate most recently to work with the late Dr. Monroe Wall and now-83-year-old Dr. Mansukh Wani who first isolated Taxol/paclitaxel from the Pacific yew tree, Taxus brevifolia. Using the technology available almost 40 years ago, they solved the chemical structure of this complex molecule comprised of 11 chiral centers, a tremendous accomplishment even with today’s tools. Their lesser-known discovery, camptothecin from the Chinese tree of joy, Camptotheca acuminata, gave rise to two semi-synthetic derivatives that have become FDA-approved chemotherapeutic drugs.  When I co-authored my first peer-reviewed publication in 1987 on the use of camptothecin to map sites of transcriptional activation in the Drosophila hsp70 gene promoter, little did I know that I would one day have the honor of working beside the co-discoverers of this compound.

There are many other areas I hope to address as my tenure at SBM proceeds.  The drug interaction potential of herbal products is a major issue of public safety, especially with St. John’s wort.  The cherrypicking of in vitro studies by herbal marketers as “scientific proof” for their remedy’s effectiveness is so rampant that even a paper from our research group is used to improperly promote a milk thistle product. Finally, I also hope to combat the misperception that natural products cannot be patented so there is no financial incentive for them to ever be developed as drugs.

I’ve had the pleasure and accidental good fortune of interacting with some tremendous leaders in the area of natural products chemistry and pharmacology to the point that I sometimes feel a bit like Forrest Gump.  I am grateful that their encouragement and mentoring has brought me to a position where I can periodically discuss these issues with the engaging contributors and readership of Science-Based Medicine.

Posted in: Herbs & Supplements, Medical Academia, Pharmaceuticals, Science and Medicine, Science and the Media

Leave a Comment (15) ↓

15 thoughts on “A natural product of his environment

  1. Joe says:

    David,

    Welcome. I have long been interested in this subject; but only to the extent that I noted that herbal products were not adequately studied and were, ultimately, contaminated drugs (to the extent that they were active, at all). It is much easier to point to the foundational problems with, for example, chiropractic, naturopathy and homeopathy. Several of the authors, here, have observed that herbs represent the sCAM approach that is likely to produce useful results.

    Recently, I have become interested in learning more specifics about herbs. I look forward to your posts.

  2. wertys says:

    Welcome to the blog David. Your particular expertise will be invaluable around here, let me tell you !

  3. Harriet Hall says:

    This “short history of medicine” has been widely quoted:

    2000 B.C. – Here, eat this root.
    1000 A.D. – That root is heathen. Here, say this prayer.
    1850 A.D. – That prayer is superstition. Here, drink this potion.
    1940 A.D. – That potion is snake oil. Here, swallow this pill.
    1985 A.D. – That pill is ineffective. Here, take this antibiotic.
    2000 A.D. – That antibiotic doesn’t work anymore. Here eat this root. . .

    Welcome aboard! I’m particularly looking forward to your debunking the “no financial incentives” myth. Also, I’d be very interested to hear your opinion of The Natural Medicines Comprehensive Database.

  4. Jules says:

    So nice to have someone with a science background for once!

  5. overshoot says:

    Synergy and safety of whole natural medicines? My favorite is white willow bark: the tannins make it practically impossible to overdose on the salicylate.

  6. Oldfart says:

    What I’d like to know is how investigators know where to look to start with? There are literally millions of possible plant extracts and, out of these, a few good medicines have been discovered. Just how did those investigators happen to pick just the right line of investigation? From old witches tales? Or did they have a much more logical approach? Or did they try a shotgun approach? For every useful herbally derived medicine, are a thousand not useful? That sounds expensive. How many do we miss?

  7. Thank you very much for all of your kind wishes and words of welcome. I hope to meet your expectations.

    Oldfart, plant medicines used by indigenous peoples have been studied quite exhaustively in the field of ethnobotany, popularized by the late Richard Schultes (see his classic, “The Plants of the Gods: Their Sacred, Healing, and Hallucinogenic Powers”) and his student Mark Plotkin (see “The Shaman’s Apprentice”) – these are examples of work by a couple of a few hundred scientists who have taken this approach.

    The NCI-supported research group to which I belong is looking for novel chemical diversity wherever it can be found: plants, filamentous fungi, cyanobacteria, etc. Random, novel plant samplings (performed under the UN Convention on Biological Diversity and other nation-specific regulations) and selected culturing techniques are only modestly costly, as is the preparations of organic and aqueous extracts from these sources. Some use MS techniques to examine directly the compounds in the crude extracts while others use crude bioactivity-directed fractionation where the assays employed classic, cell-based endpoints as well as biochemical assays against novel targets. In the meantime, the pharmacognosy chemists use a process of dereplication to rule out plants and compounds that may have been studied before using compound databases and a terrific natural product literature database (NAPRALERT) developed by Prof Norman Farnsworth at Univ of Illinois at Chicago.

    So, there is some selectivity applied to this seemingly random approach before the most costly and time-intensive work begins: the purification of bioactive compounds and the solution of their structure. Depending on the natural products chemist and the abundance of the compound(s) in the source material, this can take anywhere from a couple of months to more than a year. That is why we are extremely careful in our prioritization scheme. Even a 0.5-5% hit rate produces far more work for the chemists than we have hands in the lab. Yes, we may miss something, but we keep all extracts and annotated database information for our growing library to test later for any new disease targets that may be elucidated in human pathophysiology.

    Using the examples of my senior mentors, Dr. Wani and the late Dr. Wall, their two discoveries, camptothecin and taxol, led to the identification of two novel biochemical mechanisms for antitumor activity. As the fruits of the Human Genome Project are realized, someone must also be broadening our diversity of small molecules that may selectively target these gene products. Natural products can be at least a starting place for contributing to this chemical diversity.

    If anyone cares to read more about the discoveries of camptothecin and taxol, my colleague Nick Oberlies and I prepared a 2004 review article for the Journal of Natural Products outlining the accomplishments of Drs. Wall and Wani and their contributions of bioactivity-directed fractionation to the discovery of therapeutic natural products:

    http://pubs.acs.org/cgi-bin/sample.cgi/jnprdf/2004/67/i02/html/np030498t.html

  8. Welcome! Great first post and great followup in the comments! Interesting stuff!

  9. David Gorski says:

    I can see that Dr. Kroll will quickly become a popular figure here, given his area of expertise.

  10. Joe says:

    David K,

    The two figures (timelines) in your JNP paper are rather illegible, even when electronically magnified. Are they available in a better format? If not, I’ll survive.

  11. Joe,
    Apologies for the delay. Try these two PDFs for better graphics for the timelines of the discoveries:

    http://www.rti.org/brochures/taxol_timeline.pdf
    http://www.rti.org/brochures/camptothecin_timeline.pdf

  12. Joe says:

    Excellent, thanks!

  13. Lemonade Lily says:

    David

    Just found your post – and looking forward to more….esp. on synergy.

    I am studying herbal medicine and am questioning everything I am learning as I come from a scientific background. You have touched on a couple of my ‘questions’ in your post, viz. herbalists use the ‘synergy’ word rather frequently and I cannot find much in the literature to back this idea up, and they also say that herbs are ‘safer’ than isolated pharmaceuticals.

    Re. synergy, clearly there are ‘interactions’ but surely these could just as easily be deleterious? Interesting you say ‘whole herbs’. Herbalists generally use teas and tinctures….these are extracts of whole herbs….

    Yes…I am looking forward to more posts…..

    LL

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