Category: Drug Discovery

Failure as a Necessary Step in Drug Development (Tip of My Hat to David Kroll)

The Forbes magazine has an impressive line-up of columnists; I follow many of those who write on the sciences and healthcare-related topics. One of them is Dr. David Kroll, a pharmacologist by profession and passionate, long-time science communicator. His column yesterday had especial interest for me; in it, David took the example of Dr. Derek Lowe—a pharmaceutical industry scientist who’s also a prolific and erudite blogger—who was apparently his inspiration for starting his own blog, and mentioned an intriguing thing Dr. Lowe had said during a Question and Answer session with Karen Weintraub for STAT News (quoting from David’s column including original links, below):

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2015 Nobel to Traditional Chinese Medicine Expert is a Win for Evidence-based Pharmacognosy

Yesterday, on October 5, 2015, one half of the Nobel Prize in Physiology or Medicine was awarded to scientist and pharmaceutical chemist Tu Youyou (alternatively, Tu Yo Yo, 屠呦呦 in Chinese), for her discovery of the anti-malarial Artemisinin. (The other half went jointly to William C. Campbell and Satoshi Ōmura, for their discovery of a novel therapy for roundworm infection.)

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Tuberculosis, the global scourge, and a new drug-design strategy

Every year on March 24, World Tuberculosis (TB) Day is observed to commemorate the discovery of the etiological agent of this disease, the bacterium Mycobacterium tuberculosis by noted German physician and microbiologist and Nobel Laureate, Robert Koch (1843-1910). The infection occurs via inhalation of the air-borne bug; therefore, the disease primarily affects the lungs, but it can spread to other parts of body as well, such as the central nervous system (brain and spinal chord), bone, and internal organs. If adequate treatment is not instituted (and sometimes despite therapy), a person with active TB disease will likely die. In the United States, in 2010 (the latest year for which statistics are currently available), of the nearly nine hundred deaths in which TB was suspected, TB was confirmed in roughly 4 out of 10 cases, and a total of 569 people died from TB. Globally, in 2012, an estimated 8.6 million people contracted TB, of which 1.3 million died.

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PLOS One paper on Anthelmintic Efficacy of Gold Nanoparticles: My Questions to Authors

Every so often, some paper happens to grab my attention for various reasons. As I read the paper, often I have questions. Not all of those questions, unfortunately, can be easily submitted for answers. In recent times, one such paper was published earlier this month in PLOS One. The great benefit of the Open-Access model of PLOS is that it allows a reader to ask questions directly of the authors. This level of engagement is very laudable, especially to someone like me who has an interest in the communication of scientific facts.

This 2014 PLOS One paper by Kar et al., titled: Anthelmintic Efficacy of Gold Nanoparticles Derived from a Phytopathogenic Fungus, Nigrospora oryzae, stands on two premises, both of which are interesting to me as an infectious-disease researcher, and as someone interested in ethnobotany and ethnopharmacology, the medicinal uses of natural products.

  1. Enzymes and/or other bioreactive molecules released by certain organisms (a phytopathogenic fungus in this case, Nigrospora oryzae) into the culture medium have the ability to reduce gold chloride into elemental gold nanoparticles.
  2. The elemental gold nanoparticles have antihelminthic properties against certain soft-bodied parasites (cestode worm Raillietina sp. in this study), in that these nanoparticles appear to destabilize their ultrastructure, disrupting the parasitic physiological functions and causing paralysis and death to the worm.

This interface between elemental chemistry and biochemistry has been known for a while; various enzymes and other bioreactive molecules of microbial origin have been successfully used to generate nanoparticles of elements such as gold and silver. Nevertheless, I still find the idea fascinating, rather attention-worthy, and ‘cool’. In the paper, the authors have convincingly and painstakingly demonstrated and characterized the generation of gold nanoparticles employing multiple techniques.

However, it was regarding the second part – the claim of anti-helminthic efficacy of the gold nanoparticles – where I found I required some further clarifications in order to understand the authors’ work more comprehensively. The journal being PLOS One, the opportunity was afforded to me to put in a set of questions for the authors in the comments. I am using the medium of my blog to keep an additional record of the questions about the scientific principles, that bothered me.

The authors mentioned in the discussion:

It is noteworthy to mention that the culture filtrate had no effect on Raillietina sp.

To me, this seems to indicate that the demonstrated vermicidal (worm-killing) activity was entirely due to the gold nanoparticles. The authors have devoted an introductory paragraph to – and provided historical and modern references in support of – the idea of clinical efficacy of gold nanoparticles. The ultrastructural electron micrographs in the results showed the effect beautifully, and the additional demonstration that four key worm enzymes were being inhibited provided a biochemical basis for the physiological effect.

However, this raised three major questions to which I couldn’t find the answers in the text of the paper:

  1. What is the exact mechanism by which the gold particles exert their physiological functions on the worms? In other words, how do these nanoparticles interact with the surface (known as ‘tegument’) of the worm? Is the interaction purely physical, or physico-chemical, or biological? Are they taken up – actively or passively – by the worm through its surface?
  2. Will this vermicidal effect be same regardless of the process of the generation of gold nanoparticles, or, for that matter, the particular enzyme/biomolecular reducing agent used? In other words, if the gold nanoparticles are generated by some purely chemical means, or if the culture filtrate of some other microbe (different from Nigrospora oryzae) is used as the source of the reducing agent that converts gold chloride to gold nanoparticles, will the effect on the worm remain the same?
  3. Is this action a specific property of elemental gold, or its nanomolecular form? In other words, will nanoparticles similarly generated from other noble and non-noble elements work in the same way? If not, what is/are the special characteristic(s) that confer(s) the vermicidal ability upon gold nanoparticles?

I hope, dear reader, that you are following my train of thought. Quite apart from these three questions, my confusion about the physiological action of the gold nanoparticles depicted in the paper was compounded because the authors also mentioned:

Changes in the tegumental architecture on treatment with gold nanoparticles suggest that the phytopathogenic fungal products bring about permeability changes in the tegument of the cestodes.

I found it really difficult to reconcile this statement with the earlier one. What exactly is the role of the fungal products in killing the worm (beyond production of the gold nanoparticles)? The authors clearly mention in the methods that “… produced gold nanoparticles were separated out from the culture filtrate by centrifugation […] and the settled nanoparticles were washed thrice with de-ionized water.” I think it’s safe to assume that fungal products were adequately washed off the gold nanoparticle preparation at this point. So, where is the interaction between the worm and phytopathogenic fungal products at the later, ‘treatment’ step?

This brought me to another fundamental question that bothered me for a different reason. If there is, indeed, none, i.e. no interaction between the fungal products per se and the worm, what was the necessity to devote two whole paragraphs in the introduction, to the purported use of natural products against helminthic worms in ‘traditional’ medical systems? How exactly is that information relevant to this otherwise-interesting paper? (This is my question to the Editor and the reviewers as well, because I think this question should have been asked at the level of peer review prior to publication.)

As I mentioned in the beginning, I have an abiding interest in medicinal uses of natural products. History of medicine is replete with grand examples of medicinal properties of substance derived from plants and microbes. However, there are many layers of difference between “having a medicinal property” and “being a medicine” – the main difference being rigorous testing and understanding of the mechanisms of action of such substances, both in vitro and in vivo, without which they cannot be elevated to the high standards expected of pharmacoactive agents used to treat medical conditions. Sadly and unfortunately, many quack peddlers of pseudoscience tend to ignore this aspect altogether, and start pushing substances of doubtful provenance as ‘cures’ under the convenient guise of “traditional medicine”, which often involves untested or poorly tested herb- or plant-extracts, drawn from folklore and myths. It behooves those of us, who care about public health and scientific integrity, to make an effort to examine all such claims critically, seek evidence, and debunk them if the empirical evidence is lacking.

Do watch this space. I shall update if and when I receive answers to my questions from the authors. Meanwhile, if you find something interesting in the paper that I have missed, or if you have answers to my questions, please let me know in the comments.

UPDATE 1: End of February, no answer forthcoming from authors till date. My mistake; on February 28, the authors did respond at the PLOS ONE site after the original paper. The essence of the response is that they are doing further studies. I shall await their new results eagerly.

  • Kar PK, Murmu S, Saha S, Tandon V, & Acharya K (2014). Anthelmintic Efficacy of Gold Nanoparticles Derived from a Phytopathogenic Fungus, Nigrospora oryzae. PloS one, 9 (1):e84693 PMID: 24465424

Exciting Science: Oncolytic Viruses (Review published in PLOS Pathogens)

Science is awesome. But I expect you already knew that, dear readers o’mine. In science laboratories across the world, every day dedicated researchers are testing ideas, generating and evaluating hypotheses, critically analyzing observations, and thereby, making significant contribution to the humanity’s attempts to understand in greater depth and detail the wonderful natural world that surrounds us, of which we, along with other living beings and non-living objects, form a part.

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