December 2014

1. Medical Innovators: What makes a great medical innovator?: David J.A. Jenkins, FRSC

2. Science for the public good: Andrew Miall, FRSC

3. Electrochemical treatment (ECT) of Cancerous Tumours: Ashok K. Vijh, FRSC

 
1. Medical Innovators: What makes a great medical innovator?: David J.A. Jenkins, FRSC
Co-Authors: Viranda H. Jayalath MSc, Vivian L. Choo, Arash Mirrahimi, Kristie Srichaikul, Laura Chiavaroli, Russell J. de Souza, John L. Sievenpiper, Stephanie Nishi, Cyril W.C. Kendall

David JenkinsOne of the fallouts of the Industrial Revolution was an increased desire among Western nations for standardized testing and uniform curricula to train the engineers, draftsman and technicians on which the economies of industrialized nations depended. The need to train technicians remains as obvious now as it was in the 19th century when W.S. Gilbert, with tongue‐in‐cheek, extolled the value of “the pass examination of the institute” (in the Gilbert and Sullivan comic opera, “H. M. S. Pinafore”). During the latter part of the 19th century and for much of the 20th century, traditional universities resisted this push, valuing discovery for hiring and promotion purposes over teaching, from which much of the funding to run these institutions was derived. However, medicine with its rapidly growing body of basic science and large financial clout has helped to bring in standardized tests and examinations throughout the university curricula, especially in the basic sciences, and so elevated the importance of teaching. Nevertheless, there remains a lingering debate over the value of education versus teaching: education emphasizes the development of each individual student’s potential based on the student’s aptitude and interests, in contrast to teaching, where the teacher programs pupils with a standard slate of facts and formulae and the ability to recognize the appropriate situations for their use.

Governments and official bodies side with the teaching concept for the effective programming of their industrialized populations. The argument quoted is that a technically skilled workforce is urgently needed in this increasingly mechanized/electronic age. Nowhere more obvious is this requirement than in medical education where uniform high standards of performance are the expectation. That the practitioners of medicine should be uniformly excellent and trained with extreme rigor to enhance their excellence would appear obvious in the face of the exponential growth of basic scientific knowledge that underpins decisions affecting life and death. Much has been written about the ideal methods for medical student selection and the teaching processes to be used that ensure maximum knowledge retention. To a large extent, the focus has been on the examination with answers that are either right or wrong as the driver to enforce the learning of facts and processes.

However, what is largely absent from the debate is the question of exactly what is a medical education for. Is it to effectively enable application of pre‐existing technical knowledge, or is it to discover new “cures”? Do these two functions go hand‐in‐hand or do they require different skill sets and ways of thinking, and hence different approaches to selection and training?

We wish to address this question through an assessment of the lives of the great innovators, defined as those who have changed the practice of medicine over the past 3 centuries. If they had applied to medical school today, would they have met current medical school entrance requirements? This question is very relevant now that the MCAT is being updated, 87 years after it was initially developed at the George Washington Medical School as the Scholastic Aptitude Test for Medical Students. This test’s original intent was to reduce the rate of medical school drop‐outs.

A brief glance at past innovators suggests that the paths that led to the great discoveries are varied, and that uniformity (at a high level), although the appropriate standard for routine medical practice, may not be the hallmark of medical innovation (or innovation in any field).

We therefore propose to assess the lives of ~100 great medical innovators spanning the last 3 centuries since the beginning of the Age of the Enlightenment. What was the nature of the education of great innovators, their sources of inspiration, the support they obtained, their mentors, setbacks, barriers, and how they overcame them? Was recognition instant or itself something of a struggle?

Medically-qualified Fellows of the Royal Society of Canada, selected at random, will be invited to form a 12‐member jury to judge who the great innovators in medicine were over the last 300 years. Fellows, the Jurors, will be provided with a tentative list to modify as they see fit and invited to add names to or subtract names from the list. To maintain approximately 100‐110 names on the list, jurors will be asked to delete the same number of names as they would wish to add. This process will not be iterative, a simple majority decision to add or subtract a name will be sufficient.

Data on  lives of these innovators will be extracted from the literature by 2 independent reviewers and placed under specific “headings”, depending on the interest to be studied, with any disagreement settled by consensus. Each innovator will be scored based on the mean of the individual component headings (each “heading”, rated on a scale of 1‐4: excellent; adequate; no data; not satisfactory). In the case of the MCAT, all‐ round excellence is required to guarantee medical school entry. We realize that for many the appropriate data may not be found in the primary sources to be used, and that this approach may favor those with more interesting careers or for whom acclaim came during their lifetime resulting in the generation of more early life biographical material.

We see a number of manuscripts derived from various assessments of these data. Furthermore, considerable controversy is inevitable due to the necessarily subjective nature of the assessments, incomplete or inadequate data, and the scope and breadth of this undertaking. However, even if it achieves little more than to stimulate debate on innovation, the exercise will have been worthwhile.

We plan to send the draft of the first manuscript to all members of the Jury to determine whether any would wish to be a coauthor and possibly contribute further to the manuscript. As is customary, the Principal Investigator will be the final arbiter of changes to the manuscript.

The list of the 100‐110 innovators will be published as part of the first manuscript and act as a resource for all who wish to use such data, in addition to the original team, for further publications.

We do not view this list as the absolutely definitive list of the top innovators but rather those who made important and generally recognized individual contributions as judged by a respected and impartial jury of medical scientists.

We will solicit Fellows’ interest in participating by e‐mail. If within 2 weeks of receiving this e‐mail, no response is received or, for those who initially show interest but are unable to complete and return their list within a further 4 weeks, we shall assume that there is a lack of time or interest, apologize for having further wasted their time, and make a replacement selection at random from the list of Fellows remaining.

We hope this endeavor is seen as useful with implications not only for medical education but education in general.


2. Science for the public good: Andrew Miall, FRSC

Andrew Miall

During my service on the Alberta Environmental Monitoring Panel in 2011 there were two particular issues that occupied a considerable amount of discussion time. Firstly there was the question of who should be responsible for monitoring the Athabasca River Basin for the possible contaminating influence of the Oil Sands operations? And, secondly, why had existing water monitoring programs received so much criticism, whereas the air-quality work that was being done was being almost universally applauded? The first question is all about who owns the environment and the second question, as we discovered, has a lot to do with the nature of science, and how it is carried out and put to use for the public good.

That last expression, the public good, carries a great deal of implied meaning. The environmental health of the Athabasca region is ultimately the concern of all Canadians, with the health of the local residents, including several sizeable First Nations communities, taking priority. This is what government is supposed to be all about: the public good. Which took us to the second-order question, which government? Municipal, provincial or federal? It became clear that the federal government and the Alberta government had separate but interlocking responsibilities, reflecting the history of environmental regulation and the federal-provincial separation of powers and accountabilities. Only the senior levels of government, not the corporate sector, nor NGOs, can ensure the health of the environment, although the user-pay concept also became clear to us, meaning that those who profit from operations that cause environmental damage must build the cost of management and clean-up into their business plans and be able to provide the necessary funds to cover these costs.

A much broader question is, what else should the government be responsible for to maintain the public good? There has been considerable political debate in recent years about the downsizing of the science functions in government laboratories, and arguments heard that much of what they do is better done at universities. But this brings in (or should, if we want to have a proper debate about the public good and not about politics) the significance of our second question, the nature of science and how it is best put to good use.

It would seem to me that the regular monitoring and collection of some kinds of basic data, such as weather documentation and forecasting, the regular collection of social and economic indicators, the continuing well-being of essential national commodities including air and water, the safety of food and drugs, and the safety and proper functioning of our transportation systems, are essential functions of government, which is why government downsizing may be cause for concern. Are we, as a nation, doing the essential things? I would maintain that the overall ecological health of the environment, including fish and wildlife, are part of this essential government work, and I would add geological mapping, which provides basic background information on resources, soils, groundwater, and so on.

But is some science better done at universities? Or can it be trusted to the corporate sector? On the Alberta Environmental Monitoring Panel we addressed this question, and the nature of the water and air monitoring work then underway in the Athabasca region helped us to answer this question. Water quality work was currently being carried out by an industry-funded organization largely staffed by secondment from the corporate sector, together with some junior provincial employees. There was very little government oversight, few of the staff had received any specialized training, laboratory analytical functions were largely contracted out, and none of the product was independently evaluated. As a result, nobody trusted the output, and it took independent scientific research at universities to point out the deficiencies. By contrast, the air-quality monitoring work was headed up by a former senior federal air-quality scientist. His team had developed several new monitoring techniques by carrying out some basic research, some in-house and some in consultation with specialists in various North American research Process of Scienceinstitutions. They had developed their own protocols and procedures for real-time air testing such as, for example, following an industrial incident at a processing plant.

It became clear that the necessary science includes a spectrum of activities. Field monitoring of environmental indicators can be a fairly low-skilled, technical operation so long as the protocols are well defined. However, deciding what needs to be done and how to do it can involve original science, in other words, project research. The potential division of labour became clearer to us (see diagram). Long-term, repetitive, technical work is best done by government which should be able to guarantee stable, long-term funding, whereas original research is typically a shorter-term operation and can be done by outsourcing to university-based research teams, or by bringing in short-term research personnel, such as a graduate student carrying out thesis research, or a post-doctoral fellow. Building and maintaining relationships between government laboratories and universities is the best way both to keep the monitoring work going and to ensure that it is scientifically up to date. Some research functions (analytical services, personnel) need to be retained within government laboratories, to ensure continuity over the long term, to help skilled personnel build meaningful careers devoted to public service, and most important of all, to ensure that senior officials have available the best in-house advice to offer to the government, as required.

The corporate sector, however well-intentioned, should not be trusted with operations that unavoidably affect their bottom line, unless ways can be found to offset the primary function of the corporation, which is to make money for its owners. Some industry organizations such as the Canadian Oil Sands Innovation Alliance (COSIA) may meet this condition, but it is ultimately not answerable to the public, and the continuation of the organization as an effective manager of corporate environmental work depends largely on the continuing goodwill of senior management.

Our conclusion was that essential environmental work needed to be independent of government and the corporate sector, and the subsequent actions of the Alberta and federal governments indicate that they have accepted this recommendation. On the more general question of science for the public good: well-funded laboratories with enough resources and flexibility to work with universities and other research institutions would seem to be essential components of the government landscape in a modern, developed society.

3. Electrochemical treatment (ECT) of Cancerous Tumours: Ashok K. Vijh, FRSC
Co-authors: Simone Chevalier, Michel Ladouceur, Yosh Taguchi

Ashok VijhElectrolysis of cancer tumours (or rather of the saline fluid component of the tumour) can provide a “novel” approach for the electrochemical treatment (ECT) of cancerous tissues. Hydrogen evolution at the cathode causes cavitation (and hypoxia) of the tissue and chlorine evolution at the anode causes its bleaching, both thus contributing to tissue necrosis. Changes in pH caused by these electrode reactions lead to electroosmotic movement of water from the anode to the cathode, causing dryness of the tissue in the anodic area, and, its oedema near the cathode area, contributing further to the necrosis(1-3).

Recently, the team at our Institute (Hydro-Quebec Institute of Research) and a large number of collaborators in the Faculty of Medicine of McGill University have reported a pioneering study (4) on the electrochemical treatment of prostrate cancer.  We wish to introduce the Fellows of the Academy of Science to this approach that has involved collaboration between electrochemists, physicists, electrical engineers, surgeons, oncologists, veterinary scientists and molecular biologists (4).  First, we give below a brief introduction to the theory of this approach to killing solid cancerous tumours.


Phenomenology and Mechanism

The electrochemical system involved in ECT may be schematically depicted as: 
Image 1

 

 

 

The total applied voltage, V, in this system is constituted by various components and can be written as
 

(1)
where  , is the reversible potential between the hydrogen and oxygen electrode (=1.23V) or between the hydrogen and the chlorine electrode (=1.36V);is the anodic overpotential during ECT and its minimum expected value will be ~0.3V, for conditions of detectable oxygen or chlorine evolution;  is the cathodic overpotential during ECT and its minimum expected value will be ~0.1V, for conditions of detectable hydrogen evolution; IR is the resistive drop in the tumour (note: its value during open circuit measurement with a high-input impedance voltmeter will be 0V; however, during electrolysis involving the passage of high currents, IR would become significant, e.g. ~1-10V);   pH is the voltage drop between the anode and the cathode due to the pH gradient in the tumour; at the end of ECT, it can change up to 10pH units (i.e. 0.590V); R is the gas constant, F is the Faraday and T is the temperature in degrees Kelvin.

Thus at the beginning of ECT with minimal D.C. (Direct Current) current (~1mA) and uniform pH (neutral) between the anode and the cathode, the required voltage can be as low as 3-4V. Towards the end of ECT (high pH gradient, dry anode-tissue interface and thence high IR), especially with a high current (~100mA) and thence high hanode and hcathode values, the required voltage could begin approaching 15 to 20V.

In a typical tumour ECT, a direct current (d.c.) voltage of 8.5V is applied between two platinum electrodes inserted 3cm apart in a cancerous tissue (e.g. liver tumour), causing a flow of 30mA electrolysis current; this current is made to flow continuously for 69min giving the passage of total charge of 124C (2). More generally, voltages of about 6-10V with currents of 40-100mA are applied to platinum electrodes embedded in the tumour from 1-3cm apart, with electrolysis being carried out for 1-2h with the passage of charge being in the neighbourhood of 100-200C (3). The main observations are as follows:
1.    Water in the tumour migrates from the anode to the cathode caused by electro-osmosis.
2.    The anodic “site” in the tissue becomes strongly acidic and the cathodic site strongly alkaline.
3.    Higher concentrations of Na+ and K+ in the tissue around the cathode (which  also becomes strongly alkaline) are observed; not much change in the concentration of multivalent cations such as Ca2+, Mg2+, Mn2+, Cu2+ and Al3+ occurred during the ECT.
4.    The denaturation of protein is caused by the ECT; haemoglobin is converted to acid haemin around the anode and alkaline haemin around the cathode.
5.    Chlorine and hydrogen evolution are observed at the anode and cathode, respectively; chlorine causes, not unexpectedly, some bleaching of the local tissue whereas hydrogen produced local cavitation.
6.    The cell metabolism and its existing environment are disturbed severely by the electrochemical treatment, causing the destruction of tumour cells rapidly and completely.

Although a number of reactions and events, that may contribute to the destruction of tissue, take place during the ECT treatment, it seems that water transport from the anode to cathode is the fundamental event, together with acidity changes associated with the electrode reactions at the anode and the cathode (2,3).

We note that before the ECT, the initial pH of the tissue is around 7, i.e. neutral or nearly neutral. When the d.c. power is on during the ECT, there are the usual electrolysis events giving the evolution of H2 at the cathode and O2+Cl2 (depending on the single electrode potential of the anode, the proportion of O2 and Cl2 will change; the anodic potential in turn depends on the parameters of electrolysis) at the anode.

Salient Results
Our extensive experimental studies on prostrate cancer tumour Xenografts in nude mice, in collaboration with the team at McGill University, are available in reference (4).  The salient features are as follows:

Electrochemical Therapy (ECT) is attractive, as it relies on locally-induced reduction-oxidation reactions to kill tumour cells.  Its efficacy for prostrate cancer was assessed in human PC-3 and LNCaP tumour xenografts growing subcutaneously in nude mice (n-80) by applying two stainless steel vs. 4 Platinum-Iridium (Pt-Ir) electrodes to deliver current densities of 10 to 35 mA/cm2 for 30-60 min.  The procedure was uneventful in 90% of mice.  No difference in tumour vs. body temperature was observed.  Changes at electrode-tumour junctions were immediate, with dryness and acidity (pH 2-3) at the anode and oedema and alkalinity (pH 10-12) at the cathode.  This was accompanied by cellular alterations, found more pronounced at the cathode.  Such acidic and alkaline conditions were cytotoxic in vitro and dissolved cells at pH>10.  In mice, tumour destruction was extensive by 24 h with almost undetectable blood PSA (prostrate specific antigen) (LNCaP model) and covered the whole tumour surface by 4 days.  ECT was most efficient at 25-30mA/cm2 for 60 min, yielding longest recurrence free survival and higher cure rates, especially with 4 Pt-Ir electrodes. ECT is thus a promising option to optimize for organ-confined prostrate tumours (4).

References
(1)    B. Nordenström, “Electrochemical Treatment of Cancer”, Ann. Radio, 28, 128-129 (1985); idem, “Survey of mechanisms in Electrochemical Treatment of Cancer”, Eur.J. Surg.Suppl.. 574, 93-109 (1994).
(2)    A.K.Vijh, “Phenomenology and Mechanisms of Electrochemical Treatment (ECT) of Tumours”. In Modern Aspects of Electrochemistry, Vol. 39, Eds. C.G. Vayenas, R.E. White and M.E.Gamboa-Adelco, Springer, New York (2006), Chapt. 5, pp. 231-274.
(3)    A.K. Vijh, “Electrochemical Effects in Biological Materials: Electroosmotic Dewatering (EOD) of Cancerous Tissue as the Mechanistic Proposal for the Electrochemical Treatment of Tumours”, J.Mater. Sci.: Materials in Medicine, 10, 419-423 (1999).
(4)    F.L.Cury, B. Bhindi, J. Rocha, E. Scarlata, K. El Jurdi, M. Ladouceur, S. Beauregard, A.K. Vijh, Y. Taguchi, S. Chevalier, “Electrochemical Red-Ox Therapy of Prostrate Cancer in Nude Mice”, Bioelectrochemistry, in the press (2014).