Lessons from Galvani’s and Volta’s Competitive Spirit

Tyler Shewbert

Luigi Galvani’s experiments testing frog legs to see whether electricity was responsible for muscle contractions was easily reproduced by scientists for decades after his initial experiments. This reliable reproducibility allowed other scientists including Allesandro Volta to derive their own hypotheses behind what was causing the muscle contractions. While the theoretical framework to explain the contractions had not been developed, the results of the experiments sparked the development of electrophysiology and contributed to the development of the battery by Volta. In recent decades within the biomedical field there is a solid theoretical framework for the development of experiments, however those experiments have low rates of reproducibility. This is causing economic damage by increasing rates of failure in drug trials in later stages. Scientific progress relies on discarding failed hypotheses and the development of experiments that allow for reproducibility by others to confirm or deny hypotheses. Modern science can still learn from the competition and mistrust betweeen Volta and Galvani.

Introduction

In the late 18th century Luigi Galvani began experimenting with frog legs. His methods included using the lower half of a frog which had been severed from the body and had exposed nerves. He explored the effects of electricity on muscle movement within the legs. Initially he experimented with external sources of electricity such as Leyden Jars. Electricity induced contractions in the leg muscles of the frogs. He then experimented with atmospheric causes of electricity and found this had little effect. He concluded that the muscle had some sort of intrinsic electricity within it [1]. A scientific contemporary of Galvani, Allesandro Volta, contested Galvani’s explanation that the muscle contractions were due to intrinsic electricity and were instead caused by the metals used in connecting the nerve to the muscle, and that the muscle was simply reacting to the electricity in the metals. Both Volta and Galvani ended up pursuing further experiments in animal electricity to support their own theories [2]. Galvani ended up producing a contraction by connecting the two nerves from each leg together [1]. Volta countered that he could produce electricity by mixing silver and zinc, and that metals were responsible for the contractions, eventually developing the electric battery [1]. Out of Galvani’s experiments came two major breakthroughs: The eventual development of the field of electrophysiology and Volta’s development of the battery [2]. Galvani’s method was simple enough to be reproduced by other scientists. Eusebio Valli could reproduce Galvani’s experiments with the same results as could others [2]. The lack of acceptance of Galvani’s hypothesis of animal electricity was due to Volta’s success with the electric battery and a lack of theoretical framework that could explain the results.

In recent decades, the inability to replicate results has begun to plague the biomedical field, particularly within preclinical research [3]. The ability to attain “robust, reproducible results” is essential to directing the direction of further research [4, 5]. Often the original researcher of a published finding is themselves unable to attain the same results [4]. This has been attributed to a desire for “flashy results” that “ignore the lack of scientific rigor” [4]. It is necessary for scientific results to be efficient and if the majority of preclinical research is not reproducible, the results are inefficient [4]. Galvani’s methods produced reproducible results that allowed science to progress without a strong theoretical framework. Today there is a strong theoretical foundation for which biomedical research is done, but the experimental framework is failing in developing effective and efficient methods for developing experiments which allow for reproducible results.

Results and Discussion

As reported by Begley and Ellis in Nature, clinical trials in onocology have the highest rate of failure when compared to other areas [5]. They attribute the high failure rate not only to the difficulty treating cancer but also to the “quality of published preclinical data”. The effectiveness of drug development relies heavliy on the availiable literature [5]. The problem is that the results of preclinical studies are be taken at face value, and this causes problems later in clincal trials. Amgen studied fifty-three papers that were considered “landmark” studies and found that in only 11% of the cases were the results scientifically confirmed [4, 5]. This has a negative economic as well as a scientific impact. When preclincal studies are used for drug development and there is less than a 50% reproduciblity rate, clinical trials fail [3–5]. This has led to an overall decrease in the rate of success for Phase II clinical trials from 28% to 18% in the years 2008–2010 [3].

Contrast this with Galvani’s work. Volta was able to replicate Galvani’s expirment and by doing so was able to develop hypotheses that enabled him to eventually develop the battery [1, 2, 6]. If Volta had been forced to question Galvani’s methods due to inability to dervive the same result, he would have discarded the Galvani’s expirments, and Volta might not have began exploring the electric relationship between zinc and silver that lead to his development of the battery [1]. Galvani himself was able to further his expirements because of the consistency of his work which eventually led him to fairly accurate conclusions with regards to the conduction of electricity within animals [1, 2, 6]. He was able to develop a hypothesis that the electricity was conducted by means of a watery interior with an oil exterior which was shockingly close to the model developed by Hodgkin-Huxley [2]. If Galvani’s expirement had not produced consistent results it would have not been taken seriosly by himself or his contemporaries. These consistent results allowed Volta to develop an end product in the electric battery that ended up having signifcant economical value and Galvani to suggest there was an “intrinsic” electricity in animal.

Biomedical research is in part driven by the ability to produce tangible economic results. As failure rates of clinical trials increase, the research community could learn some lessons from the distant past in the form of Galvani and Volta competition and practices. There was a fundamental mistrust between Galvani and Volta which caused Volta to check Galvani’s expiriments and Galvani’s theory of animal electricity. Begley and Ioannidis reached a conclusion that “science operates under the trust me model that is no longer considered appropriate in corporate life nor in government” [4]. They state that endorsing the current state of research that is “producing results the majority of which cannot be substantiated” would be erronous. To rectify this, they suggest “rethink[ing] methods and standardization of research practices” so that the focus would not promote the pursuit of studies that might have flash and gain headlines but little substance for further research and economic benefit [4].

The research community would benefit from standards and practices that produced results that could be readily verified by others. This would encourage others to use the solid foundation built upon reliable data for developing further hyprotheses. From Galvani and Volta’s competion two thing can be learned that are applicable to today’s environment. The first is that a solid methodology rooted in reproducible results will spark further expirementation that will have solid results. The second is that a lack of trust among scientists has the benefit of sparking competition to develop solid expiriments to proove one’s own hypotheses.

Outlook and relevance of work

The reproducibility of Galvani’s research contributed to the development of electrophysiology and the development of the battery by Volta. The point of contention between Galvani and Volta was not whether Galvani’s methodology was sound, since Volta could achieve the same results. Their problem was a lack of a sound theoretical framework to interpret the results and a fundamental healthy mistrust between them. Due to Galvani’s sound methods and reproducible results, science could develop further because the hypotheses the results created needed further experimentation and testing, eventually leading Volta to develop the battery to defend his hypothesis and Galvani’s experiment connecting the nerves of the two frog legs to defend his.

The biomedical field could benefit from a shift in thinking. Rather than releasing methods that produce results researchers cannot even reproduce in their own labs, science would benefit from a reduction in releasing results that might cause sensation in the public and make sense within the theoretical framework, but do not produce the same results twice. The scientific community would benefit in the same way that it did when Galvani and Volta were competing to explain their own theories. If the methods are sound and reproducible, other researchers will have the opportunity to challenge the originator’s hypothesis and put forth their own hypothesis to explain the results. This would not slow down progress but rather help along the development of the theoretical framework by making sure that other researcher’s claims have been properly validated.

References

[1] Piccolino M. Luigi Galvani and animal electricity: two centuries after the foundation of electrophysiology. Trends in neurosciences. 1997;20:443–8.

[2] Piccolino M. Animal electricity and the birth of electrophysiology: the legacy of Luigi Galvani. Brain Research Bulletin. 1998;46:381–407.

[3] Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011;10:712-.

[4] Begley CG, Ioannidis JPA. Reproducibility in Science. Improving the Standard for Basic and Preclinical Research. 2015;116:116–26.

[5] Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature. 2012;483:531–3.

[6] Piccolino M. Luigi Galvani’s path to animal electricity. Comptes rendus biologies. 2006;329:303–18.

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In Defense of Radioisotope Powered Pacemakers

A Medtronic Pu-238 powered pacemaker
Tyler Shewbert

Starting in 1970 radioisotope powered pacemakers were implanted in over 3000 patients worldwide. These devices had longer lifetime power supplies than battery powered pacemakers therefore eliminating the need for battery replacement surgeries [1, 2]. A thirty-one year study performed by the Newark Beth Israel Medical Center of 139 patients showed that nuclear-powered pacemakers required less surgeries than a control group of lithium battery-powered devices [2]. This same study showed that cancer rates for patients with nuclear-powered pacemakers were similar to a control group with battery-powered devices [2]. The feared increased cancer rates did not materialize [1, 2]. With improvements in modern electronics technology and improvements in semiconductor energy conversion efficiency, radioisotope pacemakers can once again reliably provide pacing services for patients whose life expediencies are greater than twenty years, reducing the need for invasive surgeries to replace batteries. A new generation should be developed.

Introduction

A radioisotope power source takes the heat from the decay of a radioactive substance and generates heat through some sort of thermal energy to electrical energy conversion process using either the thermoelectric effect or thermionic effect [1–4]. Pacemaker devices of the 1960s had short battery lives, ranging from twelve to eighteen months [1–4]. A proposal was made to use radioisotope power sources which would have longer lifetimes and require less surgery since each time a battery had to be replaced surgery was needed. The Atomic Energy Commission had a guideline for 90% device reliability over ten years [2]. Several manufacturers developed nuclear-powered pacemakers using either thermoelectric or thermionic power conversion systems [1–4]. Two isotopes, Pu-238 and Pm-147, were chosen as the heat source [1–4]. The amount of radioactive material in each device ranged from 0.105 to 0.40 grams [3]. A majority of the developed devices used Pu-238 due to its 87.7 year half-life [3, 4]. In previous experiments Pu-238 capsules of 30–50 grams were implanted within dogs to test for carcinogenic effects. These experiments showed no significant change from a control group [3, 4]. There were members of the medical community that did not trust those experiments and believed that the prolonged exposure to implanted radioactive materials would cause cancer [5]. However, this did not happen. In a long term study the rates of cancer in two control groups, one with nuclear-power pacemakers and those with battery-powered pacemakers, showed no statistically significant difference in cancer rates over thirty-one years [2]. The major drawbacks to the nuclear-powered pacemakers were the availability of nuclear fuel, the excessive size compared to other pacemakers of the period, and the stringent FDA and NRC regulations compared to non-nuclear devices [1]. If nuclear-powered devices were developed using modern electronics technology the size would be smaller. However, the strain on Pu-238 sourcing would be significant since neither the United States or Russia is producing any currently for commercial use, but there are other isotopes such as tritium that could be used that are widely available and would not require as much regulation [6].

Results and Discussion

The original motivation for nuclear-powered pacemakers was the need for a pacemaker power source that lasted longer than a year to eighteen months [1–4]. However, this is not as much of a concern with today’s pacemakers. With new lithium batteries, modern pacemakers have an expectancy of around ten years [7]. While this is an improvement, an otherwise healthy individual in their early forties might have as many as four battery replacement surgeries within their lifetime. This is where a new generation of nuclear-powered devices will be useful. It will enable a long-term patient to require less surgery.

The results of three decades of tracking patients reveal that nuclear-powered devices worked well. The study performed by the team at the Newark Beth Israel Medical Center was revealing. Over fourteen years they implanted and tracked the progress of 132 patients [1, 2]. Of these patients, twelve needed surgery because they needed mode changing, and the devices they had implanted did not have the ability to be changed remotely [1, 2]. Power failure occurred in only one case [1, 2]. Fifteen were removed because of component malfunctions and eight units because the high pacing threshold had been passed [1, 2]. After fifteen years, the survival rate was 99% for the power systems and 82% for the entire pacing system [1, 2]. The malignancy rate was similar to that of the normal population and tumors were not concentrated around the pacemaker as had been feared but randomly distributed as in a normal population [1, 2].

From the study by the team at Newark Beth Israel Medical Center a few conclusions can be made. First, nuclear-powered pacemakers are a reliable power source for pacemakers. The failure rate over fifteen years was less than 1%, which was better than the NRCs recommendation of 10% over ten years. Second, the fear of increased cancer rates that had been mentioned by Hart, the FDA, and the NRC proved to not materialize. The exposure to low-levels of chronic radiation was not a concern. Third, the exposure to radiation for patients was well within the limits that the NRC has set up for workers in nuclear sites [1–4]. According to EW Webster, as mentioned in the 2006 paper by Parsonnet, the requirement for the use of a fluoroscopically-controlled replacement for battery-powered pacemakers would expose the patient to 1.6 times as much radiation as 15 years of pacing using a Pu-238 powered device [2]. As of May 2004, twelve of the 139 patients were still being followed, and one patient still had their original pacemaker thirty-one years later [2]. Two other major studies reached the same conclusions with regards to the safety and reliability of nuclear-powered pacemakers and therefore the Newark Beth Israel Medical Center can be considered a good survey of other studies [2]. Nuclear-powered pacemakers were successful.

The major drawbacks of the technology were that nuclear-powered pacemakers were larger than the battery-powered devices of the era, the surgeries required for replacing the pacemakers due to pacing problems, and the regulations and risks involving handling of nuclear fuel [1]. With improvements in pacemaker technology the first two drawbacks would be significantly reduced. Pacemakers electronics are much more advanced than in the 1970s. The concern that Hiram Hart and others had concerning increased cancer rates never materialized and therefore should not be a concern in the future when considering whether this technology should be revisited.

There is also a modern solution to the drawback of nuclear fuel handling. There has been improvement in betavoltaic devices over the past forty years. These devices had been originally considered as a power source for pacemakers in the 1970s [3, 4]. Betavoltaic power sources use b particle decay as method of generating current as opposed to a decay found in Pu-238 devices. Early semiconductor devices were not well suited for b decay power conversion and this was a major reason why Pu-238 was chosen. However, semiconductor energy conversion technology has improved since the 1970s and there is once again renewed interest is using the technology for long-term, low power needs [8]. While early betavoltaic pacemakers used promethium as an isotope, the increased efficiency of energy conversion technology has enabled the development of betavoltaic devices using tritium, an isotope of hydrogen, and other less radioactive substances as the energy source [8]. Using less radioactive isotopes could allow for a reduction in the regulatory framework that the NRC and FDA has imposed on nuclear-powered pacemakers. This would reduce the costs associated with production and ultimately the disposal of the device, both of which had been major costs due to the specific handling requirements of Pu-238 and promethium.

Outlook and relevance of work

Nuclear-powered pacemakers have a successful history of providing long term, reliable power to pacemakers with similar side effects that of a battery-powered device. With improvements in modern pacemaker electronics technology and improvements in semiconductor energy conversion technology the time had come to revisit the use of radioisotopes as power sources for pacemakers, particularly with patients who are expected to have multi-decade survival timelines.

While using Pu-238 would prove a hassle due to the lack of supply and stringent regulations, developing betavoltaic-powered pacemakers would be a logical course to take. Tritium is widely available in seawater so the main issue would be making sure the size of the tritium storage is the size a battery would use in a pacemaker. This is because tritium’s half-life is only 12.5 years, but two packages of tritium could be used in sequence to extend the lifetime to twenty-five years [8]. If less radioactive isotopes could be used in modern nuclear-powered pacemakers the regulations could be revisited, simplifying the process and therefore reducing regulatory costs. The advancement in pacemaker electronics technology would mean that there will be less pacemakers replaced due to pacing and lead problems that occurred in the ones implanted in the 1970s and 1980s.

Developing long-term pacemaker power solutions using radioisotopes would once again allow patients, particularly those who may have a pacemaker for forty years or more, to reduce the frequency of surgery. Over a multi-decade length of time, this could potentially reduce the cost of the pacemaker since there would not be a required surgery every ten years or so. The fears of radiation causing cancer was proven to be false by the first wave of nuclear-powered pacemakers and a new generation of devices would be able to use improvements in energy conversion technology and pacemaker technology to allow for more efficient and reliable devices than the first generation.

References

[1] Parsonnet V, Berstein AD, Perry GY. The nuclear pacemaker: Is renewed interest warranted? The American journal of cardiology. 1990;66:837–42.

[2] Parsonnet V, Driller J, Cook D, Rizvi SA. Thirty‐One Years of Clinical Experience with “Nuclear‐Powered” Pacemakers. Pacing and clinical electrophysiology. 2006;29:195–200.

[3] Huffman FN, Norman JC. Nuclear-fueled cardiac pacemakers. Chest. 1974;65:667–72.

[4] Norman JC, Sandberg Jr GW, Huffman FN. Implantable nuclear-powered cardiac pacemakers. New England Journal of Medicine. 1970;283:1203–6.

[5] Hart H. Nuclear-Powered Pacemakers. Pacing and Clinical Electrophysiology. 1979;2:374–6.

[6] Association WN. Plutonium. World Nuclear Association; 2017.

[7] Mallela VS, Ilankumaran V, Rao N. Trends in Cardiac Pacemaker Batteries. Indian Pacing and Electrophysiology Journal. 2004;4:201–12.

[8] Bourzac K. A 25-Year Battery. MIT Techonology Review: MIT; 2009.

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