Why are we doing this and where did Whyville come from??

Well, I suppose, in some sense, the reason that I finally decided to jump into the blogosphere was to try to provide an answer to those questions.  As may perhaps now be apparent, the answer is kind of complex – and has become more complex as time has gone on and it is ever more apparent why we would have done this “had we known then what we know now”.  The Whyville team and I will be forever grateful to Whyvillians for that ongoing education.

However, although still early in the overall exposition, perhaps you will indulge an effort to explain why, in 1984, I THOUGHT I should start playing with games embedded in social (virtual) worlds as a mechanism for engaging elementary and middle school aged children in science education.

The answer then had to do with computer simulation technology and the importance of models as a tool for understanding complex things, Whyville’s core technology.  It also came from a deep sense that many, even in science and especially in biology, did not themselves understand the importance of model-based discovery.

Three weeks ago I helped to organize a meeting in Cambridge England celebrating the remarkable accomplishment of Sir Allen Hodgkin and Sir Andrew Huxley 60 years ago, who built a mathematical model as a tool to understand the way in which neurons communicate with each other electrically.

Without mentioning Whyville of course (few in neuroscience know about my ‘other life’), my opening talk at the meeting asked how it is that the results of the Hodgkin / Huxley model have been largely accepted, while their modeling methods still seem foreign to so many biologists.  After all, IT HAS BEEN 60 YEARS!!!  In fact, while giving the meeting introduction, it occurred to me that the meeting in Cambridge might have been the first in the entire history of biology to be organized around an actual model.   Physics has been organized around and by models for 400 years.

This observation (another example of learning by doing), in turn inspired me to submit the commentary copied below to Nature Magazine, which has just rejected the publication because of “pressure on space in our pages”.

No such pressure here however 🙂  although I realize that this commentary may stretch the interests and willingness of those who follow this blog.  I am hoping that those who do fight through it might better understand Whyville’s origins as well as my own perhaps somewhat over-assertive commitment to Whyville as an idea.

 

Commentary on:  “60 Years of the Hodgkin-Huxley Model.  In celebration of the 60th anniversary of the publication of the Hodgkin-Huxley model of the action potential”, Cambridge UK July 11-13, 2012.

 

The contrasting role of standard models in biology and physics: considering the 60 years anniversary of publication of the Hodgkin Huxley Model for the neuronal action potential.

The announcement of the Higgs Boson on July 4 attracted widespread attention among physicists and the general public in large part because it confirmed a theoretical prediction made almost 50 years earlier regarding a particle key to the relation between elementary particles and the forces between them. As such, the discovery of the Higgs boson has been reported as a triumph for the partnership between theory and experimental practice in physics.  A week after the announcement of the discovery of the Higgs Boson, a symposium took place at Trinity College in Cambridge, England, celebrating the 60th anniversary of the original publication of the Hodgkin-Huxley (HH) mathematical model for the initiation and conduction of the neuronal action potential which provides a fundamental mechanism for communication between neurons.  Like the Standard Theory of elementary atomic particles, the original publication of the HH model both unified a diverse set of experimental observations and made a series of predictions for phenomena not yet observed, or at the time observable. As was made clear in the symposium at Trinity College, experimental research in the subsequent 60 years has largely confirmed those predictions and placed the HH model at the center of our understanding of the electrical activity of nerve tissues throughout the animal kingdom from the squid’s giant axon to Human brain cells.

While Alan Hodgkin and Andrew Huxley received a share of the Nobel Prize in 1963 for their work, the success of their model in predicting the ionic processes underlying the generation and propagation of the action potential remains largely unheralded even within neuroscience.  Most neuroscience textbooks instead simply refer to the HH model as a “description” of the ionic basis of the action potential, failing to include any discussion of the scientific process represented by the model, or its role in organizing and leading 60 years of subsequent experimental and theoretical investigations. Typically, there is also no mention of the fact that the HH model today provides the basis for most ongoing efforts to build realistic models of brain circuits and understand brain function and dysfunction.  While the discovery of the Higgs Boson is lauded as a triumph for the Standard Theory of elementary particles, the similar accomplishment of the model built by Hodgkin and Huxley is largely neglected.

Prior to the HH model in the late 19th and early 20th century there was considerable disagreement and confusion about the cellular and biophysical mechanisms responsible for the action potential.  While the action potential itself had been recorded as early as the mid 1860s by the German physiologist Julius Bernstein, there was considerable debate regarding both the ions involved and the mechanism(s) responsible for their movement across the membrane.  In 1937 Alan Hodgkin showed that the action potential depends on regenerative changes in electric charge movement across the membrane, with the change in potential propagating down the axonal fiber.  Contrary to the then prevailing view (associated with Bernstein) that these ionic movements resulted from a transient breakdown in the axonal membrane, Hodgkin and Huxley working together showed that the action potential exhibits a brief transient period when the internal negativity of the membrane potential becomes positive, an “overshoot”, requiring a more sophisticated membrane mechanism than previously assumed.  After World War II, Hodgkin and Huxley returned to their experimental work using a state of the art feedback amplifier to perform voltage and space clamp measurements on the squid giant axon.  Combining the voltage clamp with ion replacement experiments, they measured for the first time in detail the flow of potassium and sodium ions crossing the membrane and their corresponding conductance changes generated during the action potential.

This experimental work was published in a remarkable series of 5 papers in the Journal of Physiology in 1952. While the first 4 described the experimental results, the crowning achievement was the 5th paper, which included the mathematical model itself in the form of 4 ordinary differential equations.  Even today, this sequence of 4 + 1 represents one of the best, and perhaps also one of the clearest demonstrations of the value and proper use of models in biology, exemplifying the links between theoretical ideas and experimental studies.

Hodgkin and Huxley themselves were very aware of this unifying use of their model, making it clear in their paper that more than a description of the phenomena, the model was an essential investigative tool.  Thus, they state:

In order to decide whether these (experimental) effects are sufficient to account for complicated phenomena such as the action potential and refractory period, it is necessary to obtain expressions relating the sodium and potassium conductances to time and membrane potential.”

expressions” in this case of course being the model’s equations which both provided concrete definitions of the processes involved as well as a means to link separate experimental results into a larger understanding of mechanism.  In addition to helping coordinate the experimental results, the model was also used to explicitly rule out mechanisms that were inconsistent with observations:

“…  we shall consider briefly what types of physical system are likely to be consistent with the observed changes in permeability.”

and:

The object … is to show that certain types of theory are excluded by our experiments and that others are consistent with them.”

In this way, Hodgkin and Huxley used the model to test and reject existing ideas about the origin of the action potential, including, importantly, their own:

Consider(ing) how changes in the distribution of a charged particle might affect the ease with which sodium ions cross the membrane … we can do little more than reject a suggestion which formed the original basis of our experiments (Hodgkin et al., 1949).”

To this day, perhaps the highest (and rare) mark of any model is to rule out the author’s own previous beliefs and speculations.

Beyond testing proposed mechanisms, perhaps the greatest achievement of the HH model was in making a series of predictions related to membrane mechanisms not yet described and data not yet obtained or obtainable.  Specifically, the core model prediction was that the movement of sodium and potassium ions through the membrane are independent and controlled in different ways.  While Hodgkin and Huxley could not have known the underlying biophysical mechanism at the time, their model, in effect, predicted not only the presence but also the core functional properties of individual membrane bound ion channels not clearly identified until the invention of patch clamp recording techniques for which Erwin Neher and Bert Sakmann shared the Nobel Prize in 1991.

It is our view that in a science still dominated by descriptive studies, in which the large majority of submitted grants and research projects do not reference or include a quantitative theoretical basis for the work, the history and success of the HH model stands as a testament to the value of modeling, theory and simulations in understanding complex phenomena.  By not emphasizing the predictive nature of the HH model, and the relationship between the construction and testing of the model with experimental data and the subsequent success of its predictions, we deny our students knowledge of a critical component of the scientific process and one of its greatest successes to date.

the plague unveiled at the symposium which now pays tribute to the experimental and theoretical work performed at Trinity College on the neuronal action potential

As was clearly apparent at the symposium at Trinity College, the HH model, like the Standard Model of particle physics, continues to provide the quantitative underpinning for our understanding of the electrochemical properties of the brain and in particular, how its neurons communicate with each other and with the outside world. The HH model and its derivatives also provide the foundation for almost all efforts to build biologically realistic brain models including the compartmental modeling techniques introduced by Wilfrid Rall and his collaborators in the 1960s.  All the major simulation software packages, including GENESIS and NEURON are based on the HH equations, as are large-scale simulation projects like the Blue Brain project aiming to model the mammalian cerebral cortex. These computational efforts, however, continue to involve a relatively small number of neuroscientists and an even smaller number of experimentalists. Perhaps, revisiting the history of the HH model, and presenting the model as a set of predictions rather than the now accepted description of the action potential, might provide a pathway for more neuroscientists, and perhaps even more biologists in general to value, understand, and participate in modeling studies.