BioEssays Vol. 2, No. 3 99

Cancer Research, Yesterday and Today"

There was a time within easy memory when cancer was regarded within the upper circles of basic biomedical science as an unapproachable and therefore not very interesting research problem. Twenty years ago it was generally viewed as an essentially unsolvable puzzle, too profound and complex to be attacked by any imaginable research technology, simply beyond the reach of science.

Not to say that excellent research was not going on. It was, and indeed the groundwork was then being laid by the molecular biochemists, virologists, immunologists, and cell biologists for what was to follow. But at that time, in the 1960s, the cancer problem had not yet engaged the full force of intellectual attention in biomedical science at large, as is the case today. It was not yet perceived that there could be ways into the very depths of the problem. The time, it was said, was not at hand.

In the early 1970s the magnitude of the problem as a cause of incapacitation and death in human beings was recognized as an increasingly serious matter, and pressures were brought on and by the Washington administration and Congress to do something much more ambitious in the way of research. Advisory committees and panels went to work, putting together what soon emerged as the 'Conquest of Cancer' plan, backed by the assurance of greatly expanded budgets for cancer research. The arguments over how to go about it were intense and sometimes bitter. Some of the scientific advisers asserted that it was just too early for a full-scale attack ; too much fundamental information was lacking. Others believed that the country should invest heavily in applied science, in an endeavour to improve what already existed in therapeutic, diagnostic, and preventive medicine.

This was, as it turned out, one of the luckier turning points in the history of biomedical science and the inevitable politics associated with science. Two things happened at about the same time. Research funds became available on a scale to attract many investigators, especially the youngest and brightest, into a field that they might otherwise not have chosen to enter. This in itself was an important event but if it had occurred by itself we would not find ourselves where we are in the mid-1980s. Money is of course crucial for the pro- gress of science, but money alone cannot make science.

Science makes itself, grows itself, and is transfonned by its own upheavals and surprises, and this is what began to happen, quite coincidentally and spontaneously, at just the

time when the new cancer research program was launched. The biological revolution, as it was then termed, which had begun with the discovery that DNA was the essential genetic material, possessing a molecular structure to account nicely for replication and duplication, was suddenly transformed into a new revolution superimposed on the old one. First came the discovery of cellular enzymes specifically designed to clip segments of DNA at predictable sites along the molecule, and at the same time an array of vastly improved instrumentation techniques for sequencing the molecular fragments, and finally, like a burst of drums, the brand new, unpredicted and astonishing technology of recombinant DNA. Cancer had become, almost overnight, a new kind of adventure for the cell biologists, experimental pathologists, virologists, immunologists, and geneticists, and it moved to the centre of biomedical science as the most fascinating and engaging of puzzles.

And so it is today. The recombinant DNA technology, surely the most important scientific advance of the century in biology, was soon reinforced and supplemented by the invention of hybridomas and the elaboration of monoclonal antibodies, now indispensable for the identification of gene products and surface markers in transformed cells. The role of oncogenes and their mobile geometric localization at different sites within the genome, the existence of enhancing genes and the crucial role of their location in relation to oncogenes, the mode of action of cancer viruses, the complex defense mechanisms mediated and modulated by the various T-lymphocyte populations - all these and more break- throughs still to come have changed everything about the cancer problem.

I have never known a time of such high confidence and exhilaration within the community of biomedical scientists, especially among the youngest investigators just coming on the scene at the postdoctoral level. Cancer research has turned into something like a running hunt. The fox is not yet within sight, but it is at least known that there is indeed a fox, and this is a great change from the sense of things twenty years ago. At that time it was generally believed that cancer was not one disease but a hundred, all fundamentally different and each requiring its own unique penetration. Today it

* This article is reprinted with permission from Cancer Today: Origins, I Prevention, and Treatment (1 984 National Academy Press).

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100 BioEssays Vol. 2, No. 3

EDIT0 RIAL seems much more likely that a single mechanism, or a set of mechanisms, lurks at the deep center of every form of cancer. It is even conceivable, in this writer’s optimistic view, that when all the facts are in, there may emerge a totally new, still unpredictable combination of applied pharmacology and immunology for reversal of the process and for its prevention.

The way ahead is now open for the clinical scientists and epidemiologists to begin asking questions, unthinkable a generation back, about the role of environmental factors, including nutrition, in the causation of cancer. Very likely, the rising generation of oncology investigators will become even

more dependent on experimental animal models for answers, but in vitro cell culture systems will also have more to offer than every before.

LEWIS THOMAS President Emeritus, Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, New York 10021, USA

MOLECULAR BIOLOGY AND BIOPHYSICS OF ION CHANNELS Richard D. Keynes

Summary

The transmission of electrical impulses in nerve and muscle cells depends funda- mentally on the operation of spec@ ion channels in their membranes, Recent technical advances in electrical recording from cell membranes have permitted the analysis of the properties of single ion channels and the measurement of gating currents. The results have revealed considerable complexities, in particular in the operation of voltage-gated sodium channels, and in the relationships between the several open and closed states of the channels. An important new development is the cloning and analysis of the structural genes for the acetylcholine receptor and sodium channel protein, which promises to yieldfresh insights into the functioning of these proteins.

Ctasses of Ion Channel

The study of ion channels dates from the introduction forty years ago of micro- electrode techniques for the measure- ment of intracellular potentials in single nerve and muscle fibres, followed shortly afterwards by the development of the method for holding the membrane at a predetermined potential and measuring the corresponding current flow that is known as ‘voltage- clamping’. It was quickly concludedl that the changes in ionic permeability responsible for the conduction of impulses in nerve and muscle resulted from the presence in the membrane

of channels, highly selective for either Na+ or K+ ions, whose openings and closings were controlled by the electric field, and these therefore became the foundation members of the ‘voltage- gated’ class of channel. It was also found that the changes in ionic per- meability responsible for junctional transmission between nerve and muscle or between one neurone and another were brought about by the opening of channels of a second class, those responsive to the release of specific transmitters by the nerve endings; the doyen of the class of ‘chemically gated’ channels was the acetylcholine receptor at the neuromuscular junction.2 Within these two broad classes, we can now distinguish a number of types of voltage-gated channel characterized by their different ionic selectivities and kinetics, and a plethora of chemically gated channels which respond to dif- ferent transmitters.

There is in addition a third and less-well-defined class of ion channel gated by factors such as mechanical stretch of the membrane, internal Ca2+ ions and agents like cGMP. The membership of this class has recently been increased with the extension of the voltage-clamp technique3 that has made it possible to measure the current flowing through individual channels in very small patches of membrane, and has revealed the presence of all three classes of ion channel in a wide range of

e~citable.~ The purpose of this article is briefly to review the present state of knowledge with regard to the molecular mechanisms involved in the functioning ofionchannels, with particular emphasis on the voltage-gated sodium channel.

The Hodgkin-Huxley Equations

The classical description of the kinetics and steady-state properties of the sodium and potassium conductances in electrically excitable membranes is em- bodied in the Hodgkin-Huxley equa- tions for the squid giant axon’ (Fig. l). The general picture is that when the potential across the membrane is altered in a positive direction under voltage- clamp conditions, the sodium channels open with a brief delay, but remain open for only a short while because of the subsequent onset of a process known as ‘inactivation’ that closes them once

dm _- - am(l-rn)-&m, dt dh dt - = ah( l -h)-bhh,

Fig. 1. The Hodgkin-Huxley equations describing the time- and voltage-dependence of the sodium and potassium conductances of the nerve membrane.‘ g ~ a and g~ are constants. rn, h and n are dimensionless parameters which vary between 0 and 1 . The a’s and P’s are forward and backward rate constants which vary with membrane potential in a vrescribed fashion. living cells not previously classifiei as .