The question has been asked innumerable times but has been answered to the satisfaction of few. Science is based on the experience that nature gives intelligent answers to intelligent questions. To senseless questions, nature gives senseless answers – or no answers at all. If nature has never provided an answer to this question, perhaps something is wrong with the question.
The question is wrong indeed. It has no sense, for life in itself does not exist. No one has seen or measured life. Life is always linked to material systems; what man sees and measures are living systems of matter. Life is not a thing to be studied; rather, “being alive” is a quality of some physical systems.
A look at the living world reveals an incredible variety of shapes, sizes, forms, and colors. There seems to be an infinite variability among living systems. How can man approach such complexity? How can he ask intelligent questions?
One key to an intelligent approach may be the simple fact that things can be put together in two different ways: randomly or meaningfully. Things put together in random fashion form a senseless heap. Nine persons selected at random and placed together probably will form nothing more than a slightly puzzled collection of nine individuals. Nine persons selected and combined in a meaningful fashion may form a championship baseball team. The whole in this case is more than the sum of its parts – it is what is called organization.
If an atomic nucleus is combined with electrons, an atom is formed. This atom is something entirely new, quite different from electrons or nuclei alone. When atoms are combined, molecules are formed. Again, a new thing is generated with strikingly different qualities. Smaller molecules – say, amino acids – may be combined to form a “macromolecule” – perhaps a protein. This macromolecule has a number of amazing qualities. It demonstrates self-organization – the ability to create more complex, higher structures. It may act as an enzyme to speed up a particular chemical reaction, or it may act as an antibody to neutralize the effects of some other specific protein molecule. Proteins can be created in a literally inexhaustible variety of forms, each with its own qualities.
Macromolelcules may be combined to form small “organelles”, such as mitochondria or muscle fibrils. When they are combined, the result is a cell – the unit of life, the miracle of creation – capable of reproduction and of independent existence.
The more complex the system, the more complex its qualities. Organs may be built from cells; from organs may come an individual organism, such as a human being. Individuals in turn may be combined to form societies or populations, which again have their own rules. At each level of complexity are new qualities not present in the simpler levels. The study of each level yields new information for the biologist.
The history of biology has been marked by a penetration into ever smaller dimensions. In the sixteenth century, Vesalius was dependent on his unaided eyesight for his study of the human body. In the following century, the optical microscope led to the discovery of many new details of structure. Marcello Malpighi observed the capillary vessels that complete the cycle of blood circulation and showed that even such tiny insects as the silkworm have an intricate internal structure. Anton van Leeuwenhoek described blood cells and the compound eyes of insects. Robert Hooke described the cellular structure of plants.
As microscopes were improved, more and more details of structure were described. By the nineteenth century, it was becoming clear that all complex organisms are composed of semi-independent units called cells. The major structural features of cells were established. Bacteria were discovered and studied.
In this century, the electron microscope has taken the scientist down to molecular dimensions, and he has learned to observe with x-rays as well as with visible light. Organic chemistry was established in the nineteenth century, and by the beginning of this century, it was clear that this approach could be applied to the study of living systems. Biologists have had to learn a new anatomy – the anatomy of molecules. Chemists and physicists have penetrated the atom, first finding the elementary particles and then moving still deeper into the realm of wave mechanics. The discovery of the wave properties of the electron has given a deep insight into the nature of biological reactions.
As scientists attempt to understand a living system, they move down from dimension to dimension, from one level of complexity to the next lower level. I followed this course in my own studies. I moved from anatomy to the study of tissues, then to electron microscopy and chemistry, and finally to quantum mechanics. This downward journey through the scale of dimensions has its irony, for in my search for the secret of life, I ended up with atoms and electrons, which have no life at all. Somewhere along the line, life has run out through my fingers. So, in my old age, I am now retracing my steps, trying to fight my way back toward the cell – the organism.
I have concluded that life is not linked to any particular unit; it is the expression of the harmonious collaboration of all. As I descended through the levels of complexity, I studied simpler units and found myself speaking more and more in the language of chemistry and physics.
J. F. Danielli has shown that the subcellular organs of various cells are interchangeable. They can be transferred from one cell to another, much as organs can be transplanted from one human individual to another. The parts of the cell have no individuality. The quality of individuality resides in the higher organization – in the cell or the individual.
No one yet knows the higher principle that holds a cell together. Perhaps the answer will be found in irreversible thermodynamics. The good working order of a living cell may correspond to a stable state with a high probability of occurrence. Perhaps some new principle – as yet undiscovered – keeps the cell together. Living systems do not only maintain their good working order but they all tend to improve it, to make the working structure more complex. When the fundamental principle that holds the cell together is found, perhaps we will then also understand what brought together the first living system and understand what drives living systems toward self-perfection.
Scientists know today that rather complex molecules – amino acids, nucleic bases, even macromolecules – can under certain conditions be built without intervention of living systems. They are still seeking the principle that brought them together for the first time and that makes these systems improve themselves by building more complex structures capable of more complex functions.
Biology is a very young science. It has called itself a separate science for only some eight decades. No one can expect it to find the answers to all questions. The most important questions are yet unanswered – perhaps unasked. What biologists can do – what they are doing at present – is to ask questions that seem answerable with present techniques. They ask questions about structure and function, from the nature of consciousness down to the behavior of electrons, hoping that some day all of this detailed knowledge will come together in a deeper understanding.
Perhaps some day they will find a new way of looking at things. The best scientists, with the aid of giant computers, cannot yet fully explain the behavior of three electrons moving within an atom. Yet those three electrons – even dozens of electrons – know exactly what to do and never miss. In essence, nature may be far simpler than is believed.
To see the solutions, scientists must preserve a certain naivete, a childish simplicity of the mind, an ability to recognize a miracle when they see it every day. The solution may be far closer than it seems. It was a hundred years ago that H.P. Bowditch, one of the first American physiologists, showed that after a frog’s heart have been stopped for a while, its first beats are rather weak. The heart gradually regains its original strength, with the record of the heartbeat rising like a series of stair steps. Bowditch called this phenomenon “the staircase”.
One might expect the heart to be stronger after a rest. Yet what is observed here can be considered a general quality of living systems. Life generates life: rest or inactivity causes life to fade away. Muscles weaken if they are not used: they become stronger if exercised regularly.
This principle is one of self-organization, one of the most striking differences between a living system and a nonliving one. A machine is worn out by usage. A living system is worn out by inactivity. Living systems are able to organize and improved themselves.
S. J. Hajdu and I tried to discover the mechanism that produced the Bowditch staircase. We found that potassium leaks out from the heart fibers into the surrounding fluid when the heart is not beating. When the heart resumes its activity, the potassium is pumped back into the heart fibers. The change in strength of the heartbeats is caused by this change in the distribution of potassium. The movement of the potassium back into the fibers, against the potassium concentration gradient, increases the amount of organization or order in the system. The entropy of the system is decreased. Ernst Schrodinger in 1944 suggested that the ability to decrease entropy is the most characteristic feature of living systems. In a living system, the decrease of entropy leads to further decrease of entropy, to greater order. The increase of entropy leads to further increase of entropy, the maximum state of entropy being death.
Further pursuit of these thoughts would lead into abstract speculation. I would like to point out, however, that these abstruse questions are not at all far from the sickbeds of suffering patients. One of our most important drugs is digitalis, which is used to stimulate failing hearts. Hajdu and I showed that digitalis helps the heart to pump potassium back into its fibers and to retain it. The inability of a heart to maintain its potassium concentration may be one cause of its failure.
Living systems are clearly different from nonliving systems. There must therefore be a difference in the way these two kinds of systems are thought about. Physics is undoubtedly the most basic science. In a way, biology is only an applied science, applying physics as a tool for the analysis of living systems. However, there are distinctions between physical and biological events.
Suppose a process, left to itself, is likely to occur 999 times in one way for each time that it occurs in another. The physicist concerns himself primarily with the first way. Physics is the science of the probable.
Biology is the science of the improbable. On principle, biological reactions must be improbable. If man’s cells worked only through the probable reactions, they would soon run down in order to regulate itself, a cell must use improbable reactions and must make them take place through very specific tricks. The cell may make use of just that one way in a thousand that the physicist ignores.
The cell finds a way to make the reaction go at just the right moment and at the desired rate. The reaction may be improbable, but if it is thermodynamically possible, the cell will find a way to use it.
Physically, all of us – you and I – are improbable. The probability of atoms happening to come together in the complex structure that makes up my body is so tiny that it is practically equal to zero.
Another difference between the physical and biological approaches to the study of a reaction lies in the matter of isolation. The physicist is apt to attempt to isolate the reaction he wishes to study. In biology, single reactions are rarely encountered. Most biological reactions are parts of complex chains. They cannot be fully understood except as members of the chain, or even as parts of an entire living system – the living biological entity.
For example, one of the most important biological reactions is the “electron flow” that underlies photosynthesis and biological oxidation. These processes generate the energy that keeps living systems going. In these reactions, electrons “flow” from molecule to molecule. If an electron moves from molecule A to molecule B, it leaves a positive electric charge on molecule A. This charge tends to pull the electron back toward A. Electrons could not move against such a strong electrostatic attraction. However, if molecule A is a member of a chain and simultaneously receives an electron from a third molecule, its positive charge will be neutralized. There will then be nothing to pull the electron back toward A. Thus, where electrons cannot move from A to B in an isolated system, they can “flow” without difficulty if A and B are members of a chain.
Like many biological researchers, I have often worked for long periods, using all the tricks of chemistry, wave mechanics, and mathematics to understand a certain reaction. In the end, I have found that the cell carries out this reaction in the only way that it could be accomplished. In my long research career, one of the greatest mysteries to me was the way in which a living cell – without the aid of computers or even a brain – could find this single path to the necessary result.
In one way, the discoveries of genetics have made our understanding of evolution even more difficult. A cell does not directly alter the molecules in evolution. Instead, it alters the code of the nucleic acid in its chromosomes. Then all of the descendants of that cell make the appropriate changes in the molecules involved in the reactions. In most cases, a number of genes must be altered to accomplish a meaningful change in a chemical reaction. If all of these genes were not changed simultaneously, only confusion would result.
According to present ideas, this change in the nucleic acid is accomplished through random variation. The nature of protein molecules formed in the cell is determined by the code of the nucleic acid. If I were trying to pass a biology examination, I would vigorously support this theory. Yet in my mind I have never been able to accept fully the idea that adaptation and the harmonious building of those complex biological systems, involving simultaneous changes in thousands of genes, are the result of molecular accidents.
The feeding of babies, for example, involves very complex reflexes. These reflexes require extremely complex mechanisms, both in the baby and in the mother, which must be tuned to one another. Similar mechanisms are involved in the sexual functions of male and female animals. These mechanisms must be tuned precisely to one another in order to achieve successful copulation. Thousands of genes must be involved in the coding of these mechanisms. The probability that all of these genes should have changed together through random variation is practically zero, even considering that millions or billions of years may have been available for the changes.
I have always been seeking some higher operating principle that is leading the living system toward improvement and adaptation. I know this is biological heresy; it may be ignorance as well. Yet I think often of my student days, when we biologists knew practically nothing. There was then no quantum theory, no atomic nucleus, and no double helix. We knew only a little about a few amino acids and sugars. Al the same, we felt obliged to explain life. If someone ventured to call our knowledge inadequate, we scornfully dismissed him as a “vitalist.”
Today also we feel compelled to explain everything in terms of our present knowledge, identical twins are often exactly alike in the smallest details of physical appearance, indicating that the instructions of building this entire structure must have been encoded in the genetic materials that they share. All the same, I have the greatest difficulty in imagining that the extremely complex structure of the central nervous system could be totally described in the genetic codes. Thousands of nerve fibers grow for long distances in order to find the nerve cell with which they can make a meaningful junction. Surely the nucleic acid did not contain a blueprint of this entire network. Rather, it must have contained instructions that gave the nerve fiber the “wisdom” to search for and locate the only nerve cell with which it could make a meaningful connection. Perhaps this guiding principle also is related to the way in which the first living system came together.
I do not think that the extremely complex speech center of the human brain, involving a network formed by thousands of nerve cells and fibers, was created by random mutations that happened to improve the chances of survival of individuals. I must believe that man built a speech center when he had something to say, and he developed the structure of this center to higher complexity as he had more and more to say. I cannot accept the notion that this capacity arose through random alterations, relying on the survival of the fittest. I believe that some principle must have guided the development toward the kind of speech center that was needed.
Water B. Cannon, the greatest of American physiologists, often spoke of the “wisdom of the body.” I doubt whether he could have given a more scientific definition of this “wisdom.” He probably had in mind some guiding principle, driving life toward harmonious function, toward self-improvement.
Life is a wondrous phenomenon. I can only hope that some day man will achieve a deeper insight into its nature and its guiding principles and will be able to express them in more exact terms. It is this mysterious quality of life that makes biology the most fascinating of sciences. To express the marvels of nature in the language of science is one of man’s noblest endeavors. I see no reason to expect the completion of that task within the near future.
