Existo, Ergo Pars Evolutionis Sum—or What is Life?

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Existo, Ergo Pars Evolutionis Sum—or What is Life?

Already the Old Greeks …

Organized thoughts about the definition of life and the way it may function started in the original Greek culture. Democritus proposed that the essence of life was the presence of a soul, the psukhē . Empedocles speculated about the essential role of the four elements soil, water, fire, and air, corresponding to four of the five Platonic bodies—excluding the dodecahedron (the quintessence)—as the elements constituting different forms of life. Aristotle introduced hylomorphism: the importance of the relation between matter and form, often considered the first scientific approach to finding a definition of life. For him the soul could have different forms—the vegetative, the animal, and the rational form. The latter was reserved for humans, highlighting their capacity for consciousness and reasoning. Hippocrates formulated the first structured system for classifying diseases. The common denominator was proposed to be an imbalance of the four temperaments or humours—sanguinic, choleric, melancholic, and phlegmatic—an imaginative way of understanding the body-soul complex.

In all these attempts to understand the essence of life, it was assumed that life had a purpose and was goal-directed—it had a teleological dimension. The results of rational hypothesis-driven experimental science introduced in the eighteenth century came to challenge these concepts. During the last fifty years, remarkable advances have been made in the field of life sciences.

The Molecules of Life

As the fundamentals of chemistry started to be understood in the early nineteenth century, it became clear that a distinction between inorganic and organic—that is carbon-dependent—chemistry needed to be introduced. It was soon found that this separation was not absolute, since inorganic compounds were found to be capable of combining into organic ones. Still, the idea prevailed that the function of organic molecules in a living system involved forces outside the field of chemistry. These nebulous forces were collectively referred to under the rubric of vitalism. It was also believed that life could originate spontaneously under certain conditions. Louis Pasteur could disprove this, but he retained the belief that certain life processes, such as fermentation, required the intact cell—a form of vitalism. Buchner proved that this was not true, and received the 1907 Nobel Prize in Chemistry—the first one in organic chemistry—for his identification of enzyme-driven fermentation. Clearly some steps in metabolism depend on a large number of components’ interacting in a very complex way, but given time, experimentalists have managed in most cases to establish even complex chains of reactions in cell-free systems.

Vitalist ideas, however, lingered on, and in the 1930s when physicists highly successful in advancing their own field reflected on entering the scene of biology, there were thoughts like those introduced in Niels Bohr’s lectures on Light and life . His idea was that as in physics, where elementary units could be either waves or particles, molecules participating in organic chemical reactions might have a dual—or even multiple—nature. Erwin Schrödinger in his book What is Life? had similar thoughts. Bohr inspired Max Delbrück to get involved in biology, and he came to focus on the genetics of bacteriophages (viruses that infect bacteria). The contributions of the phage group, together with discoveries by chemists and crystallographers, eventually resolved the central question of the nature of genetic material. The virus particles were found to be packages of genetic information, and served as a vehicle for transferring this information from an infected cell to a healthy cell that then became infected. The crucial information-storage molecule of life was found to be DNA. The particles of many forms of viruses contained this kind of nucleic acid, but it was also found that many viruses used the other kind of nucleic acid, RNA, to serve the same function.

In further advances of fundamental knowledge, the central genetic dogma was discovered, namely that the linear message of DNA can be transcribed into RNA, which can then be translated into an amino acid chain, which after folding in turn forms the final protein. The genetic code of the linear nucleic acids—triplets of nucleotides—was deciphered and found to be universal. Thus all the forms of life we see today originated from the same ancestor, emerging some 3.8 billion years ago. Proteins cannot transfer information to nucleic acids and change their sequence, but they can influence each other and direct the process of folding. A completely new perspective on “what is life?” could now be given.

Techniques were developed for reading the books of life, allowing the determination in 2001 of the positions, for example, of the two times three billion nucleotides in the segmented linear human genome. The speed and efficiency of identifying the information carried by nucleic acids is increasing rapidly. The approach to determining the digital linear information in nucleic acids is referred to as metagenomics. Through the use of data-mining experiments, a wealth of information is presently being accumulated.

With time, interest shifted from not only reading the books of life to being able to write them as well. First, the relatively limited genetic material (the genome) of certain viruses was successfully synthesized. Recently, however, it has been possible to construct the whole genome of a bacterium containing more than one million building blocks, the nucleotides. This synthetic genome was found to contain all the information needed to manage the different functions required for the full life of the bacterial cell. This scientific discovery means that it has been possible to recapitulate in the laboratory the achievement of evolution during the first two billion years that it was at work. It is a fundamental discovery to be able to prove that DNA contains all the information needed to control the life of bacteria. It remains to be seen whether DNA is the sole source of information, as we move from synthesizing genomes of the simpler forms of cellular structures, the prokaryotes, to those of the markedly more complex eukaryotes. The synthesis of life will be a highly prioritized research area in the coming decades.

Life is Ubiquitous

Until recently, it was possible to study cellular life forms only if they could be made to replicate in the laboratory. The great advance of Koch and Pasteur during the late nineteenth century was that they identified pathogenic bacteria by making them grow on artificial media. Using such an approach, it has been possible so far to identify some 6,000 kinds of bacteria, but this number now turns out to represent only a small fraction of all the different bacteria on Earth. The true number may be a million times higher. The invisible world of microorganisms turns out to be exceedingly important, both quantitatively and qualitatively. The total biomass of these life forms is larger than that of all those we can identify with our senses. The role of microorganisms in the interaction of all forms of life—what we call ecology—remains to be determined. Much more knowledge is needed to describe the true nature of the phenomena included in this buzz word. Just as an example we can consider our own bodies. Each one contains ten trillion cells, generally “playing” together without a conductor in a harmonious way—the beautiful homeostasis. In addition, however, it contains a ten times larger number—a hundred trillion—of microorganisms. Each of us is a walking community, demonstrating the major importance of cooperation among different forms of life. The nature of the microorganisms in our bodies is currently described by the already mentioned metagenomic technique. Thus their nature, and the critical body functions they provide, will soon be elucidated.

It is only recently that it has become possible to characterize the genomes of microorganisms that we cannot make replicate in the test tube. The approach is to break down the DNA into small fragments and determine the nucleotide sequences of all of them. Once the sequences of a wide range of randomly generated fragments are known, the researcher attempts to reconstruct the whole genome using overlapping sequences. This is just another example of how the introduction of metagenomic analysis of genome fragments has revolutionized the modern approach to biology. It is now possible in principle to identify the presence of any form of life in samples from any part of nature. During recent years one has begun to study oceans and lakes. They contain on average one million microorganisms and ten million viruses per millilitre. Already the initial studies have shown an amazing variety of life forms, in particular microorganisms and viruses, containing genes for a plethora of previously unknown proteins. The more one studies, the more one finds. Some metagenomic analyses of soil, even deep in the ground or in mines, have been performed. Wherever one looks, one finds a range of life forms that generally have not been seen before. We are just beginning to study the diversity of cellular forms of life and their appearance in different habitats—even extreme ones—on Earth. Only when we have done this can we give full meaning to the term “biological diversity.”

The Tree of Life is Extensively Redrawn

For a long time it was believed that Homo sapiens has a very special position among all forms of life. It was proposed that various forms of life progressively led up to us, humans being the ultimate product of “the great chain of being.” This belief started to change once one started to understand the decisive role of evolutionary phenomena in the emergence of new forms of life. Darwin’s publication in 1859 of On the Origin of Species was a watershed event. In the late nineteenth century, evolution was presented mainly as a struggle for existence, in which the most competitive form survived. Alfred Tennyson called it “evolution, red in claw and teeth.” Further studies have clarified that this is not an accurate description and in fact cooperation—reciprocal altruism—is more important than competition. Thus it can also be said—with equal correctness—that “evolution is green in mergers and acquisitions.” We humans are one good example of this, as already mentioned. However, not only are our bodies walking communities, but we as individuals are also highly social primates, with proven success at building exceptionally advanced cultures. The recent amazing advances in furthering the societal enterprise come from science and technology. The result of our success has been that we are now in control of our own evolution. We are the only species that can describe its own genome. We are also the only species that can contemplate its impact on the balance of nature, and decide whether we want to destroy our world or be responsible stewards, moving towards a sustainable—a presently worn-out word—future.

Until a few decades ago the tree of life was divided into two trunks, one for bacteria and one for nucleated cells, the eukaryotes, which formed organisms of varying degrees of complexity. Then another domain was added, as a result of studies by Carl Woese. He showed that besides eukaryotes there were two distinct domains of bacteria, now referred to as Bacteria and Archaea . With all the new data generated by metagenomic analyses, the numbers of representatives in the two bacterial domains are rapidly increasing. In the end we may end up with perhaps six million, instead of six thousand, “species” of bacteria. The term “species” is in quotes, because a lot of genetic material flows horizontally between bacteria, making it difficult to formulate a robust definition of “species.”

Surprisingly, viruses have been totally overlooked in relation to the tree of life. For anthropocentric reasons, we have so far primarily studied viruses that can cause disease in us humans, or in animals and plants that we use for food or other purposes. In us humans alone, a single species, we have identified some 1,100 different viruses. However there are reasons to believe that wherever there are cells there are viruses. Thus the tree of life is surrounded by a cloud of—as yet mostly unidentified—viruses. Still today it is not appreciated that viruses are the most abundant life entities in the entire biosphere. We will return to them, their evolution, and definitions of life below, but let us first look at our own short history. We might do well to remind ourselves that our branch—our needle?—is a very tiny part of the whole tree of life.

Dramatic Events in the Evolution of Modern Man

The branch of primates that led to the development of modern humans separated from our closest relatives, the chimpanzees, about six million years ago. Our tool-using skills and our relative brain size increased, and spawned many lines of primitive humans that went extinct. Last among these were the Neanderthals, from which Homo sapiens separated about 500,000 years ago. They went extinct some 30,000 years ago.

Let me make two particular comments on our brief history. The first concerns what I would like to refer to as the most amazing and significant accident in the course of evolution: that is the emergence of consciousness. Sometime in the recent history of primates—before or after our separation from the Neanderthals—there must have been a time when an individual looked at his reflection in a water pond and concluded “This is me.” But there were also, as a corollary of this appreciation, other ensuing reflections. These concerned time and meaning. The identification of a “self” led to the conclusion that there is a time before and a time after—a time for birth and a time for death. It also led to the question of meaning: why am I here, and what is the purpose of it all? Other questions of meaning concerned what is the origin of the starry sky, of the cyclic behaviour of the sun and the moon, of the rain and thunder, and so on. In order to explain these phenomena beautiful myths were created and carried on through generations by oral tradition. Although this may appear offensive to some, it serves to remind us that evolution does not have a meaning or a purpose, either before or after the emergence of consciousness. Nature is just nature, evolving under the prevailing fortuitous conditions, and influenced by tectonic movements of land masses, shifting conditions of relationships between actors in the solar system—Earth, moon, and sun—impacts of meteorites, and in particular volcanic eruptions. There is nothing in nature that is foreseeable and stable; the only “natural” state is unpredictably changing conditions and the establishment of transitory ecological balance. This means that attempts to live in harmony with nature need to be adaptable. We humans represent a remarkably adaptable species.

The exodus of representatives of the 180,000 years-old Homo sapiens from their cradle in Africa occurred some 60,000 years ago. Using their intelligence and social skills, humans came to spread over the major parts of existing land masses. They settled in the most diverse conditions, from the arctic to the deserts. We have the unique capacity to create conditions that let us survive in many different habitats. By genetic selection, different physiognomies developed which allowed optimal adaptation. We lost the black pigment in our skin that our African forefathers had, and there were also other adaptations in skin colour and the length and characteristics of our faces. What were for a time called races, and are today more appropriately referred to as ethnic groups, developed.

The second particular aspect of the development of modern humans relates to their unique capacity to read faces. In early hunter-gatherer communities, which included mostly genetically closely related individuals, this ability provided valuable information about who could be trusted and who could not. This situation changed once humans started to form permanent settlements some 10,000 years ago—a blink of time in evolutionary developments—after the introduction of agriculture. Remarkably, social networks with separate trades developed, and increasingly complex societiesbegan to interact with one another. However, the capacity to form complex social interactions also had a cost. In the interactions of developing human civilizations, the existence of different ethnic groups came to pose a problem.  Man could use his important capacity for discriminative reading of faces when it came to individuals that looked similar to him, but less so in meetings with those of a different ethnic origin. The result was xenophobia, furthering animosity and violence between larger groups of humans. This came to be one important contributing factor in the bloody history of mankind.

The genetic diversity of modern man has been shaped by four selective conditions. One of these is fortuitous and strikes blindly: local or more general climatological changes that are more or less incompatible with the survival of humans, and result in the extinction of all or most of a group of them. Besides these bottleneck effects, there are three more factors involving environmental change that force the selection of individuals with altered genetic makeup. One is the already-mentioned adaptation to completely new environmental conditions, leading to the establishment of ethnic groups of individuals. The other two concern the food we use to sustain ourselves and our exposure to infections. The latter two environmental changes have developed mainly since the time when the first sedentary civilizations were established. For the first time more food was produced that what was needed for the survival of those who produced it. Labour in the group could be differentiated: besides the farmers, some became soldiers to protect the group, others became priests, etc. Changed eating habits, like drinking of milk, resulted in genetic selection of individuals tolerant of the new nutritional sources. The increased number of people living together opened up the possibility of epidemic viral, bacterial, and parasitic infections. Again, individuals with an increased resistance to infections were selected. Even taken together, however, the genetic differences among individuals representing the young human species are very limited. We are still a very homogenous species, and there is no limit to reproductive interactions. In fact recent amazing data have shown that we could reproduce with our distant relatives the Neanderthals. The genome of us who are the offspring of humans that moved out of Africa contains between one and four percent Neanderthal DNA, but interestingly the DNA of the descendants of our ancestors who remained in Africa does not have any such DNA.

The Need for a Second Green Revolution

The footprint of man on Earth has increased dramatically during the last fifty years. This is due to the success of our civilisation in developing markedly improved conditions for survival, including some major advances in medicine. This development will continue until we reach a state when there is a balanced rate of reproduction. Already today more than fifty percent of all women in the world have fewer than 2.1 children, the number that is needed for a balanced reproduction, but the higher rate of reproduction of the remaining women currently causes a continued increase in the global population. This may change in the future, depending on our success in achieving the global emancipation of women, leading to their own control of reproduction and a capacity to act in society under the same conditions that men do.

As mentioned, we have only very limited insight into the balance of actors participating in the ecological interplay. In particular, we do not know enough about the most important actors, the microorganisms. Still, politicians advised by environmental scientists attempt to formulate rules for what can be called “ecological” food products, and people believe that we improve our world by buying such products. However, conditions of life are rarely black and white. The production of food that sustains our lives has evolved since the introduction of agriculture. We use animals and plants, adapted for our own purposes, that would never survive under “natural” conditions. We have selected these sources of our food—often monoclonal—by exploiting spontaneous unique genetic changes that increase their quality and yield.

During the 1950s there were serious concerns that it would be impossible to produce enough food for the rapidly growing human population. It was projected that there would be starvation in large parts of the world by the 1990s. This did not happen. As predicted, the global population doubled from three to six billion humans during the fifty years after the Second World War, but the amount of food tripled, owing to increases in the yields of husbandry and the cultivation of plants. This event is referred to as the green revolution. Another three billion people will be added to the global population by 2050, and to feed them we will need another green revolution. This can be managed because we no longer have to rely on fortuitous spontaneous changes of the genetic material to improve the quality and quantity of our food. Due to the advances of molecular biology we can now both read and write the books of life. Today, therefore, we can introduce changes in the genetic material of different kinds of plants in a more secure and goal-oriented way, and produce the food we need in increased quantities and with improved quality. However, the use of genetic refinement (improvement)—in a political twist often referred to as “manipulation”—has come under debate, and amazingly the Eu ropean Union’s definition of “ecological” food precludes the use of genetic refinement in its preparation!

Are Viruses Dead or Live Material? The Definition of Life Revisited

We have already mentioned viruses several times. They are parasites in cells, and their life cycle therefore can be separated into two phases. One is the virus particle, the passive form for transporting the infection from one cell to the other. Many kinds of viruses are represented by particles with a strictly symmetrical shape, which allows them to aggregate into crystals. The observation of virus crystals, first in the 1930s, led to the conclusion that viruses represent dead material. However, when a virus particle attaches itself to a cell and deposits its genome into it, dramatic things can happen. The virus genome takes over control of the cell and directs it to produce the building blocks of new virus particles. Because of their dependence on cells, it is tempting to propose that viruses must have emerged after the establishment of cellular organisms, and further that they do not fulfil the definitions of life. However, this conclusion is highly contestable, and depends on the agreed-on definition of “life.” One would think that the recent impressive advances in molecular biology would make formulating such a definition easier, but that turns out to not be so.

It has always been a conundrum how to classify viruses. Are they dead or live materials? In fact it took me some fifty years before I found a satisfactory answer to this question. The answer is that it is inappropriately posed. The question we have to answer first is what definition of life we should use. Many different definitions have been proposed, and many of them start from cellular entities with varying degrees of independence from the environment. There is a major difference in the complexity of prokaryotes and eukaryotes, but there is no difficulty in accepting that microorganisms are alive. Still, in the world of microorganisms there are examples of dependence on other cellular structures for their survival, for example in rickettsia. In truth there is no coherent, or even resilient definition of cellular life.

If instead we take a chemical perspective, like the one proposed by Gerald Joyce, we can say that life is a (self-sustaining) replicative chemical system with the capacity to make errors, allowing it to be subject to evolutionary changes. This definition is independent of cellular structures, and could include viruses. The question to be asked, then, is not whether biological entity X is alive or dead, but whether it participates in evolution. If one asks this question of viruses, the answer is a resounding yes. Paraphrasing Descartes’s Cogito ergo sum —“I think, therefore I am”—one can state Existo, ergo pars evolutionis sum —“I exist, therefore I am a part of evolution.” The tree of life, as we said, is surrounded by a cloud of viruses, and even satellite viruses parasiting on them, and in fact even simpler biological entities that contain nucleic acid but do not code for proteins, like viroids. This new perspective on actors in evolution, rather than on cellular actors with some capacity for replication under given conditions, means some major challenges to central philosophical questions concerning the definition of life, and hence also on its supposed sacred dimensions.

How Did Life Begin?

There have been many speculations about the steps that preceded the emergence of the first primitive cell on Earth some 3.8 billion years go. It is now clear that RNA emerged before DNA. RNA, but not DNA, has the remarkable dual capacity to operate both as an information storage molecule and also as an operative unit, like an enzyme. It is further speculated that various primitive replicative systems with some resemblance to present-day viruses may have evolved, and then combined step-by-step to build up progressively more complex systems. Most of what happened at this time must remain speculative, in particular since it is not possible to define the exact (changing) conditions under which precellular life evolved. In the end, all the information to run the system came to use a single code, assembled in a linear molecule using a digital sequence, first in RNA and then in a combined DNA and RNA system.

The Sanctity of Life

Human rights have been discussed in human civilization since the eighteenth century. These secular rules of conduct have evolved and become encoded by the international community, represented by the United Nations. Progressively they have been expanded to discuss not only humankind in general, but also particular groups like women and children. The basic tenet is that all individuals have an equal value and—as emphasized in particular in some eastern Asian countries—dignity. Advancing molecular biological techniques allow us to compare the genomes of two individuals with increasing efficiency and speed. All humans are closely related because of our short history, but the number of identifiable small differences increases as the resolution and interpretation of retrievable data improve. The identification of such differences, however small, may encourage a subjective division of groups of humans into “we” and “them.” Even though there are no genetically definable “races” of humans, racial thoughts readily emerge, as is well documented in human history.

Modern molecular biological techniques also allow us to examine individual genes directing the synthesis of critical proteins, or a plethora of nucleic acids that have various—mostly unknown—regulatory functions. Prenatal diagnosis would allow the selection of embryos, but the critical discussion is how the information gained should be used. What degree of handicap do we want to avoid, and what are the consequences for the attitude of society toward people who are handicapped for other than genetic reasons?

The potential of the human genome is certainly immense. As in dogs, whose characteristics vary widely but which all have their genetic origin in some different variants of wolves, most likely the cross-breeding of humans could lead to the development of individuals ranging in height between 0.5 and 3.0 meters. Is this what we would like to see? Or perhaps we could in the future use genetic “doping” to achieve the same potential difference in performance as the chemical kind, and allow world records in athletics to continue to be broken in the future.

We also want to show respect for other forms of life, but how far should we extend this respect for life? We have already taken considerable liberties in our interaction with animals in our development of husbandry. Generally we have a deeper respect for animals the more complex their life form. We do not mind killing a mosquito. However, if we really have a complete respect for what we find in nature, we should be concerned for all actors in evolution, including for example the millions and millions of viruses. This of course does not make sense, since it would prevent us from preserving our own lives and health by using vaccines and antibiotics. I argued for the destruction of all existing smallpox virus materials when the disease was declared eradicated by the WHO in 1978. This was not done in the U.S. or in Russia, because of lack of trust.

In practice we discuss cellular life, and especially human cellular life. This then leaves the extensively debated and still contested question of when human life begins. Is it at conception; later during embryonic development when the circulation of blood pumped by the heart has been established; or, as it is usually discussed, when the development of the brain has reached the state where it can register pain, or has acquired the capacity to show some kind of consciousness? These are ethical questions that cannot be decided by biologists any better than by other people, but in any discussion one has to take into account the present state of knowledge in biology and the technological advances that allow interventions in the system. It is not science fiction to speculate that our growing knowledge about stem cells and cloning will allow us one day to develop a primitive twin that we can use for spare parts as we get older. Should this be done? The advance of technology will continue to force us to formulate answers to ever more complex ethical questions.