There was never a time when I had a burning ambition to be a scientist or a biologist. I had no idea what such beings were really like. Looking back all I can see is that I was always interested in nature study. My memories begin with the fields and woods on the outskirts of the town which, with my father, could easily be reached on foot. I was inspired by Enid Blyton’s character, Uncle Merry, who cheerfully guided his nephew and niece, who were always eager to learn about wild things, down lanes and through woods. My other source of information was the wireless, and Children’s Hour. Here there was a regular visit to the caravan of Romany and his dog Raq, who revealed the delights and myteries of the countryside to the programme’s ever-questioning Aunts, Doris and Vi, as they went on virtual walks through a gypsy’s universe.
I suppose the nearest I got to learning about what it would be like to be a biologists was as a regular radio listener to Nature Parliament. This programme was first broadcast in January 1946, and had a long, and extremely successful run for any broadcast series. In the 1950s it was the most popular of all the B.B.C. Children's Hour programmes. Request Week was a broadcasting high-light for the audience, when, twice a year, children had the opportunity of voting spontaneously for their own programmes, Nature Parliament was invariably in the top flight among other popular items.
Its format was simple, consisting of a regular team of broadcasters, each member of which was eminent in his particular sphere, and, indeed, outside it. As I remember it the regular members were L. Hugh Newman, Peter Scott, and James Fisher. The Chairman was Derek McCulloch (Uncle Mac; Head of BBC Children’s Programmes).
L. Hugh Newman, who thought up the idea of a Nature Parliament, generally handled all the questions on moths, butterflies, dragon-flies, beetles, and small creatures. By sheer hard work and endeavour he had built up one of the most successful and best known of ‘butterfly farms’. Situated at Bexley, Kent, it was a centre for the breeding of moths and butterflies, for research and investigation in the world of winged creatures. It was via the Butterfly Farm’s postal sales that I spent my pocket money on eggs and larvae, and the mounted adults of butterflies and moths that I could never hope to see as an urban child. I also built up a collection of pinned insects in a glass topped display case I made from an old picture frame. I remember, at one time I had a Death’s Head Hawk and a Swallow Tail on show. I also have to admit that I played a part in the local extinction of common wildlife to extend my collection. Once I actually caught a rare exotic prize from the backyard; a Humming Bird Hawk Moth that was visiting phlox flowers on a mid-summer’s evening. Unfortunately, I did not realize that the destructive power of mites could easily be held at bay with moth balls, and my collection soon crumbled to dust.
The members of Nature Parliament were the pioneering arbingers of the current media presenters of television. Peter Scott, explorer, painter, author, and sailor, son of a greatly distinguished father, was the expert on birds, particularly in the field of migration. Ducks were his delight and wild geese his great interest. He had recently created the Severn Wildfowl Trust in Gloucestershire, where he assembled the finest collection of living waterfowl in the world, and also provided a wonderful refuge for wild waterfowl. It was from here that he founded the World Wild Fund for Nature. James Fisher, was probably one of the greatest authorities of his day on birds, and could be relied upon to answer the most incredibly difficult questions, on subjects ranging from ornithology to the probable temperature at the top of Mount Everest. He had a most pleasant wit and an apparent liking for young people. I managed to find some of his books in the local library.
Each member had many books, articles, and papers to his credit, which were all hall-marks of qualification. As a team of real experts they left no stone unturned, no reference book unthumbed in excited interest, to answer candidly the pertinent, complicated, exacting, and penetratingly imaginative questions posed by young listeners.
Much later I worked closely with Peter Scott in formulating the Wildfowl Trust’s research policy as Chairman of the Slimbridge Scientific Advisory Committee. Once I asked him if he had a favourite question and answer. He readily told me about a girl who was very interested in the Antarctic, especially in penguins. She asked if anyone could tell her, if, when she was older and went to the Antarctic and brought back a penguin, could she keep it at home, or must she give it to a zoo. Also, she wanted to know if they were delicate animals. Peter’s answer was. ‘They are rather delicate, and they have enormous appetites, so that feeding them might be rather expensive in fish. You would not have to give it to a zoo, of course, but after a while I think you would probably want to”. This is a measure of the gentleness of all the Children’s Hour ‘parliamentarians’. They always took a positive approach to the letter writers, and never disparaged even the most impractical aspect of their hesitant imaginings about nature.
The grand design
Another view of my career emerged when I began the serious study of biology in the sixth form. There, after spending a year as a wage earner, I felt a sense of entering a grand cultural design with more than 2,000 years of history. This was the historian in me, even then trying to find significance in this particular move. I had no idea that the pace of change in my lifetime would produce such a great shift in modeling living systems, which in the 1950s was still close to what Aristotle and the other Greek natural philosophers had established.
The Greek’s idea that natural phenomena could be studied and understood by man was based on the structure of organisms. Because of their faulty of reasoning, their results were often poor. After Aristotle, the Roman influence did little to encourage anatomical investigation. Galen was the outstanding anatomist in Rome, but due to his limited experience with human dissection his writings were full of inaccuracies. With the decline of the Roman Empire, Galen's writings were preserved in the Moslem world for about 1,000 years. Later, in Italy and in France, the long-lost works were translated back into Latin and Greek and were used as textbooks by medical students. Most people thought that these must be correct because they had come from the Greco-Roman classical age. During the early sixteenth century, Vesalius established the basis for modern anatomy by conducting numerous detailed dissections.
I had become part of this continuation of a sequence of serious biological modellers, who delved below the skin into the dynamics of anatomy. The first of these was William Harvey, who, in the 17th century, using a knowledge of anatomy, determined the true function of the heart and blood vessels. Other physiologists seeking to understand a function began to realize that structure and function must be studied together. Explorers returned to Europe with examples of thousands of new creatures that had to be identified and cataloged. Taxonomists devised classification systems that were based largely upon structure. This, too, broadened the study of anatomy. In fact, the records show that by the mid-16th century it was possible to compare the anatomy of humans and birds and discern great similarities in the disposition of their bones. The logical step to make a connection of ancestry in cosmic time was not made until Darwin published his theory of evolution three hundred years later.
Taking a narrower focal point, the discovery of the cell as the structural unit of most organisms was inevitable once the microscope had been invented. No single individual can be given complete credit for this discovery. Malpighi, Leeuwenhoek, and Hooke were outstanding microscopists. The first clear and precise statement regarding the cell as the basic unit of structure was made by Dutrochet in 1824. I actually made contact with this particular stream of discovery when I was invited to give the annual Leeuwenhoek lecture at the University of Leiden. Leiden was where cells were first seen with the human eye. By that time in my life, I was firmly commited to a concept I described as cellular ecology. This simply said that the way a cell functions, and even the type of cell it is, is determined by its position in a three dimensional lattice consisting of other cells, blood vessels and the fibres and sheets of non-living tissue that make up the histologists landscape. It is maintained in its correct place and function by chemical flows from the cells that surround it. Even today, very little is known about the fundamental biochemical ecology.
The concept of unity within organisms was greatly strengthened as a result of inquiry on the structure of the cell. One important finding was Robert Brown's generalization about the nucleus. Subsequent inquiry demonstrated that every cell contains a nucleus, or nuclear material, at least during a portion of its life. Another important contribution to the concept of unity was the pronouncement by Virchow that every new cell arises from a preexisting cell. Later, Flemming added greater emphasis to the concept by demonstrating that during cell division the chromosomes within the nucleus divide and are distributed equally to two daughter cells. This method of reproduction, which he named mitosis, was eventually found to apply, at least in principle, to all cells.
Various factors tended to enlarge cellular level inquiry during the nineteenth century. The investigations of Von Siebold reinforced the concept of unity and focused attention on the independent one-celled organisms. Pasteur, with his investigations of fermentation and disease, helped found the science of microbiology—a science that expanded rapidly and through which important contributions have been made to our knowledge of cells. Virchow's investigations of abnormal cells helped establish cellular pathology as a science, thus increasing the number of workers who were interested in normal as well as abnormal structure. I was following this logic when, in my proposal for a place at Oxford, I put forward a research scheme to study inborn errors of metabolism.
My research is now part of the history of cellular level inquiry and is inseparably linked with the technological developments that enabled investigators to observe and analyze the nature of cellular structures. Refinements in the light microscope reached a climax during my time in Oxford with the development of the phase-contrast microscope. At this time, however, the most dramatic development in the history of cellular level inquiry has been the impact, within the past 20 years, of the electron microscope, a prototype of which I also used for my research. Intensive research with the electron microscope has enabled investigators to see cellular structures magnified several thousand times, and also to study their chemistry at a fine level. Though there are certain limitations inherent in the electron microscope, the results of inquiry with this instrument have enabled modern biologists to develop vastly improved models of cell structures.
Another dimension of biology is investigated at the molecular level. In fact this is where I started my interest in science by stdying O-Level Chemistry. Here I learned that matter is composed of particles called atoms. The simplest forms of matter are groups of atoms that all have the same chemical properties. These simple forms of matter are called elements. There are 92 natural elements. Atoms bond with each other and form molecules. A certain amount of energy, called chemical-bond energy, is possessed by the bonds that hold atoms together. It was the bond energy that life has evolved to utilise to hold organisms together and make them grow. Nothing was known about this when I was at school.
My first link between chemistry and biology was the carbohydrates. These are an important group of organic molecules found in living matter. There are three classes of carbohydrates: mono-saccharides, disaccharides, and polysaccharides. The best-known simple sugars are the 6-carbon sugars: glucose, fructose, and galactose. The most common disaccharide is sucrose, which is table sugar. The polysaccharides are by far the most common carbohydrates. Cellulose, which is formed mostly in the cell walls of plants, is the most abundant polysaccharide. It is very resistant to digestion and is the main structural component of many familiar substances.
I learned that the proteins are among the largest molecules in living matter, and in biochemistry they are also of immense importance in the structure and functioning of organisms. The key to understanding the role of protein is an understanding of the structure of the molecule. The sequence of amino acids in the molecule is of fundamental importance. The coiling and folding of the amino acid chain is caused by the various projecting side groups on each amino acid
Water is the most plentiful molecule found in living matter. Because of the bonding arrangement within the water molecule, it has polar characteristics. This in turn explains its remarkable ability to cause other materials to dissolve within it. It had a particular fascination regarding the ability of animals to hold water within themselves as they lived within a terrestrial environment. This link between chemistry and biology came relatively late into my life, when I joined a group of fresh water and marine ecologists in the Department of Zoology at Sheffield.
Ecology is the third level of biological organisation. Prior to the twentieth century, biologists sought answers to biological problems primarily by looking to the interior of organisms. But not all biological problems can be solved by investigating an individual's organs, cells, or molecules. Specifically, there are two main aspects of an organism's exterior environment. The biotic environment includes all other living organisms, and the abiotic environment includes all the physical surroundings of the individual.
There is a hierarchy of organizational levels above the level of the individual organism. The population is the first level above the individual. It is defined as the total number of a given species within a certain space and at a particular time. The community to be the next level of organization above the population. The community may be defined as the total number of populations within a given area. A study of populations within a community shows that they are dependent upon each other. Most ecologists now prefer to study the populations of a community and their physical environment as a single interacting unit. Such a unit is called an ecosystem. The biosphere is the sum total of all life on this planet. And the ecosphere, the highest level of organization, includes the entire world and all the life that is in it.
The body has an internal ecology. For example, if harmful pathogens, such as viruses and bacteria, get past the outer defenses of the body and invade its interior, they are met by a powerful surveillance and attack force called the immune system. The chief talent of the specialized cells and molecules that make up the system resides in their ability to distinguish self from non-self. If the invading substance is different in composition from a similar substance in the body being invaded, then it is marked for destruction. Organ or cellular transplants from a donor who is not an identical twin (or closely matched genetically) are attacked and destroyed.
Sugar the stuff of life
At the time of my birth, the research are described as ‘intermediary metabolism had coalesced into a well-defined subfield of biochemistry since the turn of the century. The central task in the early history of intermediary metabolism was to discover the stages by which foodstuffs are broken down in the animal body until they form the final end products that are either excreted or breathed out from the lungs. The chemical boundaries of this problem were directly traceable to the theory of respiration proposed at the end of the eighteenth century by Antoine Lavoisier. Between 1777 and 1790 hr showed that animals burn carbon and hydrogen to form carbonic acid and water, that this process maintains animal heat, and that it is somehow connected with the mechanical work an animal performs. From that time onward chemists and biologists contended with several fundamental questions, which took on different forms with progressive changes in the state of knowledge and of the technical methods available for investigations. They asked where the combustions take place, what is the nature of the compounds that contain the carbon and hydrogen while they are undergoing respiratory oxidation, and why substances that require a much higher temperature to burn outside the organism can be oxidized within it at normal body temperature.
During the early nineteenth century advances in knowledge about organic compounds of biological origin followed on from the conquests made in organic chemistry. The European leader of this work was Germany, and an important practical outcome was the creation of its great synthetic dye industry. The work of chemists led to the generalization that there are three main classes of foodstuffs — carbohydrates, fats, and "albuminoid bodies," or as the latter were called later in the century, proteins — each of which is decomposed by combining with oxygen to form simple end products. Eventually it became possible to describe these overall reactions in terms of specific chemical equations. Thus, the oxidation of the physiologically most significant carbohydrate, glucose, was expressed as:
C6 H,2O6 + 6 02 = 6 CO2 + 12 H2O :
For protein the situation was complicated by the presence of a fourth element, nitrogen, that was not completely oxidized but excreted in the form of urea. From the time of Justus Liebig's influential Animal Chemistry of 1842 onward, however, it was generally assumed that at an early stage in their degradation, proteins are split into a nitrogenous portion that is excreted, and a non-nitrogenous portion that is further oxidized in a manner similar to the non-nitrogenous foodstuffs. By the 1860s medical physiologists were developing methods capable of measuring precisely the food intake, the excretions, and the respiratory exchanges of animals and humans. With these methods they were able to establish the quantitative proportions of each of the three classes of foodstuffs metabolized under varied physiological and pathological conditions.
The same chemical advances that enabled physiologists to deal so effectively with the overall process of respiratory oxidation persuaded them that in between its initial and final stages lay an extended hidden sequence of intervening steps. By the 1830s chemists could induce, in organic compounds in the laboratory, controlled partial oxidations that gave rise to multiple compounds containing progressively higher proportions of oxygen before reaching the ultimate breakdown products. Those who applied the growing knowledge of the chemistry of organic compounds to physiological questions inferred that equivalent series of step-by-step oxidations must occur within organisms, especially within animals. Until near the end of the century, however, these intermediate stages, thought by then to occur within the minute cells of the tissues, seemed inaccessible to direct investigation.
In the last decade of the 19th century and the first decade of the 20th century, physiological chemists began to probe more persistently the problem of what takes place between the starting and the end points of metabolism. Stimulated in part by new knowledge of the structural formulas and reaction mechanisms of biologically important compounds, they were able to propose more imposing theoretical reaction sequences to test experimentally. The work of Emil Fischer and others began to reveal the molecular architecture of polysaccharides and proteins, showing them to be made up of small units linked through characteristic types of readily hydrolyzable bonds.
As strong evidence emerged that the foodstuffs are dissociated into these smaller molecules during digestion, the main thrust of investigations of metabolic processes could be transferred, as Frederick Gowland Hopkins, the first ‘British biochemist’ put it, from "complex substances which elude ordinary chemical methods" to "simple substances undergoing comprehensible reactions." Further encouragement to the study of these reactions came from Eduard Buchner's discovery of cell-free fermentation. In the early years of this century biochemists optimistically hoped that the reactions comprising cellular respiratory oxidations too could be investigated by ordinary chemical methods in materials extracted from organized tissue. It was during those years the term intermediary metabolism began to appear with increasing frequency as the visible sign of a newly emerging specialty area.
In general discussions of respiratory oxidation the study of what were later called metabolic pathways was ordinarily not treated during the 1920s as a distinct subfield, but embedded within the broader subject of "the mechanism of physiological [or biological) oxidation processes." The dominant problem considered under this heading was still the old question of "why foodstuffs, which are generally not attacked by molecular oxygen at lower temperatures, are burned with the greatest ease to their final end products within the organism." During the 1920s debate fixed particularly on two rival theories identified with Heinrich Wieland and Otto Warburg. In 1912 and 1913 Wieland had clarified and supported experimentally the view that biological oxidations do not consist of successive additions of oxygen directly to the substrate molecules, as had commonly been assumed until then, but of the removal of pairs of hydrogen atoms, which afterward combine with oxygen to form water. The critical catalytic action required for this process to occur in organisms, Wieland maintained, was the "activation" of the hydrogen. This activation he attributed to a class of enzymes, specific to the individual substrate molecules, which he named dehydrases, (afterward called dehydrogenases).
In 1924, Warburg showed that certain iron-heme compounds can partially oxidize various biologically significant molecules, and that the reaction is inhibited by substances such as hydrogen cyanide (HCN) that were known to poison cellular respiration. Warburg inferred that there is in cells an Atmungsferment, containing iron, that "activates" molecular oxygen, alternately combining with it and transferring it to the substrate molecules. Warburg adamantly rejected Wieland's theory, and the controversy between them and their respective supporters took on during this period a sharply polemical tone."
Wieland and Warburg both investigated the oxidation of molecules they considered representative of substrates that are oxidized in cells, but they were both more interested in elucidating the general mechanism of oxidations than in the particular sequences of oxidation reactions that might comprise the integrated metabolic processes. This apparent incompatibility of Weiland and Warburg was resolved when others directed their main efforts toward the working out of such sequences. Dehydrogenation is the central principle responsible for the first chemical attack on food stuffs and the terminal process involves Warburg’s cyanide sensitive system whereby the hydrogen is combined with oxygen.
Intermediary metabolism was an active area of investigation, pursued by some of the most eminent individuals within the expanding science of biochemistry. Successes did not come as easily as those at the turn of the century might have expected, however, and by the 1930s there was still no definitive theoretical framework to integrate what biochemists had been able to learn about the compounds and reactions involved in the intermediate steps of the respiratory oxidation of foodstuffs. Investigators had, however, accumulated a promising array of methods and of viewpoints concerning the types of mechanisms that must be involved. They had identified certain organic compounds as nodal substrates in these processes. There were established theoretical and methodological assumptions that channeled research into well-outlined directions, and that delimited the range of acceptable interpretations of particular experimental results. The following section will not attempt to summarize the intricate chronological evolution of the field over these 30 years, but to survey how prior developments in that field might have looked to someone finding his place in it in 1933. As far as I am concened that person was Adolf Krebs.
In his preliminary paper Krebs's assertion that the absence of urinary ammonia in kidney diseases was due to the failure of those organs to deaminate amino acids was a speculative inference drawn from his results on normal tissue. Now he was able to back up his claim with more direct evidence. During the spring, he had carried out experiments on pathological human kidney tissue supplied to him from the clinic. With slices taken from patients who had died of tuberculosis, he could now show that those sections which presented pathological histological changes produced little or no ammonia in the presence of amino acids."
The logical fissures that appear so gaping in the first paper had not been completely closed in the second; but Krebs had managed to reduce them to modest cracks. Having rather hastily drawn conclusions that were not fully supportable by the evidence he had available at the time he published them, he had subsequently been able to produce the evidence he needed to provide sound support for most of the same conclusions. That was not exactly a classical scientific method, but he had proven resourceful enough to take several questionable conceptual leaps and still land on his feet.
In April of the previous year he had discovered, using kidney slices, the way the body makes urea as the waste product of protein metabolism. In essence, the waste nitrogen is transferred to an amino acid called ornithine, to make a larger amino acid called ornithine. Ornithine takes another transfer of nitrogen which turns it into a third amino acid called arginine. Urea is split from arginine to leave ornithine which is ready to take up more waste nitrogen. The overall picture is a cycle of reactions in which one molecule of ornithine can produce urea over and over again. Waste nitrogen never occurs as ammonia, the most obvious intermediate. He emphasised this using both normal and diseased human kidney early in the following year.
After he had finished his paper in 1933, Krebs was ready for some relaxation. In a cheerful mood he wrote to Hermann Blaschko on Easter Monday,
Dear Blaschko,
Do not be angry with me for my laziness about writing. During the last days and weeks I have had no time to rest.
I have now been sitting here in St. Peter for 4 days, in splendid summer weather, and I am spending my political leave here.
On Tuesday the blow struck us. All Jews in the Baden state service were sent home. The Chief and a few others are temporarily declared indispensable. Everyone counts as a Jew who is 25% "impure" (1 grandparent). We all had to submit geneologies, whereby some surprises came to light; for example, Post, 25%, Janssen (Pharmacology) 50%. '; Work in the laboratory was also forbidden within an hour's notice. It is likely that we shall be dismissed on June 1st.
It was on June 19th that he he decided to leave for England.
Blurred Boundaries
Immediately after the War we began day-trips from Grimsby to Hull. This entailed an exiting journey by train to New Holland, from where the paddle steamer, either the Lincoln Castle or Tattershall Castle, ferried the passengers across the Humber. It was on the first of these journeys that I first made contact with Thornton Abbey. The station was about a half a mile away, and even at this distance the great gateway dominated the view through the carriage window. Once these trips became something of a routine, the second important visual experience was a walk around the Ferens Art Gallery- after a Woolworth’s hot-dog! Then came the Hull City Museum. At that time my hometown had neither a museum nor an art gallery. Looking back, it seems incredible to me now that I had reached the age of twelve without having set foot in a museum. What started me thinking of these boyhood experiences was the remembrance of my first view of a Roman mosaic floor that was mounted on the wall of the great entrance stairwell of the museum in Hull. In particular, I recall vividly the way in which the crisp colourful design gradually became less and less distinct as I made my way up the staircase until, standing alongside it, I could only see incomprehensible patches of muddy coloured tiles. There was a similar experience of paintings in the Ferens Gallery. The thick dabs of the impressionists and the juxtaposition of the tiny dots of primary colours methodically laid on the canvas by the pointillist followers of Seurat, only appeared sensible and beautiful in an overview. Looking back on my scientific career as a biologists, I am now taking these boyhood optical illustions for the consistent mind-set that has conditioned my approach to research. They are my metaphor for individuality and independence being illusions. The American biologist Lynn Margulis has actually used pointilism as a metaphor for the organisation of life itself. She says,
“We live on a flowing pointillist landscape where each dot of paint is also alive. Earth itself is a living habitat, a merger of organisms that have come together, forming new emergent organisms, entirely new kinds of "individuals" such as green hydras and luminous fish”
These unseparable uneasy, and improbable, yet inseparable biological alliances between living things are at the core of species and ecological diversity.
To carry the art metaphor a bit further, like Gauguin who dispensed with conventional perspective and concentrated on bringing the picture surface together to make a decorative unit, so it is, but only in certain places, that animals often equibrate with plants to make an ecological pattern characteristic of a particular kind of interaction. Human landscaped gardens are the highest level of such plant/animal alliances. These kinds of blurred boundaries between life forms speak of our vision of self and our sense of place on a planet teeming with life. It is my contention that biology with physics and the arts is a blend that links cosmology and the arts with the human imagination. The universal cultural concept of ‘Mother Earth’ is an inevitable outcome of thinking across these subject boundaries.
There is no clear distinction anywhere on the Earth's surface between living and nonliving matter. There is merely a hierarchy of interactivity going from the "material" environment of the rocks and the atmosphere to the living cells. Only at great depths below the surface do the effects of life's presence fade. The great debate at these interdisciplinary boundaries concerns the question of whether the Earth is alive as a super-organism.
The concept of Mother Earth has been widely held throughout human cultural history and has been the basis of a belief which still coexists with the great religions. As a result of the accumulation of evidence about the natural environment and the growth of the science of ecology, there have recently been speculations that the biosphere may be more than just the complete range of all living things within their natural habitat of soil, sea, and air. Ancient belief and modern knowledge have fused emotionally in the awe with which astronauts with their own eyes and we by indirect vision through our TVs have seen the Earth revealed in all its shining blue beauty against the deep darkness of space. Yet this feeling, however strong, does not prove that Mother Earth lives. Like a religious belief, it is scientifically untestable.
However, in an effort to provide a scientific basis for the belief, the space scientist James Lovelock, envisioned the Gaia hypothesis. Gaia enshrines the idea that the Earth is alive. To Lovelock, journeys into space did more than present the Earth in a new perspective. They also sent back information about its atmosphere and its surface which provided a new insight into the interactions between the living and the nonliving parts of the planet. From this has arisen the hypothesis in which the Earth's living matter, air, oceans, and land surface form a complex system which can be seen as a single organism and which has the capacity to keep our planet a fit place for life.