the Leaven lives

Pharmaceuticals: a science-based industry influenced by profit. Image:bio+ve

I’ve now posted most of the initial stages of a  book that I’ve been working on. It’s about how leaven in the Bible is interpreted through the mind of a slightly deluded, molecular biologist specialising in yeast research.  In many ways, the scientific community is similar to  religion. Many people who work in it are doing so to benefit others in a collaborative effort that is occasionally overidden by other influences.  In fact leaven is used in the Bible to metaphorically represent how influence permeates through society. It has as much relevance in science as it does in religion. Money seems to fuel the same kind of corruption in science  as in religion, leading to conflict and controversy. Also both science and religion seem to discriminate against women. This all seems to have been affirmed by Paul the Apostle.. who seems to be, hypocritically, under a leaven-like influence. Paul wrote a few of the books in the New Testament but seems to have never witnessed the teachings of Jesus first hand. I believe it’s time that a pop science book addressed equality. If you’d like to read my efforts so far and leave any comments (good or bad) please visit the Leaven.

From figs trees to laboratories

[The Leaven – exploring the relationship between science and religion (cont)]

The development of yeast molecular biology can literally be used to assess the impact that the application of scientific research has had on 21st century society. Scientific researchers often describe yeast as the workhorse of eukaryotic molecular biology with many laboratories devoted to studying this single-celled organism, as much of the information derived from it can be equally applied to the study of human cells.

Most modern laboratory strains of yeast originate from one particular Saccharomyces cerevisiae strain, EM93, isolated from dried figs in Merced, California in the 1930’s by Emil Mrak. This strain turned out to be heterothallic, meaning that cells existed as two types of sterile haploids, with a single copy of each gene, that when fused together formed a fertile diploid that could perform meiosis in a similar way to that seen in human cells. Up until this point most strains studied were homothallic, this meant that all haploid cells were of the same mating type and capable of fusing together to form a fertile cell known as a zygote. The emergence of a heterothallic strain meant that the genetic stability of a culture could be placed under greater control, as it would remain haploid until the other haploid type was introduced and then through the production of mating phermones followed by cell fusion a diploid cell could be created.

Green Fluorescent reporter gene in yeast cells. Image: bio+ve

So why has yeast become such a popular organism to study molecular biology and why is this microbe chosen in favour of others microorganisms? Firstly, Saccharomyces is non-pathogenic and does not present a threat to human safety. Therefore laboratory workers do not require expensive protective equipment to practice research. Saccharomyces is also easy to contain as is not usually airborne unless transported involuntarily by animals and insects. Another reason  is the ease by which it is cultured. Yeast can be grown easily and only requires a suitable carbon source, nutrients and appropriate physical conditions to continue multiplying. Additionally, these requirements can also be used to control the rate of cell division, for instance, by altering temperature or by creating metabolic mutants. Mutants are generated either through using a mutagen or by manipulating DNA through genetic engineering. Genes involved in yeast metabolism can be mutated and then used as molecular markers. For instance if the genes for the requirement of an essential amino acid are defective then the yeast will not grow without that amino acid added to its immediate environment. If the defective gene is artificially replaced by a functional one then the yeast cell will be able to continue growing without the need for that particular amino acid. Armed with this knowledge researchers are able to introduce fragments of DNA fused to these marker or reporter genes. If the yeast is able to grow without the selected amino acid this means that the DNA of interest to the researcher has been successfully introduced into the cell. This approach has led to the characterisation of countless genes and proteins in yeast and from other organisms.

Another reason why yeast is used as a molecular model system alongside other well-known microbes, such as Escherichia coli, is because it is a eukaryote. E. coli and other bacteria are prokaryotes, in contrast to eukaryotes they only have one chromosome housed in a cell without a nucleus. In yeast cells, DNA is packaged in chromosomes stored in a nucleus in a similar way as in human cells. Yeast has 16 individual chromosomes compared to 23 in humans. Surprisingly, there are only four chromosomes in the multi-celled fruit fly Drosophila another model organism used for biological research. Yeast also has the advantage of being able to grow just as happily with one set of chromosomes, in haploid cells, as with two or more sets of chromosomes, diploid and polyploid respectively. Additionally, as yeast is a single celled organism without the complexity of cellular differentiation it can be used to study the cell-cycle at a fundamental level. It can be used to study mitosis and meiosis. Many mutations that cause human disease are introduced during meiosis. Following cell fusion or mating, two haploid cells form diploids which can produce four individual haploid cells known collectively as an ascospore. After microscopic dissection of the ascospores, researchers can study recessive mutations and the complicated exchange of genetic material during meiosis by counting the numbers of surviving progeny. The information derived from yeast studies aids the study of genes involved in tissue development and cell differentiation in higher eukaryotes, such as Drosophila. Adding to all these factors many of the biochemical and cellular functions in yeast are conserved in human cells. Yeast therefore is a simple and practical system to study the mechanism of human cell division.

Leaven in a molecular era.

[The Leaven – exploring the relationship between science and religion (cont)]

Not only does yeast now serve as one of the most important organisms throughout domestic history, in recent years it has also substantially contributed to biological research. The numerous molecular techniques that have evolved in yeast have allowed it to make an important contribution to a number of areas in science. Through studying various types of yeast and other microbes, scientists now know a great deal about the molecular processes involved in cell division, rapid evolution and disease.

Fortunately, individuals with skin diseases are no longer thought of as unclean and are normally treated within the community. Scientists have greater understanding of disease management and although quarantine and hygiene are still practiced they are now carried out in order to reduce disease transmission. In the majority of cases, people are not ostracised when they are infected by disease, although fears and anxieties can still be generated through sensational media coverage. Nevertheless, even in this molecular age, some transmissible diseases are still associated with sins of the flesh and can lead to social ostracisation.

Yeast colonies in an array. Each spot contains thousands of yeast cells. The plate shows synthetic lethal interactions when the interaction of 2 or more genes cause cell death (shown by colonies with reduced/no growth colonies). Image uploaded by Masur

There are still many diseases that generate fear because they are untreatable. Some of these have evolved through human activities, such as Bovine spongiform encepthalopathy (BSE) which gives rise to a human form of spongiform encepthalopathy called variant Creutzfeldt-Jakob Disease (CJD). The causative agent of BSE is a defective version of a protein called prion that is similar to one found in the brains of sheep with Scrapies. The prion protein is transmitted horizontically and causes disease through disrupting the normal function of the native protein. Studying the molecular mechanisms by which proteins change conformation to become prions in yeast has led to a greater understanding in the pathology of this disease. Many other human diseases, especially cancers, can be researched by studying molecular processes first in yeast.

Cancers arise when cells begin to divide abnormally due to mutations in DNA. Cancer research investigates the mechanisms that encourage these mutations to arise. The mechanism of cell division is often studied in fission yeast, Schizosaccharomyces pombe. Unlike Saccharomyces cerevisiae, which divides by budding, S. pombe divides symmetrically in a similar way to human cells. Fission yeast originates from Africa were it is found growing on banana skins and is used to ferment beer. Through research in this area scientists have reached many milestones in the mechanisms that have caused various cancers leading to greatly improved clinical treatments. Work yeast genetics has greatly contributed to our understanding of cell cycle research and has led to the award of a Nobel prize in 2001 to three scientists who led pioneering work in this area: Paul Nurse, for his work in S. pombe and human model systems; Leland Hartwell, for his work in S. cerevisiae; and Tim Hunt who used sea urchins as a model system. Researchers later found similar cell division genes in human genomes.

Scanning electron micrographs of Fission yeast (Schizosaccharomyces pombe). Image by David O Morgan.

In addition to investigating diseases, yeast is also used as a model system to research ageing. Saccharomyces cells can divide by budding a number of times but the new bud is always physiologically younger than the mother cell. Each cell produces about thirty buds depending on the environmental conditions and other factors. About thirty genes in yeast have already been found to be involved in ageing. The main factors seem to be related to metabolic capacity, resistance to stress, gene dysregulation and genetic stability. Encountering certain environments that would overload any of these factors would also affect longevity. For instance, excessive oxidative damage or radioactivity would lead to a high level of mutations that will reduce the number of times that a cell can bud. Excessive oxidation is associated with the consumption of calories; so caloric restriction should result in increased longevity. This has been demonstrated in yeast, limiting the amount of nutrients and carbohydrates available in growth medium leads to a longer generation time and life span.

The Leaven Parable

[The Leaven – exploring the relationship between science and religion (cont)]

Then the disciples came to Jesus and asked him, “Why do you use parables when you talk to the people?” Jesus answered, “The knowledge about the secrets of the Kingdom of heaven have been given to you, but not to them. For the person who has something will be given more, so that he will have more than enough; but the person who has nothing will have taken away from him even the little he has. The reason I use parables in talking to them is that they look, but do not see, and they listen, but do not hear or understand. So the prophecy of Isaiah applies to them:

‘This people will listen and listen, but not understand; they will look and look, but not see, because their minds are dull, and they have stopped up their ears and have closed their eyes. Otherwise, their eyes would see, their ears would hear, their minds would understand, and they would turn to me, says God, and I would heal them.’

As for you, how fortunate you are! Your eyes see and your ears hear. I assure you that many prophets and many of God’s people wanted very much to see what you see, but they could not, and to hear what you hear, but they did not [Mk 4.10-12; Lk 8.9-10; Matt 13.10-16].”

Jesus’ teachings and philosophies are predominately analogical; he tried to encourage new insights by allowing people to draw comparisons with familiar situations. Perhaps this is why simple foodstuffs and domestic chores feature so many times in the Bible. It is fairly evident that his preferred audience are not the wealthy or powerful so many of the terms he uses are familiar to them. By using parables he is encouraging freedom of thought in an imaginative style that would appeal to this audience. Parables encourage self-assessment, are memorable and others could pass the stories through the community. Moreover, they would permeate through society in a leaven-like manner.

Return of the prodigal son. Rembrandt, 1665.

The parables also tend to be grouped together by subject manner. For instance the parable of the Lost Sheep is grouped with the parable of the Lost Coin and the parable of the Lost Son [Lk.15]. These parables all deal with the issue of finding belief when it has been lost. In the Lost Sheep Jesus describes how joyous a shepherd is when one of his sheep strays and is found even though he has several that are not lost. Similarly, in the parable of the Lost Coin a woman loses one of her few coins searches frantically for it and rejoices when it is rediscovered. In the final parable a father celebrates when a sinful son repents, he was lost and then was found. Some of the parables are told within the context of life at that particular time in history, perhaps referring to a current or political situation. Therefore, the parables are sometimes difficult to interpret accurately.

The Leaven parable, mentioned by Mathew and Luke, is grouped with several parables describing the Kingdom of Heaven, such as the parable of Weeds [Matt. 13.24-47] and the parable of the Mustard Seed [Mk. 4.30-32, Matt. 13.31-32; Lk. 13.18-19]. In each of these parables the coming of heaven could be interpreted as the end product resulting from the growth of all these items; the leavened loaf of bread, the weed-free harvest and the fully-grown tree from a mustard seed. The parable of Weeds describes how the Kingdom of Heaven is compared to a field sown only with good seed. Any weeds that grow represent evil and are separated from the crop to be destroyed by the harvesters. In the context of the era leaven may have had a different connotation. The parable of the Leaven consists of just two sentences:

“The Kingdom of heaven is like this. A woman takes some leaven and hid it in three measures of meal until the whole batch of dough rises”
[Matt. 13.33; Lk. 13.20]

To many this parable is thought to illustrate how the Gospel will slowly permeate through society until all is converted to Christianity. This is in contradiction to how leaven is usually interpreted in the bible, to symbolically represent corruption. The leaven parable can be divided into three component parts: the leaven, the woman and the meal or flour. Each of these component parts plays a different role in the message being conveyed within the parable and are discussed separately in following posts.

…that’s not acne, it’s the wrath of God

[The Leaven – exploring the relationship between science and religion (cont)]

Communities in the Biblical era knew nothing about the causative agents of disease. Despite this, the Old Testament contains valuable guidance on how to cope with the challenges presented by contamination and disease. In this period many extremely unpleasant diseases, such as smallpox and bubonic plague, would have been endemic and had the potential to wipe out entire communities. Unsurprisingly, epidemics were thought to be plagues summoned by supernatural beings, especially as some sectors of a population would appear to have greater vulnerability than others. When Ethiopian soldiers occupied the city of Mecca in 568 AD they were so afflicted by a severe disease that the conflict was forced to end. The migrating population had no acquired immunity to this disease, which was believed to be smallpox.

Smallpox was a viral infection and a major scourge at the time the Bible was written. The first detailed observations of it were recorded in 910 AD by al-Razi, an Arabic physician. Al-Razi was in charge of a hospital in Baghdad where he wrote a treatise on smallpox. His research gave some accurate epidemiological descriptions of the disease. For instance he noted that it was seasonal, occurring predominantly in the spring and he also distinguished the symptoms of smallpox from those of measles. The treatise was translated into Greek and Latin enabling Europeans to prepare for the disease as it spread towards their continent and other parts of the world. It is not clear if smallpox was as virulent a disease in ancient civilisation as it is today, but there were clearly references to dreaded skin diseases and plagues of boils in the Old Testament. Additionally, facial lesions that could have been caused by smallpox were found on the mummified body of Ramses V, who died as a young adult. As the pustules were still clearly visible the disease may have been the cause of his death. Smallpox eventually spread globally as a consequence of migration and trading. The Spanish introduced smallpox to South America in 1507 where members of an enslaved African community spread it to the local population. The disease spread around the Caribbean and in 1520 it was transferred to Mexico. It was believed that a member of a Spanish crew was suffering from the disease when one of their ships landed in Mexico. As it was an entirely new disease the indigenous people had no natural immunity or experience in dealing with it. When it arrived from Europe it practically obliterated the indigenous people of Mexico, the Yucatan and Guatemala.

Plague in the Bible. Painting by Matthias Gerung c1530-1532

As with smallpox, bubonic plague also spread globally through migration and trading. The causative agent of bubonic plague is the bacterium Yersinia pestis. It is a characterised by dark buboes, fevers and vomiting. Whereas smallpox is restricted to humans, bubonic plague could afflict both humans and animals resulting in a higher number of transmissible routes. Recent research believed that the disease originated from Nile rats and was then transferred to Black or Ship rats via its vector the tropical rat flea. It is thought that the disease may have become more virulent in the Black rat as it seemed to cause more fatalities in Europe than in the countries it originated from, or perhaps this was quite simply because the Europeans had no innate immunity towards the disease, a similar scenario to the one that allowed smallpox to devastate the indigenous population of the Americas. In 439 BC, an epidemic of bubonic plague that originated from Ethiopia arrived in Europe; the Greek, Thucydides, who survived the disease, recorded its progress. It caused the death of one in three people in Athens, including the statesman Pericles, and is thought to have contributed to the fall of classical Greece.

There is no doubt that plagues and skin diseases preoccupied ancient societies. Hebrews believed that illness and disease were the wrath of a powerful deity and therefore religion playing a prominent role in disease management. The High Priest had the unenviable responsibility of devising and implementing a programme of disease prevention by compiling and implementing rules and regulations:

The Lord gave Moses and Aaron these regulations. If anyone has a sore on his skin or a boil or an inflamation which could develop into a dreaded skin-disease, he shall be brought to the Aaronite priest. The priest shall examine the sore, and if the hairs in it have turned white and the sore appears to be deeper than the surrounding skin, it is a dreaded skin disease, and the priest shall pronounce the person unclean.
[Lev. 13. 1-4].

These regulations were a type of quarantine to prevent the spread of disease ensuring that infected individuals were segregated from the community until they were proven to be clean:

A person who had a dreaded skin-disease had to wear torn clothes, leave their hair uncombed, cover the lower part of their face, and call out, ‘Unclean, unclean!’ They remained unclean as long as they had the disease, and they had to live outside the camp, away from others, as did any other person that came in contact with an unclean person.
[Lev. 13.45-46]

Tuberculosis was another affliction that was very widespread and seemed to occur frequently. Evidence of it has been found in human skeletal remains. The bacteria that caused this disease are similar to the Bacilli that give rise to leprosy. Therefore people who had managed to survive tuberculosis were more likely to have immunity to leprosy, which was thought to be fairly rare at the time despite it being mentioned frequently in the Bible. When leprosy is mentioned in the Bible it is probably also referring to other more common infectious conditions such as ringworm, a fungal infection that gives rise to white hairs within infected areas, as described in the text of the Old Testament:

If anyone has a boil that has healed and if afterwards a white swelling or a reddish white spot appears where the boil was, he should go to the priest. The priest shall examine him, and if the spot seems to be deeper than the surrounding skin and the hairs in it have turned white, he shall pronounce him unclean. It is a dreaded skin disease that started in the boil.
[Lev. 13. 18-20]

Another Bacillus that caused skin lesions and may well have been the disease referred to as boils in the Old Testament, was Bacillus anthracis, the causative agent of anthrax.  B. anthracis is nearly always fatal when inhaled leading to respiratory failure and septic shock within two to three days. Prognosis is also not good when the B. anthracis is digested after eating infected meat. Cutaneous anthrax is the most common form of the disease accounting for 95 percent of all cases, if untreated the fatality rate is 5-20 percent, relatively low when compared to the other forms. Anthrax legions only occur in exposed areas, such as the hands and face, and are accompanied by local swelling. Ancient remedies for treating the disease included laying figs directly upon the sore. There may have been some benefit in this as figs have been found to contain a good source of natural antibiotics and vitamin A. Other natural materials with antibacterial properties such as sesame oil and wine were frequently used to dress wounds. The Hebrews discovered that these materials had beneficial properties through trial and error, in much the same way as how they knew that leaven could sometimes be impure.

…my distant relative is a lower life form

[The Leaven – exploring the relationship between science and religion (cont)]

Through research by evolutionary biologists we have now discovered that humans are more closely related to leaven than early civilisations could have imagined. Many of the human proteins involved in the fundamental functions of the cell,such as DNA replication, are conserved in other organisms, even in yeast and bacteria. In fact some human DNA can be expressed in bacteria and yeast to produce protein. Proteins that are homologous in different species are known as orthologues. DNA processing proteins, such as Polymerases, are often found in this category. For this reason the mechanisms of mutation in mammalian cells can be studied equally as well in yeast cells.

The big question is then why did not all yeast cells evolve into complex multicellular organisms like humans or even plants? Why are there still primitive cells like bacteria? As George Carlin, so eloquently put it:

If man evolved from monkeys and apes, why do we still have monkeys and apes?

The answer is that organisms are continually evolving, they are constantly finding new ways to preserve or obtain energy, therefore new species could arise at any time and, as a consequence, there must always be lower and higher life forms. It is the diversity of Life that encourages adaptations. Through a constant competition to obtain energy, diversity provides the resources on which selection can act. For instance, a group of higher species A are infected by lower species B and some are killed. Some A species were able to survive because they have a mutation that makes them more resistant to species B  but it also makes them less resistant to species C. It flourishes until it encounters species C. As consequence of  this cycle of adaptations, species A no longer resembles its original form and becomes subspecies Ab. So evolution depends heavily on a changing environment and the ability of an organism to adapt.  This allows the evolutionary route to continue in a perpetual cycle of various adaptations until many species of organisms evolve. Darwin called this process natural selection or the preservation of favoured races in the struggle for life:

If under changing conditions of life organic beings present individual differences in almost every part of their structure, and this cannot be disputed; if there be, owing to their geometrical rate of increase, a severe struggle for life at some age, season, or year, and this certainly cannot be disputed; then, considering the infinite complexity of the relations of all organic beings to each other and to their conditions of life, causing an infinite diversity in structure, constitution, and habits, to be advantageous to them, it would be a most extraordinary fact if no variations had ever occurred useful to each being’s own welfare, in the same manner as so many variations have occurred useful to man. But if variations useful to any organic being ever do occur, assuredly individuals thus characterised will have the best chance of being preserved in the struggle for life; and from the strong principle of inheritance, these will tend to produce offspring similarly characterised. This principle of preservation, or the survival of the fittest, I have called Natural Selection. It leads to the improvement of each creature in relation to its organic or inorganic conditions of life; and consequently, in most cases, to what must be regarded as an advance in organisation. Nevertheless, low and simple forms will endure if well fitted for their simple conditions of life.

[Darwin, 1859]

Evolutionary selection relies on the chance that an adaptation will occur and that it will improve the fitness of a particular organism. This directly conflicts with early Christian beliefs that organisms do not evolve and remain as they were originally conceived.

Gradual evolution of 21st cent humans. A schematic representation by José-manuel Benitos.

The discovery of humans at various stages of evolution has diminished the concept that humans were created in their current form or generated spontaneously. Humans are thought to have evolved from primates that first appeared around 5-8 mya and share many similar characteristics to chimpanzees. In fact 98% of chimpanzee DNA is homologous to human but one of the greatest anatomical differences is in brain size. The chimpanzee’s brain weighs less than half a kilo while a human brain weighs around three times that much. Archaeological evidence suggests that three or four hominid species lived in the African continent several million years ago. Currently one of the earliest of these is known as a species called Ardipithecus ramidus.  Modern humans, Homo sapiens are thought to descend from Australopithecus anamensis, Australopithecus afarensis, Homo habilis and Homo erectus. There are other early hominids that are thought to be more distantly related Australopithecus africanu, Paranthropus aethiopicus, Paranthropus boisei and Paranthropus robustus.  The hominid that began to be dispersed around the globe was the bipedal Homo erectus. This species is thought to have evolved into Homo sapiens only 200,000 years ago, a blink of an eye in evolutionary terms.