Gregor Mendel (see here) discovered genetics because he chose to investigate heredity in domestic plants and animals. (Before settling on peas as his subject, he bred some terrifyingly aggressive bees that had to be exterminated.) From the very beginning, genetics was related to practical applications, and with recent advances in genome research and genetic engineering, that link is stronger than ever.
Research into stem cells and gene therapy offers the very real prospect that inherited disorders can be fixed at the genetic level and once-permanent injuries could be healed. Genetic modification allows genes from one species to be transferred to another, bypassing the normal rules of breeding. While such a technology (like any kind) has to answer many ethical concerns, it has the potential to transform agriculture – and even humanity itself. Additionally, the chemical properties of DNA are being explored – not for their role in inheritance – but as a material for making machines on the nanoscopic scale.
All crop plants and farm animals, and most pet animals, are the product of ‘artificial selection’. This process makes use of the same inheritance mechanisms as natural selection, but instead of the environment selecting the individuals that live or die, and which pairs get to mate, this is the decision of a human breeder. The breeder chooses individuals from one generation that have certain desirable traits, and mates them with each other in the hope that the traits will become blended together in their offspring. It can be a rather hit and miss affair – as Mendel found, not all offspring will express the targeted traits. Those that do not are excluded from future matings, but even so, artificial selection takes many generations to have a noticeable impact.
Artificial selection was the first form of genetic technology although it was practised long before the rules of genetics were revealed. Nevertheless, over the centuries it has produced many of the our most familiar plants and animals.
Around 12,000 years ago, human society began to transform from one based on hunting and gathering food, to one that grew its own supply. The birth of agriculture went hand in hand with a number of technologies – the plough, irrigation and artificial selection – that took control of crop phenotypes to maximize harvests. This last step is of particular interest. The first farmers are thought to have grown fields of grass that later became today’s cereal crops. Their ancestors were no stranger to these foods, collecting the seed grains that fell from wild grasses for grinding into meal. The ears, or fruits, of wild grasses shatter, dropping ripened grains to the ground at the slightest touch, and maximizing their chances of finding fertile soil. However, some grasses do not shatter so easily: natural selection should have selected against these plants, but early farmers realized they were easier to harvest, and grew them all together in the first fields. Today, these same mutant grass strains, which would not thrive in the wild, are among the world’s most common plants.
Many of the most common and familiar animals tend to be livestock – domestic animals that are raised for their meat, or perhaps eggs, milk, hair or skin. Similar working animals have been bred over many generations to suit human requirements. However, they all have a wild origin and many of their features can be traced to their free-living forms.
Sheep and goats are bred from desert-living mountain animals: they are able to survive in arid climates unsuited to other grazers, and herd together for protection – domestic flocks, like their wild relatives, still run up slopes when threatened. Chickens, meanwhile are domestic cousins of the Indian jungle fowl, a ground-living forest bird that is only capable of short flights and is therefore easily managed. Horses, meanwhile, are descended from fast-running grazers whose hierarchical social groups enable their domestic descendants to work well with a human trainer. Finally dogs, probably the earliest domestic animals, are tame wolves – pack animals that have merged with human families.
Often, the animals produced by deliberately crossing two very different kinds of parent not only have the traits selected by the breeder, but are also strong and healthy – a phenomenon known as hybrid vigour or heterosis. This is an example of the beneficial effects of outbreeding – the mating of organisms with widely different genotypes. The result of such unions is offspring that have the benefit of many different alleles that generally made their parents fit individuals, and winners in the continued race against predators and parasites. One of the benefits of sexual reproduction is that it promotes outbreeding, although there can also be drawbacks – occasionally, offspring inherit incompatible alleles, reducing their fitness.
The opposite of outbreeding is inbreeding, where closely related individuals mate. They share a lot of the same genes and as a result deleterious recessive alleles that would be masked by outbreeding appear in the phenotype more frequently, creating a less fit individual.
A thoroughbred racehorse is the product of hybridizing sturdy English hunting horses with fast and spirited Arabian breeds.
Animal breeders have found they can cross closely related species to produce artificial hybrids, the most familiar of which is the mule, a much-valued beast of burden that is big and strong, but also docile and rugged. A mule is a hybrid of donkey and horse, specifically a male donkey and a female horse (a female donkey and male horse produce a hinny, which is generally smaller and weaker.) A horse has 64 chromosomes while a donkey has 62. As a result a mule has 63, an odd number that makes it very unlikely that the mule can pair up its chromosomes during meiosis and produce viable sperm and eggs.
Other artificial interspecific hybrids include the zonkey (donkey–zebra), beefalo (cow–bison), wholphin (killer whale–dolphin) and pumapard (puma–leopard) The liger (opposite) is a cross between a female tiger and male lion. It has a blend of the tiger’s stripes with the lion’s paler coat – and thanks to hybrid vigour, it is huge, growing to 3.6 m (11.8 ft) long, which makes it larger than any wild cat species.
Few livestock breed more than once a year, and the long generation times, combined with obvious ethical issues, mean that it is not often possible to research the impact of mutant genes on their fitness and embryonic development. However, the same problems do not apply to Drosophila melanogaster, the common fruit fly. This little insect lives for about a month, and is sexually mature at the age of just 8 hours. It has only three chromosomes (plus two sex chromosomes), and there is the added bonus that fruit flies create giant copies of all chromosomes in their salivary glands, which are easy to analyse.
All of this makes Drosophila an ideal species for breeding in large numbers for genetic research. Dozens of mutant strains have been bred, including flies with curly wings, a range of colours for the body and eyes, shorter setae (insect ‘hairs’), and even a mutant, known as ‘tinman’, that does not grow a heart. Drosophila is also used in the early stages of researching the link between genes and ageing and brain development.
Also known as genetic engineering, genetic modification (GM) is the practice of introducing novel genes into a genome – most likely transferring the gene from one species to another. While natural selection can evolve any organism into another – an oak tree into a goldfish or a whale into a fungus – it would take millions (if not billions) of years. GM technology bypasses the rules of inheritance using a number of techniques.
The most simple is the gene gun, an air-powered pistol that fires tiny particles of gold coated with genetic material. The particles are targeted at living cells, obliterating most, but a few will be safely subsumed into surviving cells, with their DNA incorporated into the genome. Another technique is to use Agrobacterium, a bacteria that infects host plants with a ring, or plasmid, of DNA (producing tumour-like growths called galls). Genetic engineers hijack the plasmid and use it to introduce new genes (that don’t make galls), as illustrated opposite. Finally, GM can also use reengineered viruses to inject DNA into cell nuclei.
There have been dozens of attempts to create genetically modified foods – almost exclusively plants. Many have been a failure, either because the genetic modifications have not offered any benefit or because they offer a novelty that has not been met by public demand. One notable failure is the ‘fish tomato’ given a gene for the antifreeze protein used by an Atlantic flounder in the hope of producing a frost-resistant plant.
Several GM varieties of crops – including pineapple, courgette and potato – have been given genetic resistance to viruses, but the most widespread GM foods are maize (corn) and soya, modified to tolerate pesticide chemicals. But even the use of successful GM foods are heavily controlled in most countries. And more questionably, GM technology has also created a ‘terminator gene’ that prevents GM crops from setting seed. This would force farmers to always buy new supplies of seed for each season, although there is currently a worldwide moratorium on using the terminator gene in crops.
Short for ‘genetically modified organism’, GMOs include more than just GM crops. Many animals have been genetically modified for reasons other than agriculture – often outlandish ones. Some of the most successful are GM strains of Escherichia coli. Often associated with deadly food poisoning, E. coli has also been engineered to produce a variety of medicinal substances including the insulin hormone used by diabetes sufferers, growth hormone for treating dwarfism, and clottng factors crucial to the wellbeing of haemophiliacs.
Other GMOs are used as test beds for new medical treatments. They include mice that are modified with the bioluminescence gene of a jellyfish. These rodents literally glow in the dark. Another strange GMO is the ‘spider goat’, which has the gene for spider’s silk incorporated in its genetic recipe for milk. Liquid silk proteins are produced in large quantities in the milk – far more than could be harvested from actual spiders – and can be used to investigate this incredible substance.
Genetic modification is big business that requires huge outlays in research and development. As a result, the GMOs that result and the techniques used to create them are subject to fiercely defended patents. This means people and corporations actually own specific genes and have rights over every living thing that contains them, a state of affairs that sits uneasily with many people. A patented gene is recorded as a precise sequence of bases, and in order to use that gene – like any other intellectual property – a licensing fee must be paid. This raises both practical and ethical questions. Practically, how does the patent holder tell if their genes are being used? And how do they create a chain of evidence that such a gene got there through misappropriation rather than accidental cross-breeding? Legal wrangles over such issues are now common. More problematically from an ethical standpoint, patents have been applied for on genes for naturally occurring substances – including human hormones. In 2013, however, such patents were finally ruled out of order.
Clones are organisms that share the same genes: an animal that reproduces asexually is producing clones of itself. Identical twins, triplets and so on, are also clones. Cloning, however, is the technology used to artificially create clones from organisms (mostly animals) that normally reproduce sexually to create genetically unique young. An artificial clone is broadly genetically identical to its parent, but they are by no means exact copies – despite what science-fiction authors imagine. For one thing, they are separated by time, with the clone always younger than the parent. They have also developed in a different environment, which may have altered the way they grow. Many animals have now been cloned, ranging from frogs to camels, but many attempts still result in malformations. So why bother with cloning at all? The truth is that it is a powerful tool in a genetic engineer’s toolkit because it is the best way of being sure that specific genetic material is passed on unchanged. It is also closely linked to stem cell research (see here), where powerful cells can be made to fix incurable ailments.
The Pyrenean subspecies of Iberian ibex became extinct in 2000, but its skin cells have been preserved in the hope of cloning it back into existence.
This form of cloning aims to bypass fertilization and create a zygote directly from an ovum. The ovum has its nucleus removed, along with its haploid set of chromosomes. This process of ‘enucleation’ is done by hand, using an ultrafine micropipette that can push through the membrane without causing irreparable damage, and leaves the ovum with all of its organelles and other contents intact. Next, the nucleus of a somatic cell with a full complement of chromosomes is put into the ovum. This converts the ovum into a diploid cell, but it is not quite that simple. The ovum’s cytoplasm contains elements that are able to reset its new chromosomes, which have been largely turned off in its original cell home. The reset is aided by a pulse of electricity sent through the cell, and there are probably other intricate – and closely guarded – processes used by clone researchers. Once reset, the cell is able to divide and develop towards an embryo that is a clone of the original somatic cell. Clones made this way are mostly used to harvest stem cells, but can be grown into a fully formed animal.
Perhaps the world’s most famous sheep, Dolly was the first mammal to be successfully cloned. Her birth in Scotland in 1996 caused a sensation. Dolly was produced by nuclear transfer: the somatic cell was taken from the udder, or mammary gland, of her mother, and Dolly is named after a country singer famed for the same part of her anatomy.
The nucleus of the cell was placed into an ovum harvested from another sheep, so while Dolly’s chromosomes came from the somatic cell donor, her mitochondrial DNA was inherited from her egg donor. Once the transfer was successful, Dolly’s zygote was grown to blastula stage (see here) in the lab before being implanted into the uterus of a third sheep that carried her to term. (So it could be argued that a clone like Dolly has three parents.) Dolly became an international superstar, but her fame meant she was kept mostly indoors. Most sheep live for around 12 years, but at the age of six, Dolly died from a lung infection, common among sheep living indoors.
A fingerprint is a good means of identifying someone: they are effectively unique and when properly analysed, the chances that they point to the wrong person are negligible. The same is true of a ‘genetic fingerprint’, more correctly called a DNA profile. The profile does not map an entire genome – instead it is a means of comparing two samples of DNA. If a sample from a crime scene matches the DNA of a suspect, it shows that he or she was there.
A similar technique can be used to reveal a genetic relationship between individuals. The system was devised in 1984 by English geneticist Alec Jeffreys to solve a problem: human DNA is 99.5 per cent the same. So to highlight the differences he looked for tandem repeats, places where the same base ‘letter’ repeated several times. A DNA sample is cut up, and then the chunks with specific repeated sections are amplified, or copied in large numbers. These chunks have a certain length – a feature shared with relatives – and so when the sample is separated by size, it creates a unique pattern that can be compared with others.
Polymerase is the enzyme used in the cell nucleus to read and replicate a single strand of DNA. Geneticists can make use of this copying machinery to mass-produce specific pieces of DNA. The most widespread technique is the polymerase chain reaction (PCR), invented in 1983 and used in genetic profiling, but also to manufacture any large sample of DNA.
The process starts by mixing a piece of target DNA (still within a larger strand) – with polymerase enzymes, a supply of nucleotide bases, and molecules called primers. The primers are short strands of DNA that are coded to attach to the target DNA and mark the point for the polymerase to begin copying. PCR involves a number of cycles, each with three steps. First, the DNA is heated so the helix separates, then the primers are attached and, finally, the polymerases make a copy of the target DNA, plus whatever else is there. The cycle is repeated, making more and more copies – in just 30 cycles (about 4 hours) a single DNA sample can be multiplied into a billion!
The power of the chain reaction allows it to generate billions of gene copies in just a few hours.
In order to separate pieces of DNA and other large biochemicals such as proteins, a process called electrophoresis is used. It works by placing the mixture of jumbled DNA and dyes at one end of a plate of gel. (The gel is often made from agar, the jellylike polymer taken from seaweeds). The gel is swamped in a conductive material called a buffer, and an electric current is passed through it. DNA has a negative charge, due to all the phosphate ions involved in connecting up its ‘backbone’ of sugars, and this means it will migrate through the buffer away from the negative electrode, towards the positive. All the DNA sets off together, making thick bands of dye on the gel, but given more time, these will split into narrower bands, each representing a group of DNA segments with the same number of base pairs. Shorter segments of DNA will travel further than the longer ones. One gel can carry several samples, and eventually each sample creates a particular pattern of bands along the gel (as shown on here). These can be used in turn as a DNA ‘ladder’ – strands of known sizes can be used to estimate the size of bands in other samples.
A number of diseases and disorders are strongly linked to inheritance. They include problems like lactose intolerance, porphyria and some forms of Crohn’s disease, but the real list is much longer. Medical testing of potential parents has been developed to reveal the presence of these harmful genetic features. In the case of chromosomal disorders such as Down’s syndrome (see here) the test is a karyotype, which looks at the chromosomes as a whole (see here). When a disease is linked to a single gene, then tests will often look for the consequences of that gene. That might be a particular protein or the presence of a metabolite that indicates the gene is at work. Advances in genetics have made it easier, and crucially cheaper, to develop tests for particular DNA codes. But while some genetic disorders can be mitigated with drugs, they are all so far incurable. While a negative result leads to obvious relief, a positive genetic test offers little but anguish. So testing goes hand in hand with genetic counselling to give patients an understanding of the consequences.
Women can generally smell more acutely than men. One evolutionary reason for this is to help identify toxins in food that might pass to their babies in breast milk – but it also appears to be linked to mate choice. In 1995, the Swiss biologist Claus Wedekind carried out the famous ‘sweaty T-shirt’ experiment. He asked male participants to wear the same shirt while sleeping for two nights running. He then asked female participants to rate the smells of each shirt. The results showed that no particular shirt was regarded as more desirable than any other, but the women tended to prefer the smells of men who had different HLA profiles to them (see here). The reason for this seems obvious – selecting a partner with a different HLA can ensure any offspring are better able to fight disease, and also suggests that the mate is unlikely to be a close relative. In the wake of these discoveries, companies now offer genetic profiling to couples interested in putting science before romance – though some experts have dismissed the findings as simplistic.
Imagine if it were possible to replace faulty genes, or even add new ones to fight a disease. This is the goal of gene therapy, a potentially revolutionary new field of medicine that has been progressing slowly but surely since the late 1980s. There are very real dangers if something goes wrong, but signs of success are appearing.
Genes must be introduced to the body by a vector – a carrier mechanism of some sort some sort. Viruses make good vectors, but can be attacked by the immune system, and the prospect of an artificial human virus escaping into the wild is the stuff of sci-fi nightmares. Non-viral vectors, such as direct injections of DNA into the blood, have had limited success. But how should success be defined? At the very least, the DNA needs to be targeted at the tissue affected by the disease. However, the rest of the body also carries the bad gene – and so could any offspring. Germ line gene therapy therefore aims to correct the problem at source, eradicating the faulty gene from the family tree altogether.
A much-heralded future benefit of genetic technology, stem cell therapy aims to use the systems that build the body to fix otherwise incurable problems. Stem cells are the start points of a multicellular body, able to transform themselves into any cell type (see here). In the adult body, they also perform roles tasks such as building stomach lining and making blood cells, but once it is fully grown, most of a body’s stem cells turn off. Bone marrow transplantation is a form of stem cell therapy. Healthy stem cells from a donor are put inside the bones of a patient suffering from the blood disorder leukaemia, where they replace the old marrow and restore the blood to health. The body cannot mend severe injuries to things like nerves, bones and eyes, and so researchers hope to fix these, too, with stem cells. Cells may be taken from elsewhere in the body and ‘reset’ so they work anywhere, or, more controversially, they can be harvested from an embyro cloned for the purpose. It is still early days, but several successes indicate that stem cell therapy will become part of everyday medicine in the future.
The phrase ‘designer babies’ comes laden with powerful emotions, raising comparisons between babies and high-end luxury goods, such as handbags and shoes, that can be made to order. But it also suggests that genetic technology can be used to remove inherited defects that might otherwise make the child’s life a misery. As with many aspects of modern genetic science, technology is once again driving an ethical debate.
While it is almost universally agreed that it is unethical to screen sperm, eggs or embryos for sex or superficial genetic traits such as hair colour, it is already possible to edit their genomes to replace disease-causing genes with healthy versions. But why stop us there? Why not ensure the best genes for intelligence and looks are included as well? As yet, such genes are not known to exist, but where should the hypothetical line be drawn? The arguments in favour of clinical intervention are hard to resist, but are we right to block those who wish to go further?
Picture a machine of the future, some device used for lifting and shifting. Is it a mechanized hunk of metal and plastic, or made of flesh and bone? We copy biological body shapes for our robots, so why not use biological materials as well – or better still, merge the two? Such a vision of the future would be the product of synthetic biology, an emerging field where scientists take what they know about genetics, cell biology and anatomy to create organisms from scratch.
In 2010, the first artificial bacterium was produced, using the cell from a pre-existing bacterium with its DNA removed and replaced with a synthetic genome written by engineers. More recently, engineers have built cell-like vesicles out of the same lipids used in cell membranes, and they are now looking at ways of creating entirely functional cells out of synthetic, non-biological materials. It may take decades rather than years, but the more we learn about the way genes, cells and bodies work, the easier it will be to make our own versions.
The term XNA stands for ‘xeno nucleic acids’ – laboratory-made chemicals that do everything DNA and RNA can do. (xeno is Greek for ‘other’). In 2015, researchers succeeded for the first time in using a strand of pre-programmed XNA to synthesize a protein. But why should we reinvent DNA, one of the most powerful creations in the natural world?
Synthetic nucleic acids were first produced by evolutionary biologists researching alternatives that might have competed with RNA and DNA at the dawn of life on Earth (see here). The next step was to build XNAs that mirrored the form and function of DNA, using the same pairings of nucleotide bases, but are much more robust in the face of chemical attacks and temperature changes. This has opened up startling possibilities: could XNA be used inside synthetic cells, perhaps creating a whole new domain of life? More immediately, gene therapy might be used to replace DNA with robust XNAs, allowing us to artificially improve our own genomes.
