The finished image

"So God created man in His own image, in the image of God He created him; male and female He created them." - Genesis 1:27

I've been idling over the topic of this week's post for quite a bit now. There's just no easy way to introduce the subject of genetic disease. Sensitive subject matter, whichever way you look at it. To scientists, biology is at its most fascinating and informative when it goes wrong. Often, genes are named after the condition that results when they malfunction. In the lab, determining the function of a specific gene is often done by disrupting the gene in a model organism and investigating any physical changes that result. What we don't realize is how often Nature does the same kind of experimenting.

What a miraculous thing every successful fertilization event is! A sperm and an ovum fuse, forming a zygote, the beginning of a new multicellular organism, with half of its genes derived from the paternal genome, and the other half from the maternal genome. The doubling of DNA and movement of chromosomes essential to this miracle form a major chapter in any biology textbook; the meiotic mantra of prophase-metaphase-anaphase-telophase is chanted in classrooms and lecture halls across the globe. Nature is not textbook perfect, however. Chromosomes get damaged, broken, left behind. They fuse into new entities, unsure of their alliances. The DNA sequences they harbour change over time, get deleted, repeated, inverted, mutated. Here's the rub: change is good. Mutation and change is what drives organisms to adapt to new environments and new pressures. It is what enables them to succeed in the future. Curiously, mutation works blind, unable to see what natural selection is requiring from it. Not all changes are equal; not all mutants fit the mould. Nearly a quarter of all human fertilization events will be aborted - often so rapidly that the woman doesn't even realize that she was pregnant. More than 50% of all embryos miscarried in the first trimester are found to have chromosomal abnormalities. These genetic changes are so severe that they prove lethal. In fact, we all carry a few genes where one of the two copies (alleles) is functionally incapacitated in some way and is compensated for by the healthy copy on the other chromosome - it is masked, recessive. Without that healthy copy, you would probably have suffered from some genetic disorder. More likely, you would never have been born.

Fibrodysplasia. For hundreds of years the medical records noted patients who slowly "turned to stone". This is a very rare condition, striking one out of every two million people. We now know this disease as fibrodysplasia ossificans progressiva, or FOP. It is autosomal dominant - you only need one copy of a mutant gene to be affected. Mutations in several different genes can lead to FOP, but the genes all share a common developmental pathway: that of embryonic bone morphogenesis. These genes are involved in bone formation in babies, but get switched off soon after. In FOP patients, one of the genes stays turned on into maturity, with grave consequences. Slowly, muscles and connective tissue are converted to bone. Slight injuries induce massive spurts of bone growth, making surgery to remove the lumps of bone impossible - it only exacerbates the situation. Sufferers might be unable to move their necks, open their jaws or lift their hands as more layers of ectopic bone are deposited, fusing their skeletons in place. Harry Eastlack, the most well-known FOP sufferer, donated his body to the Mütter Museum in Philadelphia, where his skeleton (above) dripping with bone like a cave drips with stalactites, can still be seen. He passed away in 1973, six days before his fortieth birthday.

Lesch-Nyhan Syndrome. Decades ago, boys with this disease were often misdiagnosed as having cerebral palsy. They writhe and twist and are mildy retarded. But they also suffer from horrifying, uncontrollable urges to self-mutilate. Sufferers will bang their heads against the wall, or bite themselves. Many need to be strapped in and restrained to prevent them from chewing off their own fingers and lips, or gouging at their own eyes, screaming in pain and terror as they do so. Care-givers are also not spared, and may be sworn at or punched, often while the patient apologizes profusely for their compulsion. This terrible disease is caused by mutations in the gene that codes for the HPRT enzyme, involved in the metabolism of nitrogenous molecules called purines. When this enzyme malfunctions, there is a build-up of uric acid, which leads to gout and kidney problems and is also responsible for the changes in neurological development. Most sufferers die of kidney failure early in life. This is a recessive disease, meaning that a healthy copy of the gene will compensate for a faulty one, and the person will not be afflicted but merely a carrier. Unfortunately, the gene resides on the X chromosome. So whereas girls inherit an X from their mother and an X from their father, boys inherit an X from their mother and a Y from their father. Men make do with a single X chromosome. If it happens to contain the faulty HPRT1 gene, they will develop Lesch-Nyhan syndrome. Carrier mothers therefore have a 50% chance of transmitting the gene to their sons. Fortunately, this disease is also very rare, and typically affects only 1 out of every 380 000 people worldwide.

Fatal Familial Insomnia. We've all heard of prions, those infectious proteins hiding in our hamburgers, lying in wait for an unsuspecting victim to consume them and become another sporadic case of Creutzfeldt-Jakob disease. Prions are differently folded variants of normal proteins essential to brain function. When a prion protein comes into contact with a normal protein of the same kind, it can change the shape of that protein into the prion fold. The new prion is like a zombie victim; once bitten, it too becomes a zombie and can turn others into zombies with its lethal bite. Prion proteins form plaques of long fibres inside neurons, damaging their delicate structure and disrupting their function. Most prion diseases take the form of transmissable spongiform encephalopathies - the prion proteins are tranferred through transfusions, transplants, or consuming tainted meat. In the rare case of fatal familial insomnia, the disease is most definitely genetic: if one parent had it, then each child has a 50% chance of developing it as well. The age of onset varies from 20 to 60, so it usually strikes when patients have already had children. The symptoms of FFI are unpleasant, because it is literally a fatal case of insomnia. People with FFI find themselves terminally unable to fall asleep, inhabiting a debilitating world somewhere between slumber and wakefulness. Drastic weight loss occurs, together with decreases in muscle control. No longer able to speak or walk, they are bedridden (a cruel twist) with nothing to do but stare at the walls. Curiously, FFI does not impair cognition, or cause dementia: up to the very end, before the bliss of coma and death, sufferers are completely aware of what is happening to them. It has so far only been identified in about 40 families, and members can be screened for the mutant gene that causes the protein to assume the malignant fold. Researchers hope that the study of FFI might lead to a cure for other prion diseases like CJD, and protein misfolding diseases such as Alzheimer's disease.

Trimethylaminuria. TMAU, a metabolic disorder that sounds hilarious, yet is anything but funny for those who suffer from it. For them it is a source of much embarrassment. Also known as fish odour syndrome, this disease is again caused by a malfunctioning gene. The gene, FMO3, is located on the long arm of chromosome 1, and encodes an enzyme responsible for breaking down trimethylamine, a molecule formed from nitrogen-rich food by beneficial intestinal bacteria. The disorder is recessive, so both copies of the gene need to be malfunctioning for the disorder to manifest itself. Because trimethylamine is no longer broken down, it builds up in the body. The molecule, which has a fishy, ammonia-like smell, is released in the person's urine, sweat, and breath. No matter how often they wash, the smell is never gone for long. This disorder can be very disrupting. People who suffer from it often shy away from social interaction by isolating themselves, and sometimes struggle with feelings of guilt or depression. Although there is no cure, avoiding certain foods high in nitrogen seems to help, as do daily doses of charcoal to soak up the smelly compounds.

Huntington's Disease. On the short arm of chromosome 4 lies a gene encoding a protein essential to the maintenance of neurons, called huntingtin. The gene sequence specifies the exact order of amino acids that need to be linked together to form the functional protein. Part of this sequence is a stretch of repeats of the same amino acid, glutamine, over and over again. The exact length of this patch of glutamine repeats varies from person to person. Healthy people can have anything from 9 to 35 such glutamines linked end-to-end in this part of the protein. In people with Huntington's disease, or HD, this repeat sequence has been vastly extended, sometimes to more than a hundred repeats. Somewhere along the line, the sophisticated cellular machinery that reads and copies the genetic code had lost its place in all the repeats, reread the code again and created extra copies of those requests for glutamine in the gene sequence; HD is a codon reiteration disorder. The mutant form of huntintin no longer functions normally, and is also not broken down like it should be. Neurons start to die off. Interestingly, the longer the repeats in the mutant huntingtin are, the earlier the patient's symptoms start. HD is typically a progressive decline, with chorea and athetosis generally being the first physical symptoms. Chorea is characterized by abnormal involuntary jerking movements, while athetosis is a continuous writhing movement of the hands and feet. These irregularities in coordination increase as the disease progresses. In the later stages, speaking and swallowing are impaired. The most frightening aspects of HD are those that involve the mind itself - patients often become anxious or depressed, sometimes aggressive or compulsive. They lose the capacity for abstract thinking, for planning ahead or choosing appropriate actions. This deterioration is particularly traumatizing for children who often end up taking care of their ailing parents, loved ones who have become strangers to them. HD is an autosomal dominant disease - if you have the mutant gene, you will eventually develop the disease. Because it only manifests later in life (the average age when symptoms start is 40) HD is often only diagnosed when patients already have children. This means that the mutation gets passed on to the next generation 50% of the time. There is a very efficient DNA test available to detect the presence of the gene. However, many children of HD sufferers choose to rather not know their own fate. At the start of the 21st century, Huntington's disease is still a terminal illness with no cure. If you had a 50% chance of inheriting it, would you want to know for sure?

Let us not view this as a morose post, a mere list of genetic disease, a list of things that can go wrong. Rather, it is intended to be a celebration of the miracle of multicellular life and of how precious a healthy genome truly is. It is a salute to those brave people who live with genetic disorders; they have been of immeasurable help in the study of genes and their functions. They represent the reluctant pioneers of our collective genome, those who are sacrificing themselves in testing the limits of human evolution. Change is good.

"The living form defies evolution at its peril; if it does not adapt, it will be broken. The idea of completed man is the supreme vanity: the finished image is a sacrilegious myth." - John Wyndham, The Chrysalids, 1955