21 November 2007

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


HopSkipJump said...

I was diagnosed in 2001 with mixed papillary/follicular cancer. After two surgeries and 6 months of radiation, I have been in remission for 7 years. To be honest, the cancer was more of an issue for my family and friends than it was for me and truth be told, if you were to be diagnosed with cancer this is the one you would want.

I am still struggling to get my medication levels correct and I occasionally feel sorry for myself with the amount of times I have to go to the doctor... but your post has reminded me how truly lucky I am. Thanks for that.

Unknown said...

Dude, don't you just hate that word: "remission"? Your ordeal is over, and yet it's not. You are allowed to feel sorry for yourself, you were also drafted to be brave. And yes, you are lucky, because you live in a country that can assist you with doctors and medication. In many parts of the world people just let their tumors grow and consume them, because they simply lack the access to good medical care. It's not just genetics; it's also the environment. May the term "remission" still apply to you for a very long time to come.

Aine said...

Great post!! You could've broken this up into a series of posts on different genetic disorders. I'm envious of your ability to fuse knowledge with writing to discuss issues that are often avoided because of discomfort or ignorance.

As an occupational therapist working in rehab, I've worked with people who live with fibrodysplasia and Huntington's. And, as a bio major, I found myself just as fascinated by the randomness of genetic mutation. I wish I could peek 200,000 years into the future to see which genetic "mistakes" will have been selected and enhanced our survival. Somehow, I think the successful changes will be involved in human emotional processing and behavior (limbic system perhaps?). It seems as though human interaction has become the environmental force that exerts the most environmental pressure on our evolution.

Thanks again for the fascinating discussion!

Admin said...

super interesting post!

SleekPelt said...

Another fine post, Teoh. It makes me almost thankful for this freaking ear infection that's driving me crazy.

Before finding your blog I hadn't been interested in scientific detail for a very long time. You've affected me, Teoh.

Chris Eldin said...

This is a great post. While dark, it makes you also feel grateful.

I knew of the first one, but I had never heard of the other ones.
Aine poses an interesting question.

Anonymous said...

It's a good thing you have a blog to vent all that info you have. I think there would just be a huge explosion somewhere if you didn't. I love reading your posts, because it is book like and class like.
Thanks for another good one and boiling it down for we dummies (haha)out there.

HopSkipJump said...

Hmmmmm... NICE HEADER TEOH. Looks strangely familiar!!!

I can't believe you hijacked my friend! I'm kidding... how cool and bizarre that my real world and blog world is starting to mesh together.

She wants to get her name out there as a graphic designer... which I'm going to try and help her with in my next blog posting. I'll obviously feature you in it... :)

Unknown said...

I'm still trying to figure out how to pull it all together - it'll be better by the end of the evening...

Unknown said...

aine: that would be interesting. That's why the species concept is actually all nonsense. Every species is a 'work in progress'. You've worked with FOP and HD people? That's amazing; care to share any stories?

kristen: thanks.

sleekpelt: sorry about your ear. Hope it clears up soon. If you find yourself interested in something you wouldn't have been bothered about otherwise, then I've done my job. Awareness is power.

church lady: thanks. It's difficult to discuss disease in anything but a dark light, unless a cure is around the corner. On Aine's point, there's also something to be said for neutral mutations; changes that don't impact health. They might get fixed in small populations due to founder effects and genetic drift. Or, they might be fixed via sexual selection. Think of the peacock's tail. It has no benefit to survival, it just looks cool to females. What's going to be sexy to people in the next century?

wreckless: woah. I don't want to sound preachy or like a teacher. I just like to share. You ain't no dummy, but if the average person can understand the post, then I've succeeded.

infumb: excuse me, but she approached me of her own accord, because my blog is so inspiring... seriously though, she is fantastic. And thank you for sharing your talented friend. It's only a question of time before everyone wants a piece of her.

Adam said...

Dit maak my bietjie bang soms. Ek dink ek is geneties gepredisponeer tot kanker. Op watter ouderdom moet ek begin toets?

Btw, jy is getag...

Trundling Grunt said...

The staggering thing is how a small variation in a gene can have such a devastating effect. It makes you feel humble.

And let's face it, it mutations hadn't occurred we wouldn't be here to discuss them. Unless it did all happen on a particular day in 4004 BCE. Yeah, right.

So where's your mother's recipe then?

Aine said...

Stories? Well-- it was about 15 years ago when I worked in an "adult wheelchair community" which is only one of 3 such facilities in the US. That's why I had the opportunity to meet people with some of the rarest of conditions. Unfortunately I was merely a student at the time, so I did not provide treatment as a full-fledged therapist. But, I remember spending a day with a woman with FOP during an outing to a botanical garden. She was independently mobile in a power wheelchair (using "sip and puff" technology-- the person controls the chair by simply blowing or sipping on a straw-like device). The wheelchair was modified to fit her unique shape (arms and legs were bent in a loose fetal position, and she suffered some torquing of her trunk. The most difficult fusion for her was her neck which was gradually assuming an extended position (which would eventually interfere with safe swallowing.)) She was very interested in taking photos, so I held the camera to her eye, enabling her to choose the angle, etc, and pushed the button for her. The most fascinating aspect to me was the "hard feel" of her joints because of the bone fusion. It is a very different feel than the more common joint contractures (when muscle tone becomes abnormally high) that occur after neurological impairments (such as strokes or late stage Alzheimers).

The Huntingdon folks that I remember were a brother and sister who were in their 40s. Very intelligent, interesting, active people who had to deal with the loss of coordination and subsequent reliance on wheelchairs. They were both amazingly accepting (not depressed).

Admin said...

love the new look! the banner is beautiful!!!

twanji said...

Great post. Makes me so much more grateful about the fact that I was born and that thus far in my life I am benefiting from great health.

I love the new look - great stuff. Planning a huge change to my web-presence in 2008. Stay tuned!

singleton said...

I'm blown away with the stuff you hit on...I have a friend with FOP, very active in research and fundraising, and probably now, the oldest living young lady affected. Years ago, she was tauted in the Enquirer magazine as "The Woman who turned to Stone", I was appalled, but in her wisdom she knew the value of telling it out loud, and in spite of her body, being frozen forever in a semi sitting position, her smile carved like an ice sculpture, her spirit soars, her fight for all the little ones continues.....

Unknown said...

adam: 'n mens is sweerlik nooit te jonk vir toetse nie. Die belangrikste is om sensible te wees en nie paranoïes nie. Van 30 af behoort jy te gaan vir die prostaat "vingertippietoetsie". Nie pret nie, maar noodsaaklik.

trundling grunt: I'll give it to you as a comment on your blog as soon as I've translated it!

aine: you are fantastic and more compassionate than I'll ever be. Thank you so much for sharing; I believe it fleshes out the topic just that little bit more.

kristen: all thanks to IF's friend.

twanji: the twanje finally stoops to visit my humble webspace! Long time no see, eh?

singleton: Wow, what are the odds: such a rare condition and two regular visitors have close experience of FOP. We should never underestimate the importance of awareness, even if it's sensationalist. People with genetic disease are much more robust against failing political correctness than we are led to believe. I think most would have you treat them at face value, rather than with condescension.

Anonymous said...

When I was in elementary school, I became fascinated with deficiency diseases (scurvy, beriberi, etc.). I still am fascinated by disorders. Maybe I should have been a pathologist like I originally wanted.

morbidneko said...

beautiful, yet scary post,

it does tend to make one a bit more grateful.

am liking the new design.. nifty.

Claire said...

My son has juvenile myoclonic epilepsy, also caused by a genetic malfunction. Luckily it is (for the most part) controlled with meds.