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

The Siren song of the cloud forest

In 2002, strange photographs were being circulated via e-mail and doing the rounds on online orchid forums. As always, the photographs were tantalizingly unfocused and indistinct. What they seemed to depict was a New World slipper orchid of some kind, a Phragmipedium. This seemed like a new species, and a brightly coloured one, at that. The last time a really unusual new orchid was discovered was in the early '80s, when the fiery Phragmipedium besseae was spotted from a helicopter, growing on sheer cliffs on the eastern slopes of the Andes. Everyone likes a good mystery, and the online chat room is the premier rumour mill of the 21st century. This new thing intrigued everyone in the orchid world, but intrigue goes deeper than casual fascination for those truly obsessed with these horticultural harlots. No-one could have predicted the magnitude of the mania that was about to strike the orchid community, or how far-reaching the effects of this most severe outbreak of orchid fever would be.

In May of 2002, Michael Kovach from Goldvein, Virginia, was travelling around the cloud forests of Peru on an orchid hunting expedition. On the afternoon of 26 May, he came to the truck stop of El Progresso. In the parking lot, some local farmers were selling orchids. This is a common sight in this part of the world, and the orchids are usually collected from the wild as people clear new patches of forest in order to plant their crops. After Kovach expressed interest in the wares peddled by a brother and sister, the girl wanted to show him something special, and hurried off. She promptly returned with three potted plants with obscenely large, royal purple blossoms. Kovach knew he'd never seen anything like these before. Other Amazonian slipper orchids were half the size and in drab shades of green. He bought them all, for $3.60 a piece. This was it, his chance for orchid fame. Little did he know that his small act of exploitation by the side of the road in rural Peru would set in motion a series of events that would end up with his name living on in infamy instead.

Kovach had to get the plant scientifically described if it were to carry his name. The premier US institution for orchid taxonomy, the Marie Selby Botanical Gardens, would be his best bet. Imagine the astonished expressions of the esteemed plant taxonomists at Selby on that day when Kovach walked in with this new slipper orchid. It signified the most important discovery the orchid world had seen in over a century. The race was on: word was received that orchid expert Eric Christenson was preparing a description of a fabulous new Phragmipedium that would change slipper orchid breeding forever. Dr. Eric Christenson worked from photographs sent by Peruvian orchid enthusiasts, and with the support of the Peruvian government. He would name the new species Phragmipedium peruvianum. In order for the name Phragmipedium kovachii to be accepted by the scientific community, the Selby description had to be submitted first: the taxonomists and botanical illustrators were determined to work overtime. Selby ended up beating Christenson to print by five days. Kovach's place in history was secure. At the same time, stories began to appear in orchid forums that specimens of the new orchid were already fetching prices as high as $10 000 on the black market...

Here's the curious thing: due to CITES restrictions which control the trade in endangered species, slipper orchids cannot legally cross borders, for whatever reason. Hybrids yes, nursery-raised plants certainly, but not jungle-collected specimens. Therefore, the Marie Selby Botanical Garden was guilty of orchid smuggling, its reputation forever tainted. Oops. And the name P. kovachii can't even be retracted so that the whole sorry mess will go away, as it was indeed published first. The rules need to apply to everyone. This has happened before: even if we all like the name Brontosaurus so much more, the name Apatosaurus was assigned first, so we'll have to live with it. Whenever you hear of a botanical institution describing a new species from another country, you have to wonder how they managed to do it; even if it were tantamount to smuggling, surely the rules don't apply when it's for science? As Dr. Christenson so eloquently put it, "Anyone with half a brain cell doesn't go near them. They're the pandas of the orchid world... When somebody shows up with an orchid like that, you either quietly tell them to go away or you call the cops."

There's also the part of the story concerning the whereabouts of that specific Selby orchid after it was described. Who got to take it home when they were done? Let's just say there were police raids on several greenhouses that year. Redundancies. Lawsuits. In-fighting. Mud-slinging. The withdrawal of research grants. Thrilling fodder for a Grisham novel, no doubt. Nobody could claim orchids were boring after that. Michael Kovach least of all: he just barely escaped doing time. Others weren't as lucky. "Lead us not into temptation..."

In Peru, the government started posting fliers at every airport warning people against trying to smuggle the slipper orchid out of the country. Unfortunately, the brand new Phragmipedium was already in deep trouble. The slippery hillsides where Kovach's original plants came from were bare. The orchid was lost, nowhere to be found. Local people desperate for some income had helped unscrupulous smugglers in completely stripping the site of its thousands of P. kovachii plants. A second site was subsequently discovered and also collected out. Illegally collected orchids were now selling for $1000 each in parts of Europe. The outlook seemed bleak. Months went by, and scientists started speculating that P. kovachii could already be extinct in the wild, even with hardcore CITES regulation and the fear of spending eternity in a Peruvian prison as deterrents. Finally, a small colony of the regal orchid was discovered on a virtually inaccessible cliff in a remote part of the sub-Andean basin. The unfriendly terrain would be its protection. Getting to the site required making what Harold Koopowitz, the editor of Orchid Digest, calls "the hike from hell".

The true salvation of any species at risk from overcollecting lies in taking pressure off its natural populations by introducing it into cultvation. In a sensible move, the Peruvian government granted Alfredo Manrique of Centro de Jardinería Manrique in Lima permission to collect five - and only five - plants for preservation through propagation. With expert help from some of the world's best specialists in orchid cultivation and tissue culture, this most beautiful of New World slippers will soon be available to everyone at an affordable price. Best of all, the wild orchids will remain queens of the cloud forest, safe for the moment. In the November 2007 issue of Orchids magazine, the American Orchid Society published vanity shots of the first generation of P. kovachii hybrids, including Phragmipedium Haley Decker, pictured here. Orchid breeding is never going to be the same again.

All photographs from Centro de Jardinería Manrique, unless otherwise indicated.

Sexual frustration of the worst kind

The first reports always come from farms and small towns. Rural areas. Strange sounds in the forest at night. People call them cryptids. These creatures, presumed extinct, cast a delicious spell: we want to believe that they are out there, holding out against the odds. Survivors, after all. A flash of white on a black wing in an Arkansas swamp, and we desperately cling to the hope that the ivory-billed woodpecker has survived, that it is alive and well and breeding. Each frame of footage is cherished as grainy evidence that the thylacine still stalks the Eucalyptus forests of Australia. We want these creatures to have survived the ravages of hunting and habitat destruction. We are to blame for their disappearance. We need to ease our guilt, you see. Our desire to resurrect these species is so overwhelming that we end up ignoring all evidence to the contrary. We will not discover a live moa in a hidden valley in New Zealand. No amount of weeping will cause the cry violet to blossom in Bourgogne again. They are precious jewels lost down the drainpipe and no hook will ever be long enough to retrieve them.

Often we concentrate so much on what we have lost, that we don't notice the things we are about to lose, the findings on the other bracelets coming undone as we vainly poke around in the dark, chasing shadows in the plumbing. A small amount of organisms have indeed come back from the dead, as it were. These so-called Lazarus species, such as the painted frog and the Madagascar serpent-eagle, were reported as extinct for several years, until small populations are rediscovered. These are rare occurences, and dangerous ones for ecology in the end; they give us hope, which is so seldom of any practical use.

What a pitiful, sorrowful thing the very last wild thylacine must have been. All alone, without a mate. A population of top-end predators reduced to a single individual. The last thylacine would not even have been aware of it, of course, but it was doomed long ago. As soon as the number of individuals in a population drops below a certain threshold, the whole species collapses. Even though there are still individuals alive, the genetic diversity needed to sustain their next generation is already lost. You cannot fight natural selection with just a handful of alleles - you need the full arsenal. Imagine that last thylacine, gazing out over its dry scrubland habitat. A dead species walking. Functionally extinct.

The wonderful seaside city of Durban, South Africa, has an incredible botanic garden with a rich history. Planted in Victorian times, its mature tropical trees are a magnificent site to behold. On weekends, crowds of people enjoy a sunny afternoon picnic on its lawns. Its herbarium has collected and catalogued some of the most precious specimens of plants from all over the world and specifically the ravines and coastal forests of southern Africa. Music events, art installations and amateur astronomy nights bring people from all walks of life, not just plant lovers. Chiefly, it is indeed a plant lover's paradise: a whole avenue of Eucalyptus deglupta, the famous rainbow gum, leads to a carefully maintained Japanese garden. Tropical fruit trees grow outside, festooned with bromeliads and orchids, without the need of pampering under glass: jackfruit, cocoa, coffee, mangoes, they're all here. Ponds of waterlilies, formal rose gardens and arches dripping with purple Wisteria provide bridal couples and their photographers with many opportunities for gorgeous scenery. A Victorian orchid house gushes with colourful, heady blooms, a firm favourite with any visitor. And in the middle of it all stands a lonely looking Wood's cycad, Encephalartos woodii.

I've never been a big fan of cycads. They're big and spikey, grow exceedingly slowly, and produce no flowers. Still, the madness of cycad collectors probably exceeds that of the orchid folk. No other kind of rare plant has been as vehemently collected, illegally smuggled or heavily policed. In 1895, John Medley Wood came across a large cycad with four stems at the edge of the coastal forest of Ngoye in eastern South Africa. Luckily for the cycad, John had been curator of the Durban Botanic Gardens since 1882. In 1903, Wood sent James Wiley to collect some of the offsets growing at the base of the plant. In 1907, two of the larger trunks were collected and planted at the Botanic Gardens in Durban. However, Wood wasn't the only person interested in this cycad, apparently. By 1912, there was only a single trunk left. It is known that the indigenous people of the area sometimes use the starchy trunks as a food source, but it is doubtful that they were to blame. The plant seemed mutilated, diseased. In 1916, The Forestry Department sent this ailing trunk to the Government botanist in Pretoria. It died in 1964. All expeditions to find other specimens of Wood's cycad have returned empty-handed. It is very likely that the original plant collected one hundred years ago was the last of its kind.

Fortunately, the specimens growing in the Durban Botanic Garden thrived. Unfortunately, you need a mommy and a daddy cycad to make a baby cycad. The single specimen on the planet was a male, you see, and without a female Encephalartos woodii, no viable seed can ever be made. And yet, there are about 500 individual plants in the world now, in botanic gardens such as Kew and Kirstenbosch, and in private collections. How was this miracle accomplished? The plant regularly produces offsets at its base - all male, all genetically identical. Clones, with about as much chance of surviving in the wild as the original plant did. Functionally extinct. There has been much research and debate about using biotechnology to save Wood's cycad. It might be possible to induce one of the clones to change sex and become a female, whether chemically or using a genetic engineering approach. But even if this feat of gender reassignment surgery were possible, the genetic pool is still severely limited. Encephalartos woodii will remain in cultivation, of that there is no doubt. But genetically crippled, it could never survive in the wild.

The photograph above is of me hugging the trunk of the gigantic original cycad, first collected in 1907, still growing happily in the Durban Botanic Garden. A palaeontological relic, its chromosomes at a loss for something to do. A proud plant, but doomed like the thylacine. Its salvation through cultivation is a hollow victory. Lazarus was raised from the dead, only to die a second death. I recalled a lecture in population genetics, where the secrets of the gene were shared with me in darkened halls: "The only thing worse than somatic death, the death of the body, is genetic death, the failure to reproduce". I closed my eyes and grasped the trunk, cool and solid beneath my fingers.