As I presented my travel documents to return to Australia, Slash’s song “Back from Cali” was playing on the iPod. The lyrics were quite appropriate. I was definitely tired and broken. I had certainly lost my way. I glanced in disbelief at the news on my phone. Just bloody peachy. Another massive cyclone was making its way over from Fiji toward Australia. Cyclone Yasi was the name given to this monstrosity. This beast was even bigger than Cyclone Larry five years earlier. Only this time, instead of being chased by a cyclone while on a boat in the Coral Sea, I was about to board a plane whose flight path was on a collision course.
The flight over was a turbulent roller-coaster—exactly what my newly reconstructed spine didn’t need. I was traveling without painkillers of any sort; I had thrown away the surplus after the hellish withdrawal experience. I just had to deal with it as best I could. I was doing fine until the entire plane started shuddering like an epileptic having a grand mal seizure and the overhead bins vomited their contents. My back screamed like the tortured steel that it was. This ended up being the worst flight of my life, even worse than the medevac flight from Germany to LA. It also took longer than usual because a long, looping detour south of New Zealand had to be taken to avoid the worst of this epic storm. I arrived in Melbourne looking, smelling, and feeling like something found in a gutter.
Things had gotten a bit out of control at home during my eight month absence. The weeds reached nearly six feet, the pool was baby-crap green, and my Jeep Wrangler was so covered with dust it was a tan-orange color instead of fire-engine red. While dingoes were legal to keep as pets in Victoria, Queensland was a redneck wonderland and regarded them as pests. Consequently I had to give them up before leaving so with alacrity I rehoused them. Seventy-two hours after landing, I had the Jeep washed, the trailer packed, and was on the road to Brisbane, where I had found a house on Mt. Glorious. Rather than taking the shorter route along the east coast, I cut up through the outback, sticking to remote dusty red roads and driving at a leisurely pace. I drove only four to five hours a day before I was uncharacteristically exhausted and had to pull over and pitch a tent in the scrub. It took me eight days, instead of the usual two, to get there.
Once I dropped down the Great Dividing Range, the damage from recent flooding quickly became apparent. Houses smashed up against trees, overturned cars half submerged in putrid mud. Divots out of road edges like a giant shark had taken bites in a feeding frenzy. Rubble strewn across what was left of the road. If I hadn’t been driving a Jeep specifically modified for fairly extreme off-road adventures, some areas would have been impassable. As I drove up the side of Mt. Glorious, I felt it was a good omen when, only a few miles from my new house, I came across a particularly high-contrast Stephens’ banded snake. It was very unusual to see one out during the day, so I concluded it must have been displaced by the flooding. I had no need to try to catch it since I had finished with that area of research long ago. I just placidly watched it as it crawled across the road, giving me a pugnacious sideways look.
I pulled into the rainforest that was so familiar to me, with the colorful birds screeching greetings in their inimitable way. I was in my natural home again; so much had happened in the eleven years I had been away. I pulled up to my new house, opened the door, and took a breath. The funk of forty thousand years hit me like a moss-covered sledgehammer. Due to the incessant rain and hot temperatures, the house had grown green stubble over every surface. My furniture would be delivered the next day, and I had no choice but to spend the remainder of the day and much of the evening scrubbing, doing more cleaning than I had done in my entire life up to that point. Cumulatively. Next day, the furniture delivery crew asked me where I wanted everything set up. I had them put my bed in the middle of the living room by the wood stove heater, so that I could stay nice and toasty on the cold mountain nights later in the year. In the three bedrooms I had them set up the steel shelves to hold my mountains of field gear, surfboards, and my clothes in clear plastic bins—a home decor strategy that just screamed “A single guy lives here.”
It was only twelve hours before I met my new neighbor; I heard screams and walked outside to see what was going on. A little old lady was trying to remove a ten-foot python from her yard. It turned out she did wildlife rehabilitation and the local pythons viewed her small wallaby inmates as a convenient food source—much like when wildlife corridors were installed near one of my field sites up on Cape York. These little bridges were supposed to keep the cute arboreal marsupials from getting squashed on the road like furry cane toads. When the researchers were doing their radio tracking, it didn’t take them long to notice that there were marsupials stationary at either end of the corridor, not moving for days on end. Very unusual behavior. Further investigation revealed a large, well-fed python at each end, with a radio transmitter among the blobs of partially digested marsupial in their guts.
The python in next door’s yard was striking with its mouth open, revealing the very long teeth used to anchor on to a mammal while it threw the lethal coils around it to suffocate the victim into submission. I knew all too well what sort of tissue damage such dentition could make under the best of circumstances, let alone to the flesh of an elderly person. The snake’s variegated body writhed as it moved around erratically, determined to get past this flailing non-predator and to its desired prey. I walked back into my house, grabbed a hessian sack, and managed to get the snake behind the head with my hand in the sack. I then inverted the sack so that the snake’s head was on the inside and the long body was sticking out. There was only three feet of snake still sticking out when my moment of glory became a bit less magnificent as the snake everted its bowels all over my face, into my mouth, up my nose, and all down the front of my chest. There is nothing quite like the taste of digested marsupial for breakfast. Remembering a comment by a girlfriend that a couple of shots of vodka was useful for getting the taste of a blowjob out of her mouth, I discovered that four shots will wash away the taste of snake crap. Later that day, a polite knock on my door revealed my neighbor with a freshly baked chocolate cake as a thank-you. So it was all worth it in the end. I’ll do anything for chocolate, even go ass to mouth with a python.
My first trip back to the University of Queensland was definitely a massive case of d?j? vu, particularly once I found out where I would be setting up my new laboratory. In the eleven years that I had been gone, lots of buildings had changed hands between various schools. Everyone from the Centre for Drug Design and Development was now across campus in the splendidly constructed Institute for Molecular Bioscience, leaving the Gehrmann Laboratories behind. In the intervening years, it had been home to various research groups and, ironically, it was now under the custodianship of my new academic home: the School of Biological Sciences. Not only did I end up in the same building where I did my PhD, but on the same floor and in the same laboratory, with my former supervisor Paul Alewood’s office as mine. Needless to say, I found this appealing.
I took a walk across campus and slid into the warm waters of the university pool, where I had spent so much of my time during my PhD years. My first training session felt very flat. Rather than gliding otter-like up and down the lane, I struggled like a waterlogged poodle. I chalked it up to the upheaval and being terribly out of shape. But over the next few weeks, my muscle tone did not improve and I felt surprisingly mentally and physically listless and uninspired. I should have been on a euphoric rush, back at my beloved UQ, making a new life and leaving the smouldering wreckage of my former life behind. But try as I might, I just could not get it up. In any manner whatsoever.
Thus a new problem presented itself, one that had gone unnoticed during the months I was dazed and confused in a hospital while on a variety of opioids and their derivatives. I was unmotivated; my typical energy levels had not returned, even after I’d weaned myself off the horrid painkillers. My wasted muscles did not bounce back in tone or bulk, even when I could muster up the energy to get to the gym. I had no sex drive. My moods fluctuated between black and blacker. My mojo was gone.
Luckily, my Californian ER mate Sean Bush had warned me to look out for exactly these symptoms. It was something he had noticed in car-wreck victims who had suffered severe spinal injuries resulting in extreme surgery followed by lengthy hospital stays. The combination of the shock to the system and the chemical overload from the months on massive amounts of long-acting opioid painkillers made the body’s biochemistry and delicately balanced hormone pathways go haywire. In effect, my endocrine system rebooted full of all sorts of start-up errors. I was no longer Mac; I was now Windows.
After seeing a primary care doctor, I was referred to Dr. Russell Cooper, an endocrinologist who specializes in exactly these sorts of issues. After a battery of different tests, the picture was quite clear. I was producing almost no growth hormone or testosterone, while other elements of the androgen cycle were being made in too large a quantity. The two hormones so very central to being a man were absolutely decimated. For some reason my vitamin D levels were also way down. The amount of sunshine I’d got lately should have more than brought the levels back up from the low they hit during my months indoors, confined to a hospital bed, but somewhere in that synthesis pathway, something was off too. It was collectively a total mess. I had to think back to basic biochemistry courses from my undergraduate days and crack out biochemistry textbooks to re-familiarize myself with these extremely complex feedback pathways. The conclusion I came to was that the extreme alpha-ness that I had taken for granted, and which was such a prominent part of my personal and public identity, was gone.
I did some digging into the scientific literature and was gobsmacked to discover the impact that opioid painkillers had upon testosterone levels. Opioids are classified as short-acting or long-acting. Short-acting opioids release medication quickly and are usually taken every four to six hours. In contrast, long-acting opioids release medication slowly and are generally taken every eight to twelve hours. While long-acting opioids are the most effective pain-management option for people with severe spinal injuries such as my own, and often the only option at all, they are also the ones that affect testosterone levels the most. In one study I came across, 74 percent of the men on long-acting opioids had low testosterone, while for the short-acting opioids the rate was 34 percent. The recovery rate was also markedly different. The risk of the drugs resulting in permanent low testosterone was almost five times higher for men taking long-acting opioids than for those taking the short-acting kind.
Intrigued, I dug further into the literature to find out what other drugs affected testosterone levels, either transitorily or permanently, and was astounded to find that the list was diverse. Antidepressants, antipsychotics, and tranquilizers were among the most potent outside of the opioids, but myriad others also made the list, including those used to treat chronic diseases such as those related to high cholesterol levels (with statins being particularly toxic to testosterone levels), convulsion and epilepsy, and high blood pressure. Furthermore, many recreational drugs had an impact, spanning the range from depressants such as alcohol and marijuana to stimulants such as cocaine. The implications of this are staggering and socially insidious. Low testosterone affects everything from the psychological wellbeing of the man, through to his basic fertility rate, through to being a major contributor to prostate cancer. In short, it was a silent epidemic.
These acute effects are separate from, but still related to, the natural drop in testosterone levels brought about by a man’s age. The idea of male menopause is typically blithely dismissed with statements like, “Male menopause is much more fun than female menopause. A female gains weight and gets hot flashes; a male dates younger women and drives a sports car.” However, it is a very real medical issue that eventually affects all males to one degree or another. “Andropause” is a much more accurate description of the usual decline in the production of testosterone as a man ages. Obvious symptoms are changes in sexual functioning, such as erections not being maintained or even obtained, or there being no “morning missile,” as well as a generalized drop in sexual interest. More subtle signs include changes in emotional stability, with the man becoming moody, irritable, sad, depressed or unmotivated for no apparent reason, or lacking in self-confidence. In my case, it was an extreme variation brought about by physical trauma combined with months on end of massive doses of long-acting opioid painkillers.
The good news is that the diagnosis—which requires blood testing on different days under different conditions—is very straightforward. In my case, the diagnosis was much more complex as I had a number of issues going on, far beyond a simple age-related drop in testosterone levels.
As with everything medical, men are pretty hopeless in seeking assistance, but this is particularly acute for problems in “that” area. This is why prostate cancer in men is far too often not diagnosed until it is too late. Men, including myself, typically try to “man up” about medical problems, gritting our teeth and quietly suffering through them. The perceived social stigma of being seen as “less of a man” exacerbates this. I say “perceived,” because I have a strong suspicion that it is only true in our own eyes. This is reflected in the changes in the medical awareness campaigns regarding prostate cancer, for example. After years of unsuccessful propaganda urging men to get checked, now the female partners are being targeted. Women are basically encouraged to nag their man into going to the clinic and getting things checked annually from an early age. Andropause should be treated no differently than menopause, since ignorance and denial can be dangerous.
If a woman has any sort of medical problem, the phone lines ring hot and very intense lunches are scheduled. There are fundraisers, charity runs, public head-shavings, cupcake support days, all organized in the name of raising awareness of, for example, breast cancer. Let me ask you, when was the last time you saw a guy running in an “I survived prostate cancer” T-shirt? By way of comparison, I can count on one crooked hand the number of friends or family who knew what I was going through. Indeed, most didn’t have the faintest of glimmers about what was going on, and reading this book will be a revelation to them. I also don’t recall being out fishing, impaling a worm on a hook and turning to a mate to say, “So, how’s your penis doing nowadays, mate?” Women probably don’t start conversations by discussing their breasts either, but after consulting with female friends, women tend to be much more in tune with their bodies, and they disseminate information to each other much better. About the only time men even mention the subject is at a funeral, with statements such as, “Gazza died of nut cancer.”
Goldilocks me had to get my biochemical “too hot” and “too cold” to some sort of “just right.” Getting things balanced took a lot of trial and error, with some pretty spectacular swings of the pendulum along the way. Androgenic storms are easily the heaviest shit I have ever had to deal with. Nothing in all my chemical wasteland history had prepared me for the emotional intensity of it. At times I would experience a fresh form of madness: complete loss of volitional control of my emotions. This was more psychologically intense than the time I freaked out on psychedelic mushrooms after making the bad move of watching the movie Scarface while tripping.
Wrapped up in a web of anger, I would hop on to my Honda Rune motorcycle and ride it at suicidal speeds along the twists and turns of Mt. Glorious, with music like “Stillborn” by Black Label Society infecting my ears. This beast was the 1800 cc love child of a power cruiser and a missile. The 110 horsepower of torque accelerated it with such force that I could pull a wheelie effortlessly even in third gear. I would try to lose myself in the tortured scream of the highly tuned engine, not caring if I lived or died: one thousand pounds of chrome and steel being ridden by a madman who was in danger of taking up a new career as a hood ornament.
In order to get some control of my life, I pruned it back savagely. In addition to stopping drinking and taking all other recreational chemicals, I stripped all my thoughts and feelings down to the absolute skeleton. Listening to the Grateful Dead’s song “Touch of Gray,” I came to the awareness that the only way I was going to survive was to tear it all down and build it back up again. There was too much mental and physical clutter. Too much emotional and biochemical entanglement. I needed to minimize external impacts, too. This did not mean retreating. Rather, I needed to cull any sort of negativity from my life. I needed to rebuild myself, starting from the biochemical ground floor up. Eventually, an acceptable chemical balance was reached, after several very difficult months. The stasis was achieved through the daily administration of prescription creams, pills, and injections that I now have to take every day for the rest of my life, including testosterone, growth hormone, and dehydroepiandrosterone (DHEA), among others. This comes at a significant personal economic toll, since my private health insurance only covers a small proportion of the prescription costs.
This was all a very interesting personal exploration. “Interesting” in the way of the Chinese curse: “May you live in interesting times.” For so long, I had defined myself by my alpha maleness. I could go balls-to-the-wall harder than anyone I knew. But now, from a chemical perspective, I was basically castrated. I might as well be ball-less for all the contributions coming from my shrunken testicles, but my endocrinologist had found the antidote to this chemical kryptonite. I thought long and hard about whether I really should care about losing my mojo when I can artificially recreate it. Does my chemistry define me as a man? Am I no longer an alpha? Am I emasculated? Or should I focus on the positive? It’s a simple numbers game—I have too little of this or that, so with appropriately calibrated doses of bioidentical compounds, the balance can be brought back to the fore. And if it can be fixed, is this all that matters? I am now not just the Bionic Man, I am also the Biochemical Man.
Once my hormones were stabilized and my life was no longer one giant emotional roller coaster, I could get down to getting my research back on track. At this time, I recruited a dozen students to establish my new laboratory, including Tim Jackson. In the decade since he had provided such invaluable help with the snake venom research in Singapore, he had followed his other great love: music. He became an electric guitarist of some note, but this alternative career universe was derailed by an idiopathic neurological disorder. With this path now closed to him, he returned to science with a vengeance. He undertook his honors research on the various small elapid venoms I had collected during my PhD years and after my return from Singapore. He showed that not only were they as complex and potent as the venoms of their larger cousins, but they were also packed full of very novel toxins with significant potential for drug design and development. He then embarked upon PhD research in my lab; it felt to me like my prodigal son returning home. My intellectual kid brother Eivind Undheim also made a reappearance in my life, undertaking a PhD on centipede venom evolution under my supervision.
My personal focus was the venom of the long-glanded coral snake, as this research had been derailed by my breaking my back. I recruited a new PhD student, Daryl Yang, to undertake this work by splitting his time between my lab and that of my long-time collaborator Wayne Hodgson. The research into the venom revealed that it caused an almost instantaneous paralysis—not a limp paralysis, like that brought about by a death adder’s venom, but a spastic paralysis that would make the snake’s prey flop around like an epileptic in a nightclub. The neurotoxins cause the muscles to spasm rhythmically, with each contraction more profound than the one before and very little relaxing between contractions as the baseline climbs higher and higher. As the snake prey tired, it would become more rigid. Inhalation would become progressively more difficult as the diaphragm became more and more tightly contracted and difficult to relax.
Suffocation would occur, but from the opposite effect on the muscles than that of the venom of a death adder or a krait, even though they are all elapid snakes. Instead of a morphine-like relaxation to death, it is a tetanic spasm. The most amazing part is that it is the same general class of neurotoxin as that of the classical elapid snake—the one that relaxes things to death. But in this case the toxin was modified to act directly on the nerve channels and turn them on, rather than blocking the message, as is normally the case. It caused all the neurotransmitters to be released at once, making all the muscles flex like the average guy while shirtless at the beach, but to the point that they are immobile. It was one of the most amazing cases of adaptive evolution in snake venom, found in the most highly refined snake. It doesn’t get any better than that.
I was also well overdue to get down to work on the sea snake samples collected over the last decade. The first order of business was to collaborate with Kate Sanders from Adelaide University to genetically barcode every specimen we had collected venom from. This was routine for my research, where I made no assumptions about the taxonomical affinity of any of the specimens, particularly highly confusing species of sea snakes. Three types of samples instantly gave anomalous results. As expected, the sea snake with the very rough scales was confirmed as a new species. As our boat captain had been instrumental in its discovery through guiding us to a variety of different sea floor habitats, we decided to recognize his pivotal role in the discovery by giving the snake the scientific name Hydrophis donaldi, with the common name of the rough-scaled sea snake.
This was not the only pleasant discovery. Among the samples I collected were those from the egg-specialist marbled sea snake and the beaked sea snake. The results from the marbled sea snake indicated that it was also a new species, but one still closely related to the population found in Southeast Asia. We gave it the scientific name of Aipysurus mosaicus and the common name of mosaic sea snake, in recognition of its intricately beautiful pattern. But the beaked sea snake samples came out as very distinct from the beaked sea snakes in Asia, to the point that they were separated by a large number of other species. This was despite these snakes looking virtually identical. It was a remarkable case of convergent evolution—the natural selection process where two unrelated animals evolve to look very similar due to the independent specialisation for a unique ecological niche. A well-known example in snakes is the similarity between the green tree python in Australia and the emerald tree boa in South America. However, this was the first time that such convergent evolution had been documented in a lethal species.
This had immediate implications for the treatment of envenomed patients, since the manufacturer of the sole sea snake–specific antivenom, the Australian company CSL, sourced the venom used in the process not from Australia but from Malaysia, because the snakes were easier to collect there. Assuming they were the same species, they had also assumed the venom was the same and therefore the antivenom would work well against either.
We worked out the chemical profile of these venoms while in parallel testing the effectiveness of the sea snake antivenom against all of our sea snake venom samples, including that of the beaked sea snake from Australia. For the sake of comparison, we also tested the venom of katuali. To our great surprise all the sea snake venoms came back as virtually identical: streamlined and simple. I concluded this was due to all sea snakes being specialists for a single type of prey: fish. This hypothesis was validated when the katuali venom also came back as extremely simple, to the point that it was virtually indistinguishable from that of the sea snakes. As these snakes also feed exclusively on fish, the evolutionary selection pressure had resulted in a chemical convergence. Even more surprisingly, not only did the CSL sea snake antivenom work with virtually equal effectiveness against all the sea snake venoms, but it also neutralized the katuali venom with the same degree of efficacy. This was unprecedented.
I also branched out into leech venom research. European leeches have been used in medicine for hundreds of years to promote bleeding. Some of the uses are based in superstition and thus of limited efficacy, or even counterproductive. However, leeches have been used to bring blood flow back to fingers that have been reattached after accidental amputation through having them feed on the affected digits. Drugs have also been developed from the powerful anticoagulants present in the leech venom. But Australian leeches have remained virtually unstudied. To jump-start this project, I chose the giant aquatic species present in Victoria. These four-inch-long beasts are a rarity among leeches in that they are predatory, not simple parasites like most leeches. They will feed on a freshwater crab, a frog, or even a small mammal and suck so much blood out that the animal dies. In order to stimulate the venom glands for the research, I needed to feed them. Due to animal ethics constraints, I could not let them feed on live vertebrates and sourcing suitable invertebrates proved impossible. So there was only one resource: me.
I placed eighteen of them on my arms and let them attach to my veins. Almost immediately, I could feel each of their slicing jaws cut deep into my skin like circular saws. They then settled down and fed. Over the course of the next hour, each drained me of over 5 cc of blood. After they were done feeding, they dropped off one by one, like drunks out of the pub right before closing, and I returned them to their containers. Each left behind a hole that was less than an inch in diameter and oozed blood for the next three days. My arms were covered with gauze that was continually soaked through. It was like having another Stephens’ banded snake bite, only this time the effects were limited to the immediate area around the wounds. It was gross, but I was not in any danger. However, it was not something I planned on doing again! And the future results will hopefully make this disgusting experience worthwhile.
During this period, one of my all-time favorite studies was undertaken, one that showed that “vintage venoms” lose none of their bite. We discovered that venoms stored for up to eighty years remain biologically active. These were the venoms I had come across at the Australian Venom Research Unit in a dusty storage closet a decade ago. Venoms are a time capsule of disappearing biodiversity and hold potential for the discovery of new medicines. The study examined fifty-two venom samples, including rare and historically important venoms. The research showed that properly stored venoms remain scientifically useful for decades and that vintage venom collections may be of continuing value in toxin research.
Venoms and toxins are a rich source of unexplored compounds which could be used in drug discovery and development. Reptile venoms have been used to develop drugs such as Captopril, which is used to treat high blood pressure, and Byetta, which is used to treat diabetes and has off-label effectiveness as an anti-obesity drug. The venoms we studied came from the invaluable collection curated by the late Straun Sutherland, and their value is a testament to his continuing impact upon venom research in Australia, long after his passing. The venoms of different species have extensive variation, so each venom sample is a precious resource which could contain the next wonder drug. Storing these samples correctly is particularly important as many venomous snake species worldwide are declining and fresh venom may be difficult to come by.
Venomous animals worldwide are disappearing due to habitat destruction, persecution through activities such as rattlesnake round-ups, and the impact of feral animals such as cane toads. Many venomous snakes have disappeared from large parts of their range, or become extinct. Collected venoms may one day be used for research, long after the animals themselves have become extinct. For example, as part of this project we studied death adder venoms from locations where the adders have been wiped out by cane toads.
Some of the Australian venoms we studied may be the only samples ever collected from a range of unique island tiger snakes which are now threatened by habitat destruction. We also studied the first coastal taipan venom collected for antivenom research by Kevin Budden in 1950. It was such an honor to work with these samples, due to their immense historical significance. I got chills holding these vials, knowing the tragic backstory. The young man who collected this venom was bitten in the process, but heroically made sure the snake was taken away for research before he went to the hospital, where he died shortly after.
After spending time planning and organizing my new laboratory, including setting up a battery of complex machinery for the experiments, I set about finishing the venom book I had started while in the hospital. Initially, the book had been a simple exercise to pass the time and keep me from losing my mind from boredom, but it had developed into something quite special. It spanned the full range: from evolutionary theory to occupational health and safety issues, to the unique nuances of veterinary care of venomous animals, to clinical treatment of the envenomed patient. It was the most in-depth book of its kind. I had engaged nearly a hundred co-authors, specialists in all the topics the book covered; it was the greatest team effort I had ever been involved in, and I was proud of how well we had all worked together. The final product was a testament to the dedication and passion of all involved. I gave it the title of Venomous Reptiles and Their Toxins: Evolution, Pathophysiology and Biodiscovery and Oxford University Press agreed to publish it. I viewed it as a true milestone in my scientific legacy.
No comments:
Post a Comment