I can’t believe it’s been a decade since I researched and wrote The Forever Fix: Gene Therapy and the Boy Who Saved…
I wrote “The Making of a Mutant” in 1978. Then a PhD student in the lab of Thom Kaufman at Indiana University, I snuck the story into a draft of a manuscript we were submitting to the journal Genetics – just to see if the boss was paying attention. The tale was about our research on the mutation Antennapedia in the fruit fly Drosophila melanogaster, which reroutes development so that legs grow where antennae normally extend.
My story was passed down to generations of graduate students, and read aloud at Thom’s 60th birthday party many years later. I published “The Making of a Mutant” at Scientific American blogs in 2012, and then here at DNA Science in 2013. It’s a geneticist’s love story for Valentine’s Day.
But never in a million years could I have imagined that my vision of a mutation that takes over a population would echo in the form of a novel coronavirus that is continually reinventing itself as it tears through human bodies and populations.
My story chronicles how the abnormal becomes the normal, and the new normal eventually spawns a new abnormal. That’s what evolution is, change at the molecular level that reverberates up through populations of organisms – and viruses. The mutations in my imagined world in a milk bottle, home to the flies, were induced – in contrast to the situation for SARS-CoV-2.
We can’t stop evolution. Mutation is a fundamental characteristic of a genetic material, endowing it with the plasticity that underlies adaptation, which fuels evolutionary change.
Evolution of SARS-CoV-2 in a Single Patient
Anton Antennapedia’s unusual cranial appendage in my tale arose from an induced mutation in the replicating DNA of the Antp gene in a sperm or egg. He was poisoned. The mutations that build the variants of SARS-CoV-2 happened naturally, spontaneously, then spread. They have come to the US through travel, but arise here too.
A recent case report in Nature from Ravindra Gupta of the Cambridge Institute of Therapeutic Immunology & Infectious Disease and colleagues, “SARS-CoV-2 evolution during treatment of chronic infection,” captured viral change in action. The researchers describe an immunosuppressed man who received convalescent plasma over the course of hospitalization for COVID-19.
They sampled and sequenced viruses on 23 of the 101 days that the man was hospitalized. Between days 66 and 82, after the first two plasma infusions, the viral population in the man’s body began to change, spawning two mutations – a small deletion that’s part of the UK variant B.1.1.7, and a single base change. Viruses with the mutations began to take over the population of viruses in the man’s body, then subsided, then re-emerged after treatment with remdesivir on day 93 and with convalescent plasma again on day 95.
The undulating mutations, coming and going in time to new infusions of antibody-rich convalescent plasma, may reflect the viral population mustering strength, attaining, as we say in biology, a selective advantage. The case report may be a microcosm of what’s happening as viral variants arrive and arise and then spread throughout the world, transmitted to more individuals than those that came before.
The forces of evolutionary change – mutation, genetic drift (chance sampling), and natural selection – have long been recognized as the bedrock of population biology. Read on for a narrative of how the forces unfold in a microcosm that mirrors, somewhat, the dynamics of a virus surging through a vulnerable human population. Are we the fruit flies trapped in the bottle?
She knew she was different long before her mother had told her the truth. A sensitive youngster, she could tell from the sneering glances of her neighbors that she was, somehow, not quite like them. True, her larval segments were squished, her head too small. Now, hidden in her cocoon, she pondered her plight as she awaited, with apprehension, the great eclosion.
What would it be like? She’d heard the exciting but also frightening descriptions of the event from the elders, but now that she was about to experience the change herself, it suddenly seemed more significant. Would it hurt? What new senses and skills would she have, and which would vanish? Would she still be different, or was the impending transformation a second chance?
As she felt her larval organs begin to slowly dissolve, Ann’s thoughts returned to the horror that her parents had endured. The others spoke of The Great Mutagenesis in whispers and, although no one would put it into words, all of the youngsters feared, deep down in their discs, that it could happen again.
Ann remembered when her mother had told her, limbs trembling, of how all of the males were plucked from their yeasty homes and placed in a new, sweetly reeking environment. The gullible males greedily sucked up the sticky goop at their tarsi.
Soon they became nauseated. Just as they felt about to expire, they were suddenly moved to a new home, where hundreds of sex-starved virgins waited, their still-wet-and-wrinkled wings shimmering, their eggs dropping unfertilized in anticipation.
Meanwhile, in another vial, dozens of newly-eclosed, pure females were snatched, their virgin wings still unspread, and crammed into tiny, hot capsules. Some fainted. All were terrified. They were placed in a dark chamber for several minutes, and then dumped mercilessly into dens of slavering males with only one thing on their cerebral ganglia.
Then males and females from both mass poisonings were isolated as pairs. Fortunately for Ann’s mother, her father hadn’t been too demanding. The couple produced a surprising number of stillbirths. Ann could remember, no more than a first instar herself, her parents hopefully watching their offspring try desperately to hatch, the fully-formed embryos, about to be larvae, quaking with the effort beneath their thin eggshells. Many of those who did burst free were sick. Other couples in the colony were having similar problems reproducing.
And then there was Ann. Ann Tennapedia, or “mutant,” as her insensitive bottlemates called her. As Ann grew, transitioning from one instar to the next, she noticed her parents glancing from her to the other larvae with a strange look in their ommatidia. When she reached third instar, which for some reason had taken an inordinately long time, she worried about what lay ahead, and finally went to her mother, seeking answers.
Ann slipped slowly into a dreamless sleep as she felt her imaginal discs expand.
After four days in suspended animation, consciousness returned as Ann became aware of new muscles and sensations. She became restless – she had to move. As she rubbed her new legs, her cocoon suddenly split apart. Soon, she was wobbling about.
The world certainly seemed different with so many eye facets! Unaccustomed to this spectacular new body, Ann at first felt a little off balance. Her head ached. She tried to straighten her crinkled wings. Ann stumbled along, noticing the stares. She must be quite beautiful!
Then Ann remembered her difficult larvahood, and quickly examined herself – 6 legs, 2 wings, and quite a lovely abdomen! She was most anxious to see her beautiful new eyes. Were they ruddy red wild type, or a pretty variant?
Ann sensed a shiny drop of moisture up ahead, and danced around it to see her new eyes in the reflection. Alas, they were a run-of-the-mill wild type, but sparkling and symmetrical nonetheless.
Her head was certainly sore. She lowered it slightly, as if she was under some great weight. Still looking in the mirror-drop, Ann could not, at first, believe what it reflected.
Her proboscis fell open and she could feel her abdomen distend in shock as she tried vainly to comprehend what was staring back at her. It must be an illusion. A cruel trick.
Coming out of Ann’s head, where her antennae should have been, were two enormous appendages!
A Drosophila den is a busy place, and life must go on despite unpleasant variants.
Ann survived. Her larval handicap had accustomed her to ridicule. Since The Great Mutagenesis, quite a few oddballs like herself wandered about. Many of the elders had died off, and not enough young adults were surviving embryohood to replace them.
One day, as Ann’s colony was transferred to a fresh new home, she sensed a certain excitement. It could only mean one thing: Orgy!
No need for her to worry her heavy head over an influx of new males. Nobody wanted her. She must be the world’s only four-day-old virgin.
Ann pitifully clung to the outskirts of the colony as the frenzied mating began. Staring into a shining droplet, much like the one that had initially revealed her gross deformity to her, she realized how hideous she truly was.
She gazed at the offensive growths emanating from her head, past her opalescent ommatidia and voluptuous proboscis, down to her admittedly fine legs. But what was this? Two of the reflected legs bore massive sex combs.
She looked down in utter confusion at her own smooth legs. Slowly lifting her head, she met the gaze of Anton O. Pedia.
The romance between Ann and Anton rivaled that depicted anywhere in the classical literature. Sensing in those first few awkward moments that they were indeed meant for one another, they entered a dreamland neither had thought possible. They danced together in ecstasy, oblivious to the revolted stares.
Soon, out of Ann’s hindquarters emerged dozens of shiny white fertilized eggs, glowing with health. Within a week, the colony buzzed with joyous larval feeding activity.
In her exhausted bliss, Ann didn’t notice that most of her offspring didn’t look like the others. They seemed happy as they munched through the maple-flavored goop that was their home. Anton, however, always the practical one, knew that many of their children were afflicted with the same empty-headedness that he himself had been ostracized for in his larvahood.
Finally, bulging and satiated, the offspring of Ann and Anton, one by one, abandoned their gastronomic way of life for the mysterious serenity of pupariation. As the incessant chomping of larval jaws diminished, Ann slowed her ovipositing and observed, with the satisfaction known only to mothers, her tanning youngsters. She knew many of them would be like herself, but didn’t share her fear with Anton. No need to worry his massive head.
Ann hadn’t been feeling well. Her frequent exhaustion made walking on the sticky ground difficult. Anton, growing weary too, had to help her.
And so as the days passed, the children of Ann and Anton melanized as their proud parents weakened.
On the 20th day after their meeting, Ann and Anton knew the end was near. As they lay silently in each other’s legs, they gazed in wonder as their offspring emerged from their cocoons, many bearing exquisite legs on their heads.
The new colony prospered. The descendants of Ann and Anton were vigorous and fruitful, and it soon became quite fashionable to display one’s antennal legs at full extension. Males with especially bulky heads were most popular with the ladies, much to the envy of those not blessed with good penetrance.
The generations passed, uneventfully, for many transfers of the stock bottle. Memories of Ann and Anton, of their suffering, of those who had lived through The Great Mutagenesis, had all but vanished.
And then it happened. Without warning, couples were violently separated, the males sent to a sticky, sweet-smelling chamber where they quickly became ill. The poor females, just like their forgotten great-great-great-grandmothers, were mercilessly crammed into tiny, dark capsules and placed in a monstrous machine that pelted them with X-rays. And the unspeakable happened – the larvae were taken, too.
Most of the colony recovered. But instead of returning to their communities, they were sent into new bottles containing wild sex maniacs of all colors, bristle types, and persuasions.
Time passed. New couplings formed, eggs were laid, and life in the lab went on.
Nine days after this Second Great Mutagenesis, the new homes of Ann and Anton’s descendants were once more lined with the darkening bodies of a new generation. The survivors watched with primeval awe as their children appeared, stretching their magnificent antennal legs towards the cotton at the bottle top in anticipation of adult life.
He knew he was different, long before his mother told him the truth. A sensitive youngster, he could tell from the sneers of his neighbors that he was somehow not quite like them. Now, hidden in his cocoon, he awaited the unknown. Would he be born again?
Casting aside his chitin covering in an orgasm of release, he tested his new body parts slowly, then stumbled forward. He looked about him at his handsome neighbors, flexing their superbly hairy antennal legs. Preening. But why were they looking at him so strangely?
Robert peered cautiously into a moisture droplet. He gazed lovingly at his well-endowed sex combs, admired and extended his phallic proboscis, and then stopped, his hemolymph turning to ice, as he scrutinized, with stunned disbelief, the perfectly-formed, wild type antennae protruding in obscene normalcy from his otherwise perfect head.