Enemy of the State

EXACTLY A YEAR ago, on a grey morning just like this one, I found myself at the corner of our street, seething with outrage. I had stormed out of the house after reading a news report. I needed fresh air, birdsong, tender first light as it broke past a dirty wadding of cloud. I needed these to reassure myself there was life beyond what I’d just read.

Paradoxically, my feet had led me here.

The corner of our street is the municipal dump: three bursting bins of garbage flanking a mountain of overspill. At 6.30 am, the fish market next to it was still two hours away from business, but the prime customers were already queued up. In the rain-tree’s canopy, egrets balanced delicately, each an alabaster amphora in a niche of green. Between lamp-posts, the taut electric lines were already inscribed with crows, sheet music for a discordant symphony. A sow marched her squealing brood into the squelch of plastic and putrefaction. A young cow browsed the menu with a rheumy eye.

In the midst of this anticipant zoo was one very energetic human, racing against the next squall of rain. Very little of her was actually visible, obscured by the gigantic polythene sack. She stood tiptoe, and plunged elbow deep in the nearest bin.

My friend Selvi begins her stint here at half-past five. She sifts the garbage for plastic waste. About seven, she sometimes pulls off the plastic she wears in lieu of gloves, props the sack against the lamp-post and joins the chai-wallah for a chat. The filth in which she labours all day seems to touch her not at all.

That morning, Selvi couldn’t afford to break for tea. She greeted me with a cheery wave, then plunged right back in, dislodging a fine black spray of mosquitoes.

I sulked home intent on what I had read, and what it would mean to Selvi.

I walk to the dump again this morning. The intervening year has been spent trying to make sense of my outrage. Selvi is my go-to for new science: I measure its discoveries by their relevance to her life.

She hurries over when she catches sight of me. Today her neatness looks aseptic, desolate. Her usually brilliant eyes are dull and bloodshot. Her tea cools, untouched.

Her neighbour’s baby, barely two, died last night. Just a day of fever—nothing out of the ordinary—and then she wouldn’t wake up. Two bottles of saline later, the baby was dead.

“Just a little fever,” Selvi muses. “Tell me, how do you explain that?”

THAT MORNING A year ago, I had read the first report of Zika virus in Brazil. As a paediatric surgeon, I should be used to babies with malformations by now; yet I’m not. Each case is a reproach to the discipline that trains us well enough to repair, but absolves us of enquiry.

The only question the parents of an afflicted baby ask is, ‘Why?’

Most of the time, there is no answer.

Yes, of course, there is plenty of information, but its implications are hazy.

When I learned of a likely link between an accruing number of babies born with brain malformations and a new virus, I was outraged. A minute on the web told me that Zika virus has been known for nearly 70 years. Another glimpse of those babies brought to mind all the babies with similar problems I’ve known.

Brazil was furthest from my thoughts then, yet every bit of the story was intensely familiar. Brazil was India, our mirror image in the Antipodes. Overcrowded cities: urban sprawl erupting from forests, every inch of land ‘developed’ by destroying natural habitats. Poverty with its callous lack of entitlements. Their population perhaps better nourished than our own, but battling Dengue and Chikungunya just as bitterly. It could all be happening here.

The dump where Selvi scavenges is a laboratory for emerging diseases. There is one such on every street in every city in India. It presents the conflation of circumstances necessary for a disease to emerge, for microbes to make the jump from one species to another, for an innocuous bystander microbe to go rogue and bite with virulence.

Most diseases that have emerged over the last two decades are zoönoses, caused by organisms which cause disease in other vertebrate species, and by a collusion of factors (usually man-made), now suddenly infect a human host. These could be bacteria, viruses, fungi, parasites, protozoa, prions—or things we haven’t encountered yet. Of them all, viruses are the most ubiquitous.

As I viewed that swarm of mosquitoes buzzing about Selvi, I wondered how many viruses they packed.

There are mosquitoes and mosquitoes, and Aëdes aegyti leads the list. Dengue, Chikungunya, Japanese Encephalitis, West Nile, Yellow Fever. Mentally reciting the litany of organisms, I wondered if Zika virus too, was already part of that buzz.

Like Selvi, most of us live or work in conditions that render us vulnerable to infectious diseases, and the worst of these today, are caused by viruses.

WHAT IS A virus? The word itself can be sourced to the Sanskrit visham, poison; has been used in English since 1398, and a Russian botanist, Dmitrii Iwanowski, became the first man to discover a virus while studying tobacco rot in Bessarabia in 1892. In our own time, the Cape Town microbiologist Edward Rybicki defines viruses as organisms on the edge of life.

Viruses do all the things that define life, and do them as if there is no tomorrow. Yet they have no recognisable metabolism; they lack the universal currency of energy, the ATP molecule; and they lack ribosomes, the cell’s basic protein-making apparatus.

Viruses overcome these inadequacies by a flagrantly parasitic lifestyle.

No self-respecting mature virus is seen without its host, although immature forms, virions, can be espied cruising. Once it lodges within a host cell, the virus gets down to its dharma— replication. It achieves this simple agenda with single-minded efficiency. Even our best machines cannot dream of matching its proficiency. Its survival strategies can out-think a multitude of Bobby Fischers. The rapidity of its evolutionary choices can almost make one believe it has free will.

In the paranoiac scenario, viruses will inherit the earth. The more rational script allows them ancestral rights over the planet. They have always been here, everywhere, in all forms of life— including, and especially, in us. Human DNA was once a virus.

In the first scenario, viruses evolved after cellular forms of life. Metaphysically, that makes them a bit like the primeval curse.

In the other narrative, the rational one, the virus was the first life-form, arising from a primitive and universal gene pool consisting of single-stranded RNA. These ancient viruses were self-replicating units. Initially, they merely replicated their molecules. Selection pressures within this gene pool gave rise to more complex molecules—‘hallmark genes’—whose job would be the production of proteins responsible for replication.

Such ‘hallmark proteins’ are found in viruses and virions— and, in no other cellular life-forms. They occur across a wide variety of viruses, and argue for a common origin predating cellular forms of life.

This ancient Virus World pervades the planet.

What is it like being a virus?

Thanks to social media, even the scientifically naïve are wise to ‘going viral’. Those two small words span light years between mere abundance and infinitude. The virus is a selfie-queen. It is constantly, and compulsively, broadcasting itself—more precisely, its self-hood.

But it cannot do this on its own. It lacks equipment and real estate. So it moves into some place where it can hang out rent free.

The virus finds a host, and moves in. In no time it has set up its very own Xerox machine, and is tirelessly making zillions of copies of its incomparable self. Silly, but basically innocuous.

Innocuous? What then of all those killer diseases?

Naturally, like all drama queens, the virus will throw a tantrum if anything gets in the way of its selfie-hood.

If the host cell calls a truce, it is business as usual. The host is infected, but not ill. If the host shows muscle, the virus pulls out all stops, bares its teeth, and gets virulent. It is now pathogenic— capable of producing disease.

The host cell broadcasts an SOS for reinforcements and declares a state of disease.

The virus is catapulted from virtual ubiquity into laser scrutiny, and in that sudden brightness there are more questions than answers.

Replication has a corollary—spread. It doesn’t help the zillions of daughter viruses, all dressed up in flashy new coats of glycoprotein, if they have nowhere to go.

The human body is a cul de sac, a dead end. At this juncture, if the virus has to disperse, it must relocate. It needs to hit the road. Due to an ancient evolutionary pact, our most prevalent virus, the dengue virus, DENV, has already booked its ride. Any moment now, the host will get bitten by a mosquito.

And DENV’s mosquito of choice is Aëdes aegypti.

Running cabeza a cabeza in prevalence with DENV is CHIKV, the virus that causes Chikungunya. DENV is a flavivirus, CHIKV is an alphavirus, but they take the same train to work. So does Japanese Encephalitis Virus which causes an inflammation of the brain that can kill or cripple. And so too Zika virus, and some others we know only as names, and probably many many more we do not know at all.

Aëdes aegypti is the posterbug for viral illnesses today, and its extermination is the bulwark of programmes to eradicate them. The National Vector Borne Disease Control Programme details various methods of Aëdecide—ovitraps, larvicide, adulticide. Spraying a general fug of pyrethrum and malathion has whizzed up respiratory problems in humans and affected the mosquito not a whit. Then there are those more sophisticated methods of biocontrol— harnessing fish with an appetite for larvæ, genetically modified mosquitoes and bacteria like Wolbachia, to do the wet work.

Considering India is almost a decade into hyperendemicity for Dengue and Chikungunya, no matter what the literature portrays, we know this strategy isn’t working.

We can persist in trying to eradicate mosquitoes and keep dying of viral diseases. Or, we can think laterally.

Like viruses do. They pick their ride.

Where Aëdes aegypti isn’t available, they whistle up Aëdes albopictus , currently cutting a swagger as the Asian Tiger Mosquito. A recently prepared catalogue of Indian mosquitoes lists 404 (and counting) species and subspecies.

Aëdes was presumed to be the only vector for Yellow Fever during the historic bid to eradicate it a hundred years ago. Out went Aëdes and back came Yellow Fever, riding in on Hemogogus.

Science has a very short memory. In the present Zika epidemic in the Americas, Aëdes is the designated vector—but it has been found in others, including the gawdhelpus mosquito, Culex quinquefasciatus, the domestic round-the-clock biter.

So, while we reconsider strategy against a 4 mg hovercraft, what’s happening at Ground Zero?

IN OUR PANIC over failing to prevent and our inability to cure, we tend to overlook what lies between.

The most obvious part of a viral illness is the patient’s experience. What does Dengue or Chikungunya or Japanese Encephalitis feel like? Look like? Answers to these questions furnish the vital story of the disease process, what we doctors call the pathophysiology, or how the body works during disease. Till a century ago, that is all we ever considered: the story of disease began, and ended, in the human body.

With the discovery of microbes and antibiotics, the narrative changed. We spoke airily of the conquest of disease, of eradication, of extermination. Such sabre-rattling (which continues still) seems foolish today. New diseases continue to emerge, as do new pathogens, but the arena remains unaltered.

The answers to any disease may lie in the body’s response, and in what controls it.

Let us consider Dengue. What happens when a mosquito bites me?

After siphoning off a gourmet meal, and paying for it with a squirt of virus-laden saliva, the mosquito buzzes off. It has no further part to play in what happens to me next.

The mosquito bite feels itchy. I scratch. Soon there’s a little red spot there, a trivial indicator of the plot unfolding within my skin.

The sentinel cells in my skin have acknowledged the virus as an antigen and alerted the first line of defence, innate immunity, with a rush of molecules that cause inflammation, to make the site of bite burn and itch. More defence cells are recruited. DENV has perfected a predilection for many of these first responder immune cells. Once it infects the cell, it hijacks the cell’s machinery to its own ends and replicates. Very soon an infinitude of new viruses step off the conveyor belt, and burst out by killing the host cell and flooding my blood stream.

I react with fever, bodyache, headache, pain behind the eyes, and general misery for the next two days. I’ll probably pop an analgesic and get on with my life. My illness isn’t merely the virus speaking. The chemicals released by my beleaguered immune system change the internal milieu of every organ in my body. These chemicals (and they are legion) are controlled genetically. This explains why everyone’s experience of DENV is not the same.

While Dengue fever can be a mild illness, its sojourn in the body is complicated. The course of illness depends on the viral load and the cell kill. DENV targets a wide array of cells, including those in the liver, spleen, bone marrow and the cells that line blood vessels. When these cells die, toxic products switch on a cascade of chemicals to alter mechanisms of blood clotting and tissue permeability. This leads to bleeding from multiple sites (Dengue Haemorrhagic Fever) or causes a massive leak of plasma into body cavities, Dengue Shock Syndrome (DSS). These complications set in soon after the fever disappears, and the falling platelet count is a warning sign. I may notice a faint purplish rash before I buckle with dizzy spells or start bleeding out, or simply fold up and die.

These fatal complications of DENV have been researched extensively. The dramatic label ‘cytokine tsunami’ has been used to explain the body’s misguided chemical response which prompts it to self-destruct. Four serovars, or types, of DENV are known. Infection results in lifelong immunity only to the infecting variety. A subsequent infection by a different serovar may be even more severe and complicated—and therein lies another puzzle.

Where did these viruses come from?

DENV, like many other viruses, started life in the tree canopy. So did the mosquito. The virus-vector bond is ancient too, and if vector competence—the vector’s ability to be infected by a virus, sustain viral replication within its body, and transmit a load of virus sufficient to infect a host—is satisfactory, the bond stays strong.

Both DENV and CHIKV now circulate solely between human hosts with the mosquito as a vector. When and why did this happen? The answer lies in the dump where I first heard Selvi’s story.

Selvi has never invited me to her house, but I know it well from her description.

It is one of the many lean-to shacks of tin sheet and tarp along the Western Express Highway. This is her third home in Mumbai. The first was off Aarey, at the edge of the National Park. She was forced to shift when a leopard carried off a toddler. The second was just behind this dump—a lovely spot, full of songbirds, but it flooded out during the 2005 monster monsoon. This spot had seemed safe, until last night.

If just a small fever could kill a baby, muses Selvi, who knows what’s next?

This dump and its surrounds, not so long ago, were woodland. Selvi’s first home was actually in the forest—the marauding leopard was merely going about its business when it mistook a toddler for a quadruped. Selvi’s second home was built on a river bed. This dump endures on the landfill of a natural lake, and carries that memory in its avian population.

Displacements, migrations.

Changes of expedience for survival.

Selvi, a migrant, understands.

THE STRATEGIES OF mosquito control all seem to begin with the water container. But how did that dabba or plastic pail get there in the first place? People came to live here because somebody cleared the land.

Hundreds of species are evicted when you cut down one tree.

All these life-forms do just what you and I would if we were thrust out of our homes—find another place to live.

For a mosquito who lives in a tree hole, it is a drastic change. Gone is the not always palatable rodent or primate host, so unpunctual, changeable as the seasons. Gone is the rough and ready nursery never moist enough for months, and then, just as you put down a fine clutch of eggs, a dry spell kills them all. Gone are the long hungry stakeouts by moonlight when one could bite in comfort only when it was pitch dark. And in their lieu are nurseries kept permanently moist, some with in-built rotifer farms to feed the larvae.

And the host? Was there ever a more willing prey? Humans smell delectable, waft CO2 with every breath in addition to the fug of odorants they trail. What’s not to like?

And the meal itself? When was blood ever so delicious, so rich in alanine, so attuned to quicker, more frequent, reproductive cycles?

And the human house is shadier, less noisy, and more refined than the tree where one was forced to put up with riff-raff all day.

This, definitely, is the life!

CHANGES IN LAND USE, over-development and urban sprawl have all been correlated with the emergence of virulent DENV strains. The more crowded a city, the greater our propinquity with other species, and easier for a microbe to make the cross-species jump.

If we consider viruses (and their vectors) as autochthonous, part of the landscape, our strategies to combat them will change. The manner in which we look at the diseases they cause will change too.

The present epidemic of Zika is a case in point. Zika seemed innocuous for years, and caused nothing more than a mild illness in humans. Its first alarming manifestation was in 2104, when cases of Guillain-Barré Syndrome (GBS), an auto-immune transient paralysis, followed Zika Fever. GBS is a known sequel to many infections and its mechanism is also known.

Then came the Zika babies of Brazil. This ‘Zika’ type of fetal damage is encountered with other infections too.

DENV, also a flavivirus, does not usually cause neurological damage. But it has the potential to do so, and has caused GBS in some populations.

CHIKV is not considered a teratogen, but it can be transmitted from mother to baby and cause encephalitis in the newborn.

And ZikV, incidentally, was known to damage the developing brain as far back as 1952.

Many viruses, same effect.

Perhaps the sensible thing would be to take the modular view and ask:

What set of circumstances produce a certain suite of disease manifestations?

What molecular/genetic factors collude in the body to produce this?

What organisms have the potential to enforce this? This would factor in the nasty surprise that ‘just a small fever’ can kill.

AS THE DISCOVERIES of science grow more brilliant and more pixelate, it falls on us to recognise that the survival of our species depends on our willingness to let other species survive.

Amongst us, the most vulnerable are the immunologically naïve—our children.

And, we are a nation unmoved by the sight of a starving child.

When any virus hits, the malnourished child will be the initial target—and also the start of an epidemic. It isn’t just the faceless starving child who will die. You could too.

Ours is a viral planet. To keep our place in it, it will require more sapience than SWAT!

denguehealthmedicinesThe Viral FevervirusZika Virus