25 Jul 17

The next step for an HIV cure is from a cow

A veritable Animal Farm has been useful to humans in medical science, from guinea pigs to cows to camels. Thankfully, science and politics don’t mix elsewhere but only in India.

The combined efforts of the human imagination have endowed inter-galactic aliens with two eyes, two ears, one nose, four limbs, and one brain. Yes. We think evolution peaked with us. An alien worthy of being our adversary has to look and think like us. Of course, it does. After all, we are the masters of this universe. We sit atop the tree of life and all what we survey from that vantage is beneath us, crawling and writhing and inept and unintelligent and wanting to be us.



Nothing could be further from the truth.



We, the people, are but a collection of living and breathing cells. We don’t sit atop the tree of life – far from it. We barely manage to hang on to one of its hundred-odd branches. We are a cog in this giant throbbing machine called Evolution. Only a cog. A cog that knows no humility or modesty; a cog that would rather believe in Social Darwinism than Darwinism.



The first of many mortal blows to our delusions of grandeur was provided by TH Huxley, a contemporary of Darwin, who proposed that man evolved from apes.



To understand how controversial this proposal was, one need only see the trolling Darwin received eight years later when he fructified Huxley’s idea into what is perhaps one of the most earth-shattering books ever written – The Descent of Man. The title itself was unacceptable to many. How could man – this embodiment of perfection, created with love and at leisure by God – how could he have evolved from an ape? After all, he was perched atop the tree of life, from where, weather and benevolence permitting, he could look out for the lesser creatures.



Well, Huxley was right. 142 years after his claim, scientists sequenced the Chimpanzee genome and found it to be 98.77 per cent genetically identical to the Human genome. And in these 142 years, loved or loathed because of it, the tree of life has rearranged its branches and its occupants constantly, so much so that it now looks like this:



That is correct. We don’t sit atop it anymore. We are barely visible; clinging on to a branch, trying to not fall off and merge once more into the mud from where we first emerged.



The modern Tree of Life is humbling to stare at, a little like that mortifying Milky-way poster with the tiny earth-pointing red arrow above the caption “You are here”. It tells us that we are just one of the animals in an Animal Farm. Such an idea was blasphemous barely a century ago. Imagine telling all those continent-conquering SOBs that their bodies had more bacteria than human cells, that bugs complete us, that humans survive only because of an exquisite friendship we have struck with the rest of the living beings; that no one is Napoleon in this Animal Farm.



Last week, one of the animals in the animal farm handed over to us a lifeline: A potential cure for AIDS.



Acquired Immune Deficiency Syndrome, or AIDS, a disease caused by the Human Immunodeficiency Virus, HIV, although not curable, is containable; and for this reason it no longer creates the sense of urgency or public fear as it used to during the 1980s, the years of its exponential rise when it was written and spoken of with dread. To be sure, the epidemic is far from over – close to 37 million humans are living with AIDS. With no functional cure or an available vaccine, all that the current cocktail of anti-HIV drugs aim to do is to improve the patient’s quality of life. This, mind, is in itself a great achievement, and one that scientists can be proud of. But to hold the chalice so close to your parched lips and yet not sip from it is, ultimately, to not have found the Holy Grail. That distance between the cup and the lip, is the difference between containing and curing.



HIV science matters – is the motto of the International AIDS Society, 2017 Conference (http://www.ias2017.org/), the world’s largest open scientific conference on HIV and AIDS, happening this week in Paris. It appears the gathered scientists would have something to cheer about, courtesy the Animal Farm.



Last week, the premier scientific journal Nature reported a finding, by Burton, Smider, and colleagues at the Scripps Research Institute, California, that has the potential to overcome the seemingly insurmountable challenge to have plagued the development of anti-HIV vaccine – our body’s inability to efficiently produce antibodies against the HIV virus so as to neutralise the infection. Less than 20 per cent of HIV patients naturally develop broadly neutralising antibodies (bNAbs) to the virus, and usually not before the infection has ravaged the body for two years running. Macaques and rabbits, too, have failed as a surrogate biological means of producing antibodies against HIV. A vaccine against HIV has remained a distant dream. Until now.



Vaccination is a method by which the human body is primed to mount an immune response against an invading foreign body or a disease-causing microbe. This immune response, call it a military manoeuvre, is carried out by two battalions acting in tandem – killer cells and antibodies. Antibodies are the ones that lay the trap. They attach themselves to the infected cells, acting at once as identifying tags and navigators for the killer cells to oust or destroy the invaders. Antibodies attach to extremely specific portions of the attacker, also called antigens. This so-called antigen-antibody interaction is the deciding factor in combating any disease.



One reason why a cure for HIV has proven to be beyond one’s grasp is that the cunning virus carries with it a defective replicating machine, and the defect is what helps it survive everything our body throws at it. This machine, called the reverse transcriptase, converts the HIV RNA into HIV DNA that is then read by the host cell machinery to make HIV proteins. The HIV reverse transcriptase lacks a proof-reading function, resulting in mistakes, or mutations, being incorporated in the transcribed DNA. Because this DNA then codes for HIV proteins, every new RNA to DNA transcription results in an altered HIV protein. In effect, the virus changes it shape constantly, and our antibodies, that were made to measure keeping in mind an earlier version of the HIV protein, are now no longer able to recognise it. Clever doesn’t quite cover it. Here is a humble microscopic inhabitant of the animal farm that has beaten us fair and square.



Not quite. Enter the cow.



Out on a limb, Burton, Smider, and colleagues attempted to test cows as biological systems in order to produce broadly neutralising antibodies against HIV. Remarkably, test immunisation with the HIV antigen resulted in a rapid and potent antibody production within two months. There it was, an alternate avenue for the production of a future vaccine and therapy candidates against the HIV; an unprecedented eureka moment if ever there was one. Upon isolation of the antibody cocktail from the cow’s blood, one, named NC-Cow 1 turned out to be especially powerful against HIV.



This ground-breaking result comes as a follow-up to Dr Smider’s earlier work on bovine antibodies, published in June of 2013 in the journal Cell.



Bovine antibodies were found to be superior to those of humans, macaques, and rabbits, both in potency and range, due to a unique structural endowment as revealed by deep sequencing. Both arms of the Y-shaped bovine antibody, called HCDR3, have ultra-long cysteine-rich regions, conferring an unusual architecture that resembles a knob on a stalk. Cysteine, a major component of human hair, and one that gives it the kink, is an amino acid that couples with another of its own through what is called a disulfide bridge. The more cysteines there are in an antibody, the more chances there are of these cysteines locking with one another, and the more they lock with one another, the more complex folds the antibody settles into. These combinations, then, are what result in a staggering array of diverse mini domains. Simply put, the knobs on the stalk can occur in various shapes, providing diverse structures for antigen binding.



What could be the evolutionary reason for cows to have developed this unusual mechanism of producing robust immune responses, is not fully understood. One theory suggests it is all to do with combating the grave risk that cows face, in picking up severe gastrointestinal infections because of their multi-chambered gut and the trillions of dangerous soil-dwelling bugs it has to ward off. Hence the evolutionary fallout in the form of increased protection.



These new results form one of the most prominent applications of bovine antibodies. Further exploration would entail mimicking or modifying them to develop anti-HIV therapy and finally, humanised vaccine products. Early days yet, but a glimpse of the future has been seen. And it involves a day of fun and frolic in the Animal Farm.



N.B. Science and politics are like conscience and realpolitik – they never mix. Except in our country. The Cow-HIV breakthrough has been received mutedly by the Indian Left wing but with unbridled enthusiasm by the Indian Right wing, that shared the report with aplomb even though it didn’t contain a single mention of the word ‘Modi’ – in appreciation or derision, the only two metrics that seem to determine clickbaits and eyeballs in the modern world. While this is a good thing – making science news go viral is always a good thing – it also reflects, in some sense, human proclivity and a manner of thinking that subconsciously searches for “usefulness” in living beings. Guinea pigs, rats, mould, Escherichia coli, even fruit flies, have over decades, shown to be far more “useful” to humans than the cow so far as medical and scientific breakthroughs are concerned. Also, and in keeping with the secular ethos of our great nation, it is perhaps pertinent to mention that antibodies from the one-humped Arabian camel are equally, if not more, “useful” to humans. One word: Camelids. There’s great future in Camelids. And now in Cowlids, too.                                                                

This article first appeared in newslaundry on Jul. 25, 2017.

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