Anne Renwick discusses the immune system and how it reacts to snake venom, the inspiration behind the creation of Cait’s character and how she becomes the heroine of VENOMOUS SECRETS.

Antibodies and Antivenom

In VENOMOUS SECRETS, our heroine possesses a secret, inborn talent: fast-forming immunity to any biologically based toxin or poison. How does that work? Antibodies.

And, thanks to COVID, by now you might have a pretty good idea just how fast your body generates antibodies – to vaccines in particular.

We’re going to cover the immune basics at a very superficial level here. (Seriously, people spend 5+ years earning PhDs just on a small topic within the incredibly complex field of immunology.)

When you are first exposed to a bacteria or virus or toxin that your body flags as a “problem”, the first line of defense comes from “Innate immunity”. 

There are cells that patrol your body, looking for abnormal tissues. You possess proteins that will counteract viral proteins, yet still other proteins that will bind any suspicious particles. All send out their own signals to recruit yet more help. Inflammation (swelling, redness, heat and pain) is part of this process. When thus called, a number of cell types are available to rush in, to eat and/or remove the substance recognized as a threat (e.g. mast cells, eosinophils, basophils and other phagocytic cells).

But what we’re after is known as “Adaptive immunity” wherein antibodies are generated. 

First, two important terms:

Antigen – the foreign substance that induces an immune response

Antibody – the Y-shaped protein that is produced in response to an antigen; binds very specifically to a particular antigen; also known as immunoglobulins; abbreviated Ab 

Upon first exposure, a cell type called antigen-presenting cells (APCs) will engulf, chew up and wave pieces of this foreign threat on the surfaces of their cells like a flag on a stick (MHC II). They present antigens for inspection. Helper T cells (CD4) will take a close look at the flag, poke at it, and consider their response. If they deem it worthy of an immune response, they explode into action. They replicate like mad. Some of their progeny go on to become 1) memory T cells, others will start sending out signals (cytokines) to mature 2) cytotoxic killer T cells (cyto = cell), and 3) they promote the activation of B cells.

And this is where we want to focus today, on B cells. These are the cells who are going to produce antibodies.

To build an antibody, we pair together two long parallel proteins, then bend half of each protein outward to form a Y shape. So there’s a stem part (two proteins close together). And the flare part (where they bend outward).

To each outward flare piece, we attach a shorter protein. 

So four proteins in all to produce an antibody: 2 long, 2 short.

The two longer proteins are called “heavy chains” and the shorter ones are “light chains”. Both the heavy and light chains have constant regions and variable regions, with the constant parts being closer to the stem, and the variable parts at the tips of the flare of the Y. 

When it finds a winner B cell with a winner antibody, they all cheer (well, not really, but…) and start making clones of the superstar. Memory B cells are filed away while other winning clones go on to form plasma cells. Plasma cells start pumping out those antibodies.

In the case of a vaccine, all this happens after your first shot, after what the vaccinologists will call your “prime”. It’s your first exposure to a fragment of the enemy.

After two weeks, if/when the antigen is no longer present, the plasma B cells start to die off and your Ab levels fall. Totally normal. Never fear, the memory B cells are waiting in the wings (well, in your bone marrow, but…).

If/when you encounter the antigen again (in vaccine terms, this is your “boost”), the memory B cells burst into action, forming plasma cells and generating antibodies right away. Not just faster, but MORE antibodies. This is the secondary antibody response.

The antibodies will bind to their antigen, sticking all over the surface and stopping the antigen from exerting its effects. From making you sick. In the case of a virus (echm, SARS-Cov-2), the viral spike 1 protein is blocked, preventing the virus from entering cells (where it very much wants to go to replicate itself). In short order, phagocytic cells (eating cells) will arrive to dispose of the sticky, clumped up mess. No fuss, no muss.

Now, depending upon your snake, venom (mostly proteins and enzymes) can have a wide variety of effects:

• Proteolytic – breaking down of proteins at the site of the bite or wherever the venom flows
• Hemotoxic – affecting the cardiovascular system in terms of heart rate, blood pressure, and/or coagulation
• Neurotoxic – affecting nerve conduction, including the brain
• Cytotoxic – killing of cells (tissue damage)

Back to immunity.

Are snakes immune to their own venom? This is a question not definitively settled, but for the most part, yes, they are immune to their own venom. Some are even immune to the venom of other snake species.

Now, because every species of snake produces a different kind of venom, you have to match the treatment of a snakebite to the kind of envenomation (bite with venom) that occurs. 

And so there exist many different kinds of antivenom. 

Every year ~100,000 people die from snake bites. Yes, antivenom (aka antivenin) exists in medical facilities. But can you reach a hospital in time? Can the rescuers reach you? Even that may not save you.

This is where the teeth gnashing occurs.

Antivenom is a blood product in limited supply; it’s not always available. It’s hard to produce, expensive to produce, and it can be dangerous to produce. Plus, the storage requirements are tricky… and it won’t last forever. So antivenom can be scarce and pricy (thousands per vial). Not to mention, there are a number of documented reactions to antivenom itself that can be quite serious. Antivenom use requires close medical supervision.

So if you’re bitten by a cobra, a toxic antigen has been introduced into your body, into your blood. If you’re lucky enough that an antivenom is available, what you’re about to be injected with is an antibody to cobra venom.

How does one make this antivenom antibody? I’m glad you asked.

Traditionally*, an animal is injected with a small amount of venom. Then, the next time, a little more venom, then a little more, then more and so on. Over time, this animal builds up immunity to the antivenom – it makes antibodies to the toxic proteins. Blood is then collected from the animal (much like a blood donation), after which the antibodies are purified out and stored in vials to await the unlucky snakebite victim.

Can we, who are not as “gifted” as Cait, become immune to snake venom?

Sorta?

There are documented cases of snake handlers allowing themselves to be lightly bitten, over and over, to the point where a full bite will not harm/kill them. For example, Rock Singer Steve Ludwin is known for this practice – and offered himself to medicine for the development of antivenom. 

In fact, there’s a special term for this practice. Mithridatism is a practice named after an ancient king who (suspecting plots against him) ingested non-lethal amounts of poisons making himself immune (so the story goes) to all known poisons. (We’re all thinking The Princess Bride and Iocaine powder, right? Yep, along those lines.) 

HOWEVER. While a person can build up tolerance to snake venom (developing antibodies to venom), it is still possible that this same venom could be unleashed upon them in lethal amounts – an overwhelm the system scenario. Venom acts quickly – there’s no time for the memory B cells to become plasma cells, to release their antibodies into the bloodstream to neutralize the venom. Any protection an individual builds up has to already be in place when the bite occurs.

Which makes Cait, our heroine, a truly exceptional individual. Once exposed to a biological toxin, her immune system produces highly tailored antibodies with incredible speed, whipping through the primary and secondary antibody response in a matter of hours. A handy scenario when one wants to join the Queen’s agents and hunt a venomous creature stalking steampunk London’s lamplit streets.

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*Today, we can produce antibodies via a more complicated method using cell culture. It is, however, technology and labor heavy, adding further to the expense. You might have heard of this method: monoclonal antibody therapy. Basically, engineered cells produce a specific antibody which is then collected and purified.