Poison as Medicine

Ellie Lobel was 27 when she was bitten by a tick and contracted Lyme disease. And she was not yet 45 when she decided to give up fighting for survival.

Caused by corkscrew-shaped bacteria called Borrelia burgdorferi, which enter the body through the bite of a tick, Lyme disease is diagnosed in around 300,000 people every year in the United States. It kills almost none of these people, and is by and large curable – if caught in time. If doctors correctly identify the cause of the illness early on, antibiotics can wipe out the bacteria quickly before they spread through the heart, joints and nervous system.

But back in the spring of 1996, Ellie didn’t know to look for the characteristic bull’s-eye rash when she was bitten – she thought it was just a weird spider bite. Then came three months with flu-like symptoms and horrible pains that moved around the body. Ellie was a fit, active woman with three kids, but her body did not know how to handle this new invader. She was incapacitated. “It was all I could do to get my head up off the pillow,” Ellie remembers.

Her first doctor told her it was just a virus, and it would run its course. So did the next. As time wore on, Ellie went to doctor after doctor, each giving her a different diagnosis. Multiple sclerosis. Lupus. Rheumatoid arthritis. Fibromyalgia. None of them realized she was infected with Borrelia until more than a year after she contracted the disease – and by then, it was far too late. Lyme bacteria are exceptionally good at adapting, with some evidence that they may be capable of dodging both the immune system and the arsenal of antibiotics currently available. Borrelia are able to live all over the body, including the brain, leading to neurological symptoms. And even with antibiotic treatment, 10–20 percent of patients don’t get better right away. There are testimonies of symptoms persisting – sometimes even resurfacing decades after the initial infection – though the exact cause of such post-treatment Lyme disease syndrome is a topic of debate among Lyme scientists.

“I just kept doing this treatment and that treatment,” says Ellie. Her condition was constantly worsening. She describes being stuck in bed or a wheelchair, not being able to think clearly, feeling like she’d lost her short-term memory and not feeling “smart” anymore. Ellie kept fighting, with every antibiotic, every pharmaceutical, every holistic treatment she could find. “With some things I would get better for a little while, and then I would just relapse right back into this horrible Lyme nightmare. And with every relapse it got worse.”

After fifteen years, she gave up.

“Nothing was working any more, and nobody had any answers for me,” she says. “Doctors couldn’t help me. I was spending all this cash and was going broke, and when I got my last test results back and all my counts were just horrible, I knew right then and there that this was the end.”

“I had outlived so many other people already,” she says, having lost friends from Lyme support groups, including some who just couldn’t take the suffering any more. “I didn’t care if I was going to see my next birthday. It’s just enough. I was ready to call it a life and be done with it.”

So she packed up everything and moved to California to die. And she almost did.

Less than a week after moving, Ellie was attacked by a swarm of Africanized bees.

Ellie was in California for three days before her attack. “I wanted to get some fresh air and feel the sun on my face and hear the birds sing. I knew that I was going to die in the next three months or four months. Just laying there in bed all crumpled up… It was kind of depressing.”

At this point, Ellie was struggling to stand on her own. She had a caregiver on hand to help her shuffle along the rural roads by her place in Wildomar, the place where she had chosen to die.

She was just standing near a broken wall and a tree when the first bee appeared, she remembers, “just hitting me in the head”. “All of a sudden – boom! – bees everywhere.”

Her caregiver ran. But Ellie couldn’t run – she couldn’t even walk. “They were in my hair, in my head, all I heard was this crazy buzzing in my ears. I thought: wow, this is it. I’m just going to die right here.”

Ellie, like 1–7 percent of the world’s population, is severely allergic to bees. When she was two, a sting put her into anaphylaxis, a severe reaction of the body’s immune system that can include swelling, nausea and narrowing of the airways. She nearly died. She stopped breathing and had to be revived by defibrillation. Her mother drilled a fear of bees into her to ensure she never ended up in the same dire situation again. So when the bees descended, Ellie was sure that this was the end, a few months earlier than expected.

Bees – and some other species in the order Hymenoptera, such as ants and wasps – are armed with a potent sting that many of us are all too aware of. This is their venom, and it’s a mixture of many compounds. Perhaps the most important is a tiny 26-amino-acid peptide called melittin, which constitutes more than half of the venom of honey bees and is found in a number of other bees and wasps. This little compound is responsible for the burning pain associated with bee stings. It tricks our bodies into thinking that they are quite literally on fire.

When we experience high temperatures, our cells release inflammatory compounds that activate a special kind of channel, TRPV1, in sensory neurons. This ultimately causes the neurons to send a signal to the brain that we’re burning. Melittin subversively makes TRPV1 channels open by activating other enzymes that act just like those inflammatory compounds.

Jellyfish and other creatures also possess TRPV1-activating compounds in their venoms. The endpoint is the same: intense, burning pain.

“I could feel the first five or ten or fifteen but after that... All you hear is this overwhelming buzzing, and you feel them hitting your head, hitting your face, hitting your neck,” says Ellie.

“I just went limp. I put my hands up and covered my face because I didn’t want them stinging me in the eyes… The next thing I know, the bees are gone.”

When the bees finally dissipated, her caregiver tried to take her to the hospital, but Ellie refused to go. “This is God’s way of putting me out of my misery even sooner,” she told him. “I’m just going to accept this.”

“I locked myself in my room and told him to come collect the body tomorrow.”

But Ellie didn’t die. Not that day, and not three to four months later.

“I just can’t believe that was three years ago, and I just can’t believe where I am now,” she tells me. “I had all my blood work done. Everything. We tested everything. I’m so healthy.”

She believes the bees, and their venom, saved her life.

The idea that the same venom toxins that cause harm may also be used to heal is not new. Bee venom has been used as a treatment in East Asia since at least the second century BCE. In Chinese traditional medicine, scorpion venom is recognized as a powerful medicine, used to treat everything from eczema to epilepsy. Mithradates VI of Pontus, a formidable enemy of Rome (and also an infamous toxinologist), was said to have been saved from a potentially fatal wound on the battlefield by using steppe viper venom to stop the bleeding.

“Over millions of years, these little chemical engineers have developed a diversity of molecules that target different parts of our nervous system,” says Ken Winkel, Director of the Australian Venom Research Unit at the University of Melbourne. “This idea of applying these potent nerve toxins to somehow interrupt a nervous disease has been there for a long time. But we haven’t known enough to safely and effectively do that.”

Despite the wealth of history, the practical application of venoms in modern therapeutics has been minimal. That is, until the past ten years or so, according to Glenn King at the University of Queensland in Brisbane, Australia. In 1997, when Ellie was bouncing around from doctor to doctor, King was teasing apart the components of the venom from the Australian funnel-web, a deadly spider. He’s now at the forefront of venom drug discovery.

King’s group was the first to put funnel-web venom through a separation method called high-performance liquid chromatography (HPLC), which can separate out different components in a mixture based on properties like size or charge. “I was just blown away,” he says. “This is an absolute pharmacological goldmine that nobody’s really looked at. Clearly hundreds and hundreds of different peptides.”

Over the course of the 20th century, suggested venom treatments for a range of diseases have appeared in scientific and medical literature. Venoms have been shown to fight cancer, kill bacteria, and even serve as potent painkillers – though many have only gone as far as animal tests. At the time of writing, just six had been approved by the US Food and Drug Administration for medical use (one other – Baltrodibin, adapted from the venom of the Lancehead snake – is not FDA approved, but is available outside the US for treatment of bleeding during operations).

The more we learn about the venoms that cause such awful damage, the more we realize, medically speaking, how useful they can be. Like the melittin in bee venom.

Melittin does not only cause pain. In the right doses, it punches holes in cells’ protective membranes, causing the cells to explode. At low doses, melittin associates with the membranes, activating lipid-cutting enzymes that mimic the inflammation caused by heat. But at higher concentrations, and under the right conditions, melittin molecules group together into rings creating large pores in membranes, weakening a cell’s protective barrier and causing the entire cell to swell and pop like a balloon.

Because of this, melittin is a potent antimicrobial, fighting off a variety of bacteria and fungi with ease. And scientists are hoping to capitalize on this action to fight diseases like HIV, cancer, arthritis and multiple sclerosis.

For example, researchers at the Washington University School of Medicine in St Louis, Missouri, have found that melittin can tear open HIV’s protective cell membrane without harming human cells. This envelope-busting method also stops the virus from having a chance to evolve resistance. “We are attacking an inherent physical property of HIV,” Joshua L Hood, the lead author of the study, said in a press statement. “Theoretically, there isn’t any way for the virus to adapt to that. The virus has to have a protective coat.” Initially envisioned as a prophylactic vaginal gel, the hope is that melittin-loaded nanoparticles could someday be injected into the bloodstream, clearing the infection.

Ellie is the first to admit that her tale sounds a little tall. “If someone were to have come to me and say, ‘Hey, I’ll sting you with some bees, and you’ll get better’, I would have said, ‘Absolutely not! You’re crazy in your head!’” But she has no doubts now.

After the attack, Ellie watched the clock, waiting for anaphylaxis to set in, but it didn’t. Instead, three hours later, her body was racked with pains. A scientist by education before Lyme took its toll, Ellie thinks that these weren’t a part of an allergic response, but instead indicated a Jarisch–Herxheimer reaction – her body was being flooded with toxins from dying bacteria. The same kind of thing can happen when a person is cured from a bad case of syphilis. A theory is that certain bacterial species go down swinging, releasing nasty compounds that cause fever, rash and other symptoms.

For three days, she was in pain. Then, she wasn’t.

“I had been living in this… I call it a brown-out because it’s like you’re walking around in a half-coma all the time with the inflammation of your brain from the Lyme. My brain just came right out of that fog. I thought: I can actually think clearly for the first time in years.”

With a now-clear head, Ellie started wondering what had happened. So she did what anyone else would do: Google it. Disappointingly, her searches turned up very little. But she did find one small 1997 study by scientists at the Rocky Mountain Laboratories in Montana, who’d found that melittin killed Borrelia. Exposing cell cultures to purified melittin, they reported that the compound completely inhibited Borrelia growth. When they looked more closely, they saw that shortly after melittin was added, the bacteria were effectively paralyzed, unable to move as their outer membranes were under attack. Soon after, those membranes began to fall apart, killing the bacteria.

Convinced by her experience and the limited research she found, Ellie decided to try apitherapy, the therapeutic use of materials derived from bees.

Her bees live in a “bee condo” in her apartment. She doesn’t raise them herself; instead, she mail orders, receiving a package once a week. To perform the apitherapy, she uses tweezers to grab a bee and press it gently where she wants to be stung. “Sometimes I have to tap them on the tush a little bit,” she says, “but they’re usually pretty willing to sting you.”

She started on a regimen of ten stings a day, three days a week: Monday, Wednesday, Friday. Three years and several thousand stings later, Ellie seems to have recovered miraculously. Slowly, she has reduced the number of stings and their frequency – just three stings in the past eight months, she tells me (and one of those she tried in response to swelling from a broken bone, rather than Lyme-related symptoms). She keeps the bees around just in case, but for the past year before I talked to her, she’d mostly done just fine without them.

Modern science has slowly begun to take apart venoms piece by piece to understand how they do the things they do, both terrible and tremendous. We now know that most venoms are complex cocktails of compounds, with dozens to hundreds of different proteins, peptides and other molecules to be found in every one. The cocktails vary between species and can even vary within them, by age, location or diet. Each compound has a different task that allows the venom to work with maximum efficiency – many parts moving together to immobilise, induce pain, or do whatever it is that the animal needs its venom for.

The fact that venoms are mixtures of specifically targeted toxins rather than single toxins is exactly what makes them such rich sources of potential drugs – that’s all a drug is, really, a compound that has a desired effect on our bodies. The more specific the drug’s action, the better, as that means fewer side-effects.

“It was in the 2000s that people started saying well, actually, [venoms] are really complex molecular libraries, and we should start screening them against specific therapeutic targets as a source of drugs,” says King.

Of the seven venom-derived pharmaceuticals on the international market, the most successful, captopril, was derived from a peptide found in the venom of the Brazilian viper (Bothrops jararaca). This venom has been known for centuries for its potent blood-thinning ability – one tribe are said to have coated their arrow tips in it to inflict maximum damage – and the drug has made its parent company more than a billion dollars and become a common treatment for hypertension.

Bryan Fry, a colleague of Glenn King’s at the University of Queensland and one of the world’s most prolific venom researchers, says the captopril family and its derivatives still command a market worth billions of dollars a year. Not bad for something developed in 1970s. “It’s not only been one of the top twenty drugs of all time,” he says, “it’s been one of the most persistent outside of maybe aspirin.”

And it’s not just captopril. Fry points to exenatide, a molecule found in the venom of a lizard, the gila monster, and the newest venom-derived pharmaceutical on the US market. Known by the brand name Byetta, this has the potential to treat type 2 diabetes, stimulating the body to release insulin and slow the overproduction of sugar, helping reverse the hormonal changes caused by the disease.

Rare cases like Ellie’s are a reminder of the potent potential of venoms. But turning folk knowledge into pharmaceuticals can be a long and arduous process. “It could take as long as ten years from the time you find it and patent it,” says King. “And for every one that you get through, ten fail.”

Since the 1997 study, no one had looked further into bee venom as a potential cure for Lyme disease, until Ellie.

Ellie now runs a business selling bee-derived beauty products called BeeVinity, inspired after, she says, noticing how good her skin looked as she underwent apitherapy. “I thought, ‘Well, people aren’t going to want to get stung with bees just to look good.’”

Ellie has partnered with a bee farm that uses a special electrified glass plate to extract venom. As the bees walk across the plate on the way to and from their hive, harmless currents stimulate the bees to release venom from their abdomens, leaving teeny little droplets on the glass, which are later collected. Ellie says it takes 10,000 bees crossing that plate to get 1 gram of venom (other sources, such as the Food and Agriculture Organization of the UN, quote 1 million stings per gram of venom), but “those bees are not harmed”.

For her, it is more than just a way to make a living: it’s “an amazing blessing”. Proceeds from her creams and other products support bee preservation initiatives, as well as Lyme disease research. In addition, she sends some of the venom she purchases – which, due to the cost of the no-harm extraction method she uses, she says is “more expensive than gold” – to Eva Sapi, Associate Professor of Biology and Environmental Science at the University of New Haven, who studies Lyme disease.

Sapi’s research into the venom’s effects on Lyme bacteria is ongoing and as yet unpublished, though she told me the results from preliminary work done by one of her students look “very promising”. Borrelia bacteria can shift between different forms in the body, which is part of what makes them so hard to kill. Sapi has found that other antibiotics don’t actually kill the bacteria but just push them into another form that is more dormant. As soon as you stop the antibiotics, the Borrelia bounce back. Her lab is testing different bee venoms on all forms of the bacteria, and so far, the melittin venom seems effective.

The next step is to test whether melittin alone is responsible, or whether there are other important venom components. “We also want to see, using high-resolution images, what exactly happens when bee venom hits Borrelia,” Sapi told me.

She stresses that much more data is needed before any clinical use can be considered. “Before jumping into the human studies, I would like to see some animal studies,” she says. “It’s still a venom.” And they still don’t really know why the venom works for Ellie, not least because the exact cause of post-treatment Lyme disease symptoms remains unknown. “Is it effective for her because it’s killing Borrelia, or is it effective because it stimulates the immune system?” asks Sapi. It’s still a mystery.

There’s a long way to go for bee venom and melittin. And it takes a lot of work – and money – to turn a discovery into a safe, working medicine. But labs like King’s are starting to tap the pharmaceutical potential that lies in the full diversity of venomous species. And King, for one, believes that scientists are entering a new era of drug discovery.

In the past, venoms have been investigated because of their known effects on humans. Such investigations required both knowledge of the venom’s clinical effects and large volumes of venom, so until now only large species, like snakes, with easily extracted venoms have been studied in any depth. But that’s changing. Technological advances allow for more efficient venom extraction as well as new ways to study smaller amounts of venom. The preliminary tests for pharmaceuticals can now start with nothing more than a genetic sequence. “We can now genomically look at the toxins in these animals without having to actually even purify the venom,” says King, “and that changes everything.” Ken Winkel thinks venomous animals will be excellent drug resources for devastating neurological diseases, as so many of their venoms target our nervous system. “We really don’t have great drugs in this area,” he says, “and we have these little factories that have a plethora of compounds…”

No one knows exactly how many venomous species there are on this planet. There are venomous jellyfish, venomous snails, venomous insects, even venomous primates. With that, however, comes a race against time of our own making. Species are going extinct every year, and up to a third may go extinct from climate change alone.

“When people ask me what’s the best way to convince people to preserve nature, your weakest argument is to talk about how beautiful and wonderful it is,” says Bryan Fry. Instead, he says, we need to emphasize the untapped potential that these species represent. “It’s a resource, it’s money. So conservation through commercialization is really the only sane approach.”

Ellie couldn’t agree more. “We need to do a lot more research on these venoms,” she tells me emphatically, “and really take a look at what’s in nature that’s going to help us.”

This story first appeared on Mosaic and is republished here under a Creative Commons license.