When I was growing up in the 1960s, chewing gum was a big deal.
TV ads showcased the doublemint twins and their stick gum, and the small squares of chiclets. Kids preferred tiny bricks of pink Bazooka with the folded-up shiny papers bearing dumb comics. Girls collected rectangular Juicy Fruit wrappers, folding them thrice in two dimensions and linking them into loooong chains that we’d save for our future first boyfriends.
We had tea-flavored teaberry gum, and a yummy licorice one with a name that is probably no longer politically correct.
Trident gum offered a sugar-free option, while Dentyne gave the illusion of health. New York City pharmacist Franklin V. Canning invented the gum in 1899, formulated to “sweeten the breath, to keep teeth white,” according to the wrapper. Dentyne cleverly combines “dental” and “hygiene.”
And an ancient song was entitled, “Does your chewing gum lose its flavor on the bedpost overnight?”
Back then, kids collected cards. The 5-card packets came with squares of a peculiar, sugar-powdered, pink polymer that would rate a top score on Mohs scale of mineral hardness. This substance was purported to be chewing gum.
I was obsessed with 1960s sci-fi, so I coveted monster cards. I tossed aside the gross gum and organized the cards bearing black-and-white images of the giant seed pods of Invasion of the Body Snatchers, the telltale neck mark from Invaders from Mars, the giant ants of Them, the blinking traffic-light-like aliens in pre-Tom-Cruise War of the Worlds, and of course Frankenstein and Dracula, Godzilla and King Kong.
I loved monster cards because I wanted to be a scientist. And I grew up to be one, working with fruit flies that had legs growing out of their mouths and heads, little beasties that would have been at home on the monster cards of yore.
I never imagined that one day, gum would protect against a deadly pandemic virus, SARS-CoV-2.
Targeting the Mouth, Nose, and Throat
Gum as a drug carrier has precedent. I took Aspergum for sore throats as a kid, now marketed by Retrobrands USA. But aspirin is a small, simple molecule.
“More recently caffeine and nicotine gums are common, but nobody could deliver proteins using gum because gum base requires very high temperature for proper rolling,” said Henry Daniell, from the University of Pennsylvania School of Dental Medicine. High temps would unravel the all-important three-dimensional shape of a protein, a bulky molecule. “But higher temperature stability of proteins made in plant cells helped us get over that difficult barrier,” Dr. Daniell added.
The COVID-dampening chewing gum that his team is developing delivers proteins produced in cells from hydroponic lettuce. The new report is published in Molecular Therapy.
The COVID gum delivers a protein, ACE2, that dots many types of our cells and controls a host of functions. SARS-CoV-2 attaches to ACE2 with its spikes and drags itself in. Then the virus takes over, pumping out its own proteins that serve as a toolkit to make more viruses. SARS-CoV-2 replicates like crazy in cells all along the nasopharynx, aka nose and throat, and if the immune response lags, zips down to the lungs.
While common sense public health measures like masking and distancing keep viruses out, flooding the mouth with ACE2 receptors that serve as decoys provides a powerful extra layer of protection. That’s what the gum does.
The gum might prove helpful, for example, in the situation of masking in a restaurant up until the food and drinks arrive, when suddenly virus-laden droplets can and do spew anywhere. Droplets spread a menu of pathogens, including, besides coronaviruses, also measles, HPV, Epstein-Barr virus, and herpes viruses. Different types of viruses bind different receptor molecules to enter our cells.
A little bit of spit is all it takes to get COVID. One milliliter of saliva, about a fifth of a teaspoon, carries 7 million copies of the SARS-CoV-2 RNA genome. A droplet is a thousandth the volume of a milliliter, but still large enough to carry the virus. “The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission” provides the measurements.
But it seems as if nothing about SARS-CoV-2 is ever as we expect. Viral load in saliva can be high whether an infected individual has symptoms or not – and many people don’t. I’m pretty sure I had a whopping load in my nasopharynx because I tested positive in seconds and a month after having COVID, I’m still sometimes dumping tons of seasoning on foods that I can’t taste. The virus replicates in salivary glands and oral mucous membranes.
A Chewing Gum Anti-infective Blocks Receptors
The “chewing gum topical delivery approach” introduces plant powder made from lettuce cells that contain the protein ACE2 (for angiotensin converting enzyme 2), which SARS-CoV-2 binds. ACE2 is the receptor, the gateway into our cells.
ACE2 receptors normally dot cells in the nose, mouth, lungs, heart, blood vessels, kidneys, liver, and gastrointestinal tract. Too little ACE2, from the virus hogging the receptors, ushers in inflammation, cell death, and organ failure, especially in the heart and the lungs.
Several research groups are working on the decoy ACE2 proteins. Anum Glasgow and colleagues at UCSF describe developing such a “receptor trap” that binds SARS-CoV-2 spikes, keeping them out of our cells. Thanks to computer engineering, the doctored receptors bind the hotspot of the viral spike (the receptor binding domain) with 170 times the strength of the natural interaction between virus and host protein. And the engineered ACE2 receptors keep the entire virus out.
FDA hasn’t yet approved receptor traps as antivirals, but several drugs that introduce ACE2 in a nasal spray are in development. But that might not be enough.
The work described in Molecular Therapy targets the salivary glands, which several other viruses infect – Zika, herpes simplex, hepatitis C, cytomegalovirus, and Epstein-Barr. And as SARS-CoV-2 has evolved from subvariant to subvariant, more of it is concentrating in the salivary glands – viral load in people with the delta variant is 1,260 times higher than in those with earlier versions of the virus, much of it swimming in the salivaries.
Dr. Daniell describes the background of the invention and how it works.
“Our university developed the SARS-CoV-2 mRNA vaccine and several other groups have made important contributions, and yet the majority of developing countries are not yet vaccinated. In Africa, even donated vaccines couldn’t be delivered because of the inadequate cold chain network. So, I am determined to find ways to control infectious diseases using approaches that don’t require the cold chain. Protein drugs made in plant cells are stable for many years when stored at ambient temperature. Because oral transmission of SARS-CoV-2 is 3 to 5 orders of magnitude higher than nasal transmission – four spoken words ‘Aah’ releases more virus in the aerosol than one hour of mask-free breathing – and infection initiates in the throat, chewing gum should be ideal to decrease self-infection and transmission. Therefore, we used chewing gum loaded with viral trap protein made in plant cells to debulk SARS-CoV-2 in saliva.”
Why not gargle with an anti-COVID mouthwash? Because as anyone who’s chewed a stick of Juicy Fruit or a piece of Bazooka knows, gum stays in the mouth longer.
COVID gum could also be used during dental procedures on infected patients. “This general concept could be extended to minimize infection or transmission of most oral viruses,” the researchers write.
The researchers tested the ability of chewed gum to neutralize the viruses in saliva on swabs from hospitalized infected patients from the tongue and gums, where the receptors are dense. They used the “microbubble SARS-CoV-2 antigen assay” to detect viral nucleocapsid proteins, which shield the RNA genome. Increasing the ACE2 payload correlated with decreasing viral load, by 95 percent. Placebo gum had no effect.
The anti-COVID chewing gum is, the researchers conclude, “novel and affordable, and offers patients time to build immunity in countries where vaccines are not available or affordable.” The gum can protect people at home, in the workplace, and can be shoved into the cheek or politely set aside while dining out. And in the coming months, the gum could possibly prevent reinfection – something that’s bound to happen.
“We have received several positive responses from FDA on the ACE2 chewing gum and anticipate approval pretty soon. We have successfully tested control of virulent influenza stains using viral trap protein in the chewing gum and are proceeding to test HPV control in oral cancer patients and herpes in patients with cold sores. These are commonly transmitted diseases in university campuses. So, this could be the next new platform technology to control oral infections,” Dr. Daniell said.
The marketing plan is obvious.
Just as my monster cards depicted all manner of beasts, I look forward to virus cards accompanying anti-viral gum that offer photos of coronaviruses, poxviruses, chikungunya and coxsackie, influenza and hepatitis, Ebola and Zika, and more.