The cold war
Jan Carette has spent four years trying to stop mice getting the sniffles. An associate professor of microbiology and immunology at Stanford University School of Medicine, he has been investigating how to halt the ability of a host of viruses – including those behind the common cold – from multiplying and attacking their hosts.
If he and his team are successful, their work could help save thousands of lives. It could also seriously dent sales of Kleenex. Earlier this year he discovered that no matter how much of the rhinovirus – which is the cause of around half of all colds – he exposed a group of genetically altered mice to, they refused to succumb. Could this team in California have finally found the holy grail of everyday medicine: a cure for the common cold?
“I’ve always been interested in how the smallest of viruses can have such a tremendous impact on human health,” says Carette. “Cold viruses are sort of the hallmark of evolution, they can spread from one person to another person, optimising as they go. How they interact with their human host is just fascinating.”
They are also costly. A 2003 University of Michigan study estimated that colds cost the US economy $40 billion a year. “It’s quite impressive for such a little thing isn’t it?” says Carette.
The war against the cold is nothing new. Ancient Egyptians – who had hieroglyphics for both a cough and a cold, the latter featuring a bulbous nose – were responsible for the first documented cold remedy. The Ebers Papyrus, a collection of herbal remedies dating back to around 1550 BC, recommends a nasal mask of galena (lead sulphide), dry incense and honey “to drive out catarrh”. Promising a cure in four days, the prescription on the ancient scroll vows “behold it is true… Do it and you will see.” Ancient Egyptian cynics may have pointed out that four days is usually long enough to ride out the worst of a cold, even without painting your nose with lead and honey.
Physicians in fifth-century BC Greece advised bloodletting to alleviate symptoms, while the Roman doctor Celsus, operating in the first century AD, swore by large quantities of the highest-quality Italian wine. In medieval Europe, cures were curiously frog-centric, with sufferers advised to either consume them as amphibian soup, swallow them live (a literal frog in your throat) or take one in the hand and cough directly into its mouth. Skunk oil, a dirty sock tied around the neck (both early 20th century America) and a necklace made from earthworms (central Europe circa 10th century) had little effect. England turned to alcohol (“Go to bed, hang your hat on the foot of the bed and continue to drink until you see two hats,” instructed William Buchan in his 1772 book Domestic Medicine) in the 18th century before upping the ante to heroin in the early 20th. Whatever we threw at our coughs, splutters, sore throats and shivers, however, the common cold would not yield.
Saddam and the spluttering students
There are few people in Britain who know more about the stubbornness of the sniffles than Professor Ron Eccles. As founder and director of Cardiff University’s Common Cold Centre, which he set up in 1988, he spent 30 years on the frontline of the cold war. So central was he to one of the world’s only institutions devoted to the development of new treatments for coughs, colds and hayfever, that when he retired in March 2017 it closed its doors permanently. He has also written a seminal textbook book on the subject – and for that we have Saddam Hussein to thank.
“I was teaching in a medical school in Baghdad in August 1990 when Hussein decided to invade Kuwait, which came as a surprise to Iraqis, Kuwaitis and the west – and an even bigger surprise to me,” says Eccles. “All of the westerners in Kuwait and Iraq were brought to Baghdad and distributed amongst areas they thought the allies might bomb.” Eccles wasn’t actually moved – the hotel where he was staying was being used by Hussein as one of his key meeting places, so the scientist was simply confined to his room to act as a human shield while the president of Iraq directed the first Gulf War below. “I wasn’t scared, but I was bored,” Eccles remembers.
“I was teaching in a medical school in Baghdad when Saddam Hussein decided to invade Kuwait – which came as a surprise”
He put his five-star detainment to good use, however, writing up his lecture notes into a book. When he finally left Iraq two months later – along with Edward Heath and Richard Branson who’d come to pick up human shields on a specially commissioned Virgin flight – the manuscript came with him and was published a few years later to academic acclaim.
After Iraq, Eccles returned to Cardiff and continued his work. A partnership between the university and the pharmaceutical industry, the Common Cold Centre saw clinical trials carried out on new treatments. “All your lozenges, your cough syrups, your sore-throat sprays, your decongestants… pretty much everything on the counters in the pharmacy and in the supermarket we tested for safety and efficiency,” says Eccles. And he was never short of human guinea pigs. “Students are great for cold research,” he says with a laugh. “They are often in social situations where viruses spread; they tend to be young, so their immune systems are relatively immature and haven’t yet been exposed to the countless multitude of cold viruses, and, crucially, they often need the money.”
During his time at the Cold Centre, Eccles realised that there are some fairly widespread misconceptions about colds. Prime among them is that nearly all the symptoms most people attribute to the cold virus itself are actually byproducts of our immune system trying to fight it.
The cold virus replicates best below regular body temperature, at around 32°C. To slow the infection’s progress, says Eccles, your body not only increases your temperature, causing a fever, but also activates the shivers, whose rapid movement helps keep your internal temperature high. The ‘chills’ you feel are an evolutionary response attempting to drive you to look for a warmer environment, such as under a duvet, while lethargy and loss of appetite are both telling your inner hunter-gatherer not to go looking for food but to conserve energy for the viral fight being fought within. In an attempt to combat the expected lack of food, muscle and joint tissues are broken down to release proteins that can be used in the liver to produce antibodies to fight the viral infection. This process causes the aches and pains which can accompany a particularly bad bout. “It’s just the body eating itself,” summarises Eccles jauntily.
With your body cooking and consuming itself nicely, there’s one last point of weakness: your nose, an entry point for cold air and ground zero for the infection. Here, the body swells the nasal blood vessels to seal you off from the world, alternating between the left and right nostrils, so you can always breathe, albeit with some difficulty.
And then there’s that brightly coloured nasal mucus, a subject on which Eccles can get very animated. “If you look at mucus, even in health, you can find white cells, or leukocytes present,” he says excitedly. “They’re always squeezing through the lining of the nose, looking for bacteria and viruses, but when you get an infection, there’s a massive gathering of these white cells and they have an enzyme that causes the production of hydrogen peroxide. This kills viruses and bacteria, but has a slightly bluish green colour, so the more white cells you’ve got, the more colour you’ve got in the mucus.”
Once the infection is defeated, your immune system is better prepared to fight that particular strain of cold should it return – but it rarely does. Rhinovirus has around 160 known types which are constantly mutating, so the body almost never gets to fight the same battle twice. It is these multiple strains that make colds so difficult to vaccinate against. Influenza, by contrast, only has four main strains.
“You don’t want to have 160 shots to get your resistance right for a cold,” notes Carette. “Especially if the process needs to be repeated every couple of years to combat mutations.” With vaccines ruled out, Carette tried another approach. “What if rather than focusing on the virus, we looked at ourselves? What does the virus need from us to spread?” Such thoughts led Carette to the research whose results were published to great media acclaim on 16th September.
“We found when we took protein SETD3 out that the viruses weren’t replicating. They flatlined”
“Once the virus enters a cell it builds a sort of photocopying machine to reproduce itself,” he says. “From that one initial virus you have 10,000 progeny viruses – copies – that come out of the cell.” These copies spread to other healthy cells and start the process again, until the immune system realises the body is under attack and fights back. To stretch the office analogy, Carette set out to discover the viral equivalent of removing the ink from a photocopier – the substance needed to create the copies, which in the case of the rhinovirus is a particular protein produced by the body.
“There are around 20,000 different proteins and each one is encoded by its own gene,” he says. “So we set about testing each of those 20,000.” Using precision gene-editing technology, the team took out proteins one by one, to see the impact on a human cell infected with a virus. “We took an unbiased approach,” Carette says. “We just destroyed each of them, one at a time.”
Carette subjected his cells to a range of enteroviruses – a group that includes all strains of rhinovirus as well as diseases including polio. This almighty trial-and-error process uncovered a promising candidate for combating all sorts of enteroviruses. “We found one protein which really stood out: SETD3,” says Carette. “If we took it out, the viruses we exposed those cells to weren’t replicating. Their photocopiers didn’t work. The viruses flatlined.”
Having seen multiple strains of the enterovirus – including rhinoviruses, enterovirus 68, which can cause serious breathing problems and paralysis, and enterovirus 71, which has resulted in severe neurological diseases in children – neutralised in living cells in a Petri dish, it was time to move on to tests on live organisms. Enter the mice. Half the subjects had the gene that encodes the SETD3 protein removed and all were exposed to enterovirus 68, which can have effects similar to polio. The scientists then watched to see who would succumb. “One hundred percent of the mice that had the protein got the virus and died,” he says. “Whereas one hundred percent of the mice that did not have this protein survived this severe infection.”
The only other effect the team witnessed in their genetically altered rodents was in pregnancy, which led them to believe the protein may play a role in uterine contractions. Otherwise the missing protein seemed unnecessary for healthy mice, raising hopes that a safe cure could be on the horizon. Although how far off this might be is open to debate. “We had some really convincing results in mice and in human cells and the next phase would be to develop a drug [that will disable SETD3],” says Carette. “Once you have that drug, then it has to go into development. If you’re optimistic, that’s going to take five years. If you’re more realistic it’s ten years. And if you’re pessimistic, it’s 20 years.”
Eccles has mixed feelings about Carette’s findings. “I think that it is quite a breakthrough in being able to control the nastier strains of enterovirus, but I don’t think it will be as much use for treating the common cold,” he says. “By the best estimate rhinoviruses are only responsible for half of common colds. Are you going to take a medicine that will only work every other time?”
When it comes to current cold remedies, however, people seem happy to take a punt on considerably worse odds. Americans spend billions on over-the-counter cold remedies every year, often despite the lack of any evidence that they offer any sort of cure. One of the best-selling items found in the cold remedy section of many US pharmacies is Airborne, a vitamin supplement created by former teacher Victoria Knight-McDowell in 1999. As it was technically a food supplement rather than a medicine, it wasn’t subject to the medicinal controls of the US Food & Drug Administration. That didn’t stop it being branded a “miracle cold buster”, and by 2006 sales exceeded $100 million a year. But in 2008 Airborne paid $23 million to settle a lawsuit over misleading advertising. Today the label on its packet says “these products are not intended to diagnose, treat, cure, or prevent any disease”, yet it continues to fly off the shelves. “When it comes to common colds,” concedes Eccles, “people will buy anything.”
Not that Eccles believes we should just grin and bear it. “The common cold is probably responsible for the biggest economic impact on society of any disease,” he says. “On average the adult population gets two colds a year. That’s 120 million colds a year in Britain; suppose half of those colds caused a day off work, that’s 60 million days. Kids are getting seven or ten colds a year. Who looks after them when they’re ill? Someone has got to stay at home with them. It all adds up.”
The common cold can also be a killer. “One of the common cold viruses is the respiratory syncytial virus [RSV],” says Eccles. “RSV is responsible for a lot of lung disease in babies under six months old and there isn’t any cure for it at the moment. Common cold viruses are also responsible for a lot of illness in the elderly such as lower respiratory-tract infections and the exacerbation of asthma and bronchitis. The common cold viruses are responsible for a lot of what we call comorbidity in the population, [that is they co-occur with other diseases to cause serious health problems] at both the baby end and the elderly end of the spectrum.”
An actual cure based on Carette and co’s findings – even one that is only effective every other time – could save lives and be worth billions, but there’s the chance that the researchers will not see a single cent from their breakthrough. “Having identified the target alone is not enough for a patent,” Carette says. “You also need the chemical matter – a drug to inhibit that target. That is something that we’re looking for now.”
He seems unconcerned about the possibility that a big pharmaceutical firm might swoop in and gazump him now he’s identified precisely where to look. “The main focus here is academia, not commercialisation,” he says with a shrug. Besides there are other rewards on offer. “Scientists are always asked, ‘If you’re so smart, if you can put people on the moon, why can’t you cure the cold?’ God it would be nice to have an answer.”
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