This week we move from a life-threatening condition (vascular disease) to a virus that has the distinction of being one of the most widespread infectious diseases and one of the most elusive. This is the common cold. As winter approaches, we have come to accept catching a cold as an inevitable part of life. I personally consult with 50-70 people a week, so a cold is unavoidable. We are all familiar with that itch at the back of our throats that prompts that ominous feeling of impending illness. As adults we all suffer from 3-4 colds each year (children can have up to 10!). Clearly each common cold is self-limiting lasting a week or so, but such times make for a pretty miserable few days with runny noses and boxes of tissues. Common cold remedy sales in the UK reach £300m each year, though most over-the-counter products only serve to moderate our symptoms rather than provide a cure. The only fail-safe means of avoiding a cold is to live in complete isolation from the rest of humanity! Our understanding remains a jumble of folklore and false assumption. This may be about to change.
The Viruses that cause the Common Cold
Common colds are most commonly caused by rhinoviruses. Rhinoviruses (RVs) account for about 75% of colds, there are a further six other families of viruses that make up the remaining 25%. The problem providing a cure for the common cold is sheer weight of numbers. There are about 160 different RVs alone that have been identified, many of which constantly mutate making a cure elusive. Although modern science has changed the way medicine is practised in almost every field, it has so far failed to produce any radical new treatments for colds. The difficulty is that while all colds feel much the same, from a biological perspective the only common feature of the various viruses is that they have adapted to enter and damage the cells that line the respiratory tract.
RVs are amongst the smallest of viruses and measure only 30 nanometres (a nanometre is a billionth of a metre and has a prefix nm). To give you some context an atom is about 0.1nm-0.3nm, so if you were shrunk to 10nm this would be a great size to explore the nanoworld that remains invisible to the naked eye. Even a human hair is roughly 75,000nm thick. By comparison even other viruses seem large. The smallpox virus is 10 times bigger than RVs at 300 nm and the flu virus is 3-4 times bigger at 80-120nm. Within their tiny structure RVs have one strand of RNA. RNA is a chain of cells that carries genetic information from the virus to a cell’s cytoplasm. Here it tells the cell’s manufacturing machinery to make new proteins that are then assembled into viral progeny. Viruses use a combination of their own components and parts they pillage from the cell to build a “replication complex” that acts like a copy machine.
We are now much Closer to a Cure
For decades science has been looking at common cold viruses specifically in order to find their commonality and a weak spot without success. But, as it turns out, science has now been looking at us, as hosts, rather than the viruses themselves. Researchers at Stanford and the University of California wanted to see if it could identify human genes that make the proteins that many cold viruses hijack in order to replicate. This approach has now brought us much closer to a possible cure. In a new exciting report published on September 16th in the journal Nature Microbiology researchers have now identified a key protein in our cells that viruses need to multiply.
The researchers used cutting-edge gene-editing technology to inactivate single genes from human cells grown in a laboratory dish until they had systematically deleted each gene in the human genome. This is no easy task as latest estimates suggest there are about 21,000 different protein-coding genes! Each cell in this study lacked one gene and therefore one corresponding protein. First, they created a bank of cells that each lacked a one different gene, spanning our entire genome. Then they infected these cells with seven RV viruses to maximise diversity. One of the viruses was a fairly newly discovered RV type that can seriously exacerbate asthma symptoms and increase the risk of infected infants developing asthma and chronic obstructive pulmonary disease. Overall most of the viruses were relatively distant relations that make use of different proteins within cells. The study looked at which protein-coding gene was missing in the cells that continued to flourish after infection, focusing on the few whose absence thwarted all viruses. None of viruses could flourish in SETD3-deficient cells—their replication rate for the common cold was reduced 1,000-fold as compared with control cells that possessed the gene
Research has Singled out One Obscure Protein
After all this effort it became clear that the absence of one obscure protein consistently stopped the common cold in its tracks: SETD3. The researchers then turned off the gene that produces the protein SETD3 in samples of healthy human lung cells (these cells most often get infected by RVs). Within these cells the virus failed to multiply and spread. The same tests were also performed on mice with and without the SETD3 gene (poor little guys!). The mice without the SETD3 gene remained equally unaffected. Clearly the gene has evolved in nature for a reason and the protein it encodes for is important for biological function. SETD3 it appears is very important in a process called methylation. The SETD3 protein modifies actin, a protein important in cell shape and division, and muscle contraction.
If you take away theSETD3 gene what happens? The SETD3 protein appeared to be important for pregnant mice and may play a role in uterine contractions, but was otherwise apparently unnecessary for healthy mice, the researchers found. However human trials may show that SETD3 plays a much more significant role in our bodies than in mice. In other words, by inhibiting the protein expression patients may of course be put at risk, which could force scientists back to square one. However, Jan Carette, one of the lead researchers, stated that further research would focus on a drug that could safely inhibit the interaction between the virus and the protein SETD3 (rather than remove it).
New research plans to screen for chemicals that either stop RVs interacting with the SETD3 protein or degrade the protein itself. The study stated, “We have the target but not yet the drug,” he says. “We’re now focusing on that part.” The approach is known as host-directed therapy, because the treatment alters something in the host that the virus needs to function. It is hard to imagine a world without the common cold, coughing and sneezing, but this takes a little bit close to achieving that goal!!