During the first During the chaotic months of the Covid-19 pandemic, it was already clear that the new coronavirus spreading around the world did not affect everyone equally. The earliest clinical data from China showed that some people consistently outperformed others, especially men, the elderly and smokers. Some researchers wondered: What if the increased risk of serious infection and death shared by these different people is all due to differences in a single protein?
Jason Sheltzer, a molecular biologist at Cold Spring Harbor Laboratory, began talking about this opportunity with his partner, Joan Smith, a software engineer at Google, during the early days of their New York cap. “We thought the simplest explanation could be if all these factors affected the expression of ACE2,” Sheltzer says.
ACE2, which stands for angiotensin-converting enzyme 2, is a protein that sits on the surface of many types of cells in the human body, including the heart, gut, lungs and inside the nose. It is a key tooth in a biochemical pathway that regulates blood pressure, wound healing and inflammation. ACE2’s amino acids form a grooved pocket, which allows it to hold and chop up a destructive protein called angiotensin II, which boosts blood pressure and damages the tissues. But angiotensin II is not the only thing that fits in ACE2’s pocket. So does the tip of the button-like spike proteins that protrude from SARS-CoV-2, the coronavirus that causes Covid-19. Like a key that locks in a barrier, the virus enters the cell through ACE2 and then cuts off the cell’s protein production machinery to make copies of itself. An infection begins.
In the early days of the pandemic, thinking went something like this: The more ACE2 a person has, the easier it should be for the coronavirus to invade and move through its tissues, causing more serious forms of the disease. The more ways inside someone’s cells, the higher the risk for the person. That is the hypothesis Sheltzer and Smith were interested in investigating. They were not alone. When the virus spread outside China, other high-risk groups emerged: people with heart problems, high blood pressure, diabetes and obesity. Many in these groups take medications that are known to increase ACE2 expression. Then again, scientists wondered, can that protein be responsible?
But as researchers began to investigate the relationship between ACE2 and this dangerous new disease, the data refused to adapt to some neat, predictable patterns. “What we know now is that there are no simplified, reductionist explanations that can reconcile all clinical data that have been recovered so far,” says Sheltzer. Instead, a more complicated picture has emerged. But it is one that still has ACE2 at the center of the action.
Smoking dials ACE2
Sheltzer and Smith, confined to their home, could not perform any experiments to tease out their first hypothesis. Instead, they combed through existing data sets from both animal and human studies that measured the level of gene expression in different tissues. Over and over, they found that women and men produced similar amounts of ACE2 in their lung cells. Nor could they find any differences between young adults and the elderly. Aging did not change ACE2 in any way. But smoking was a different story.
When they looked at gene expression inside the smokers ‘versus non-smokers’ lungs, they saw a huge peak in ACE2 that comes from a particular type of cell: secretory of both cells. The purpose of these mucus manufacturers is to cover the inside of the airways and protect it from irritants that you can breathe in (such as tar, nicotine or any of the other 250 harmful chemicals in cigarette smoke). The more people smoked, the more their two cells multiplied in an attempt to capture these chemicals before they could damage surrounding tissue. The expanding both cell’s army anchors drove a sharp increase in ACE2, as Sheltzer and his coauthors described in a study published in development Cell in the middle of May.