Cardiologists learned that they could prevent plaque accumulation by changing diet or habits or by using cholesterol-lowering drugs like Lipitor. Beyond prevention, the doctors could forcibly widen the arterial blockade or inject clot-busting drugs. The image of scales of lead clogging old pipes, and a Roto-Rooter, was hard to shake. Coronary artery disease, it seemed then, was mainly a plumbing problem, demanding a plumber’s toolbox of solutions (to be fair, there’s a cosmos of biology behind cholesterol metabolism and its link to heart disease).
Cancer, by contrast, was an exterminator’s problem — a poisoner’s dilemma. Cancer-causing agents unleashed abnormal cellular proliferation by mutating genes involved in regulating growth. These cancer cells, occupying tissues and spreading, demanded a cellular poison — chemotherapy — that would spare normal cells and kill the malignant ones.
Cardiologists and oncologists — plumbers and poisoners — lived in different medical realms. We spoke different languages, attended different conferences, read different specialty journals. If our paths intersected, we considered the crossing coincidental, the unavoidable convergence of two common age-related illnesses on the same body.
I was a medical resident in Boston in the early 2000s when I heard a theory that would, in time, force these separate worlds to collide. Two cardiologists, Peter Libby and Paul Ridker, were thinking about plaque formation in a different way. Libby and Ridker acknowledged the role of cholesterol and lipids. But just as important was another variable, seldom discussed: inflammation — the recruitment and activation of certain immune cells. These activated immune cells infiltrated blood vessels early in the course of coronary disease and enabled plaques to grow and rupture. “Bad” cholesterol was a necessary part of the equation — it was these lipid deposits that may incite the immune cells, they proposed — but it was not sufficient.
If inflammation triggers coronary disease, might targeting it directly — beyond simply reducing cholesterol — decrease the risk of heart attacks? Over the course of a decade, Libby and Ridker found themselves focusing on a molecule involved in inflammation called interleukin-1 beta. By the mid-2000s, they heard of a new drug — an interleukin-1-beta inhibitor — that was used to treat exceedingly rare inflammatory diseases. In April 2011, Ridker’s team started enrolling 10,000 patients who carried signs of inflammation and were at very high risk for coronary disease in a randomized study to determine the effects of the inhibitor on heart disease and strokes.
The results, published this August, are provocative: Despite no change in cholesterol levels, there was a demonstrable reduction in heart attacks, stroke and cardiovascular death, particularly at higher doses of the drug. But what caught my attention was a separate analysis that asked a seemingly unrelated question: Might the drug also reduce the risk of cancer? In a paper published in The Lancet, Ridker and his colleagues found that drug-treated patients had a drop in all cancer mortality. More striking still was a stark decrease in the incidence of and deaths from lung cancer. Some element of inflammation that drives plaque formation in coronary disease is also driving cancer progression. It’s a study that needs careful replication; the analysis was designed to suggest a hypothesis, not to prove it. There are questions about drug pricing and the risks of infections and low blood counts. But if the benefit holds up in future trials, interleukin-1-beta inhibition could eventually rank among the most effective prevention strategies in the recent history of cancer.
Inflammation at the nexus between cancer and heart disease? But of course, some of you must be thinking, with an exasperated nod. You’ve had your third serving of blueberries; you’ve drunk your green tea. Wasn’t it obvious all the while?
It isn’t so simple. An avalanche of studies has implicated inflammation as a central player in many diseases — but there are inconsistencies. Consider an inflammatory illness like lupus: The risk of most cancers (except some virally related cancers and lymphomas) in lupus patients is only marginally higher. Rheumatoid arthritis increases the risk of lymphomas — but oddly lowers the risk of breast cancer. Tuberculosis, an inflammation-inducing disease, appears to promote lung-cancer risk, but in an animal study, eczema, weirdly, reduces the risk of skin cancer. Meanwhile, an alternative-medicine industry daily peddles “anti-inflammatory” diets — but which of these reduce inflammation, or what types of inflammation are affected, remains far from known.
“Inflammation,” in short, is a concept in flux — “a wastebasket word,” as Padmanee Sharma, an immuno-oncologist at M.D. Anderson Cancer Center, told me. There isn’t one inflammation: Lupus, tuberculosis and influenza all cause “inflammation,” but each might provoke different or overlapping wings of immune responses. I asked James Allison, who pioneered cancer immunotherapy, to define “inflammation,” and he paused, considering the definition. “It’s a response to injury, mediated by immunological cells. But there are dozens of cell types communicating through even further dozens of signals.”
We might imagine inflammation, then, as a fuse box that you chance upon in a new house. You are looking for the switch that turns the light on in the living room, or one that turns the alarm off (just as we’re hoping to throw the switch that disables cancer growth or plaque formation). But the circuitry baffles you. Some knobs are marked in crimson: Do Not Touch. Some carry no labels. Some do, but the writing is in a foreign language.
“Inflammation, an umbrella term, is now being broken up into many different categories,” Sharma told me. Is it chronic or acute? Is there a “right” kind of inflammation that protects us from infections and a “wrong” kind that precipitates disease? Is it mediated “adaptive” immunity — the type of immunity involving B and T cells that adapts to infections? Or “innate” immunity, the more ancient phalanx of immune responses that is preprogrammed to fight certain pathogens?
When doctors read trials like Ridker’s, we generally ask two sets of questions. The first might be loosely described as: Is it good science and good medicine? Was the concept proposed in the study proved by the trial? Were the conclusions accurate, the adverse effects acceptable? Cardiologists and oncologists I spoke to agreed on the technical accuracy of the study. One of them noted the modest benefit for heart disease; Ridker and Libby counter that the drug is at least as effective as some cholesterol-reducing medicines.
But there’s a second kind of inquiry that’s harder to put a finger on, for it lives in a nearly aesthetic realm. Does the study illuminate something strange and wonderful about human physiology? A trial might be “good”— but is it, well, “beautiful”? This study is: It links disparate arenas of medicine through a common pathological mechanism. It’s hard to know whether the illnesses in the man I met were driven by inflammation, but Ridker and Libby forced me to view his case — and a thousand other cases I’d seen previously — under new clinical lights. I will never think about patients with cancer and coronary disease in the same way.
There’s another twist of wonder, though. What are the chances that one molecule, sitting at one corner of the immune response, acts as a switch for two utterly different diseases? It must be a quirk in our design, a barely visible chink in physiology that allows us to target inflammation in a manner that doesn’t kill or maim but acts just so, disabling two terrifying illnesses. It’s as if we had walked into the basement of the new house, found the fuse box, learned to read the coded language of the labels and — in the partial darkness — pulled just one switch. And, miracle of miracles: Upstairs, only the living-room lights went on.