In two decades of practicing medicine, I've encountered a wide number of medical diagnoses. You see, it turns out that there are more than 60,000 different medical diagnoses that you can list on a patient's chart. You can actually be diagnosed with a burn injury when your water skis catch on fire. There are also codes if you need surgery after being bitten by a pig,
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hit by a spacecraft,
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stabbed while crocheting, or my favorite, due to extreme problems with your in-laws.
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But the best of all has got to be the code for getting sucked into a jet engine. And the reason that I like this one is because this is not the code for the first time this happens, but for the subsequent encounter.
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So there must be people on this Earth that have been sucked into a jet engine twice.
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But I think, you know, kidding aside, we have to recognize that every last one of us in this room is most likely to die of only one of two diagnoses. And these, of course, are either cancer or cardiovascular disease.
This speaks to the incredible public health importance of these two diseases and the urgent, unmet medical need to develop new therapies directed against them.
A lot of people are not surprised that these two diseases claimed so many lives. After all, they are very different biologically, they have different risk factors, and they affect very different patient populations. But for the next 15 minutes or so, I would like to propose a different hypothesis. That perhaps they actually have quite a lot in common. And even more importantly, I would like to suggest that if we think about them this way, we might be able to develop new therapies that could treat both diseases at the same time.
So before I tell you why I believe this hypothesis, let me lay out the counter arguments against it. I think many people would say that the old man who smokes cigarettes his whole life and has a heart attack shares very little in common with a young person who develops colon cancer out of the blue. But we now know that the risk factors for these diseases have significant overlap. And the things that cause one disease can also put you at risk for the other. Well, that may be true, but we know that genetically these diseases couldn't be more different. I'm sure many of you have heard about these cancer genes that can be mutated in families that could put both mother and daughter at risk for breast cancer. We know that those genes have nothing to do with heart attack, and that's true also. But I would point out that those genes were discovered decades ago, before the Human Genome Project and before we could scan all three billion base pairs at the same time. And when we do this for patients having heart attack, we find that the top hotspot for having a heart attack is located on chromosome nine, shown here with these blue dots. And what shocked the world when this paper was first published was that this genetic locus has nothing to do with smoking or cholesterol or diabetes. But actually seems to control a well-known cancer gene that's mutated in patients with melanoma, brain cancer, lung cancer, etc. And so for decades, we've been focusing on the traditional cardiac risk factors. But the genetics now tell us that the most important factor may actually have to do with a well-known cancer gene instead.
Well, that's an interesting observation, but we know that if you look under the microscope at these two diseases, they couldn't be more different. When I was in medical school, I was taught that cancer is really just about cells dividing too quickly. And you can imagine this lung tumor growing over time and taking over the lung, and that this has nothing to do with what happens in heart disease, which is a problem that, I was taught, was due to the buildup of cholesterol that can ultimately lead to the blockage of an artery and a heart attack or a stroke. And to be sure, both of these biological processes are critically important. But I would point out that the modern-day textbook of these diseases is getting harder and harder to tell apart. We now know that both of these conditions are dominated by the influx of inflammatory cells and immune cells and abnormal blood vessels and even stem cells. And so maybe the textbooks that I used are out of date.
Well, at this point, you might say these are interesting observations, but is there any clinical data which would suggest that patients with one disease are actually at higher risk of the other? Turns out that investigators, both in Asia and Europe, have now started to test this hypothesis. And just last year, a very important article was published out of Germany, where they looked at more than 100,000 individuals with congestive heart failure and they found that these people were at much higher risk of developing cancer. This is really interesting and suggests to me that indeed having one disease may put you at risk of the other.
But this also raises a very important scientific principle that association is not the same as causation. And if you wanted to test that hypothesis, you would have to do an experiment where you took a healthy individual and then intentionally gave them a heart attack. You'd have to let some time go by to see what changes occur throughout the body. And then you could determine if their rate of cancer was higher or vice versa, if their rate of heart disease was higher. Now, obviously, we can't do this type of an experiment in human beings. This would be unethical. But this type of an experiment is done in research laboratories every day around the world in mouse models of human disease. Just last year, two very important studies were published where investigators took healthy mice and then implanted small tumors underneath their skin. They looked at the rate at which these cancers would grow over time. And what they found in both studies was that the mice who had heart disease had much higher rates of cancer. And what was fascinating to me was that they were able to confirm these findings across a wide range of tumors, suggesting to me that really the presence of heart disease is sufficient to accelerate cancer growth.
So having heard all this, the natural question is whether we can do anything about this. So outside of my work at Stanford, one of my volunteer roles is with the American Heart Association. And one of our public health initiatives is called Life’s Simple Seven. We try to get patients with a history of heart disease to control these very simple and straightforward risk factors like exercise, cholesterol and diet. The idea here is that if you can control these, you should be able to lower your risk of having additional cardiovascular events. This is now pretty widely accepted. But what's fascinating to me is that a group of investigators have now looked at the association with these risk factors and cancer. And in a study with more than 10,000 individuals who were followed for almost two decades, they found the people who had optimal control of all their risk factors had a pretty low rate of developing cancer. But for each risk factor which fell out of control, the risk of malignancy went up. And you can see that the group who had poor control of all seven risk factors had by far the highest rates of cancer, with nearly a doubling of the risk. So this suggests to me that, in fact, if we want to control cancer, we might start by controlling our cardiac risk profile.
So this is fine and we continue to encourage our patients to do this. But the reality is that even if I had a magic wand and could somehow optimally control everybody's risk factors, we know that we would still be dealing with both the number one and number two causes of death worldwide. This tells us that we need to find new therapies that could treat or even prevent these conditions in the first place.
Now our laboratory chooses to do this with an unbiased genetics approach. We take biopsies from patients with or without a wide variety of tumors, or with and without cardiovascular disease. And instead of looking at one gene at a time, we scan the whole genome and look at the expression of all 20,000 genes. You can plot these on a plot like this where each gray dot represents its own gene. And when you acquire enough samples, you can begin to identify patterns of those genes which are bad for cancer versus those that protect against it. And do the same type of an experiment to find those things that will accelerate or prevent against cardiovascular disease. Now, I think the clever part of this approach is to integrate these and to run these analyses simultaneously. When you do this, we can begin to look at factors in the red quadrant. These are genes that we suspect should be bad for both heart disease disease and cancer and must be avoided at all costs. Or even better, perhaps we can find factors in the blue quadrant that should be able to protect against both diseases. We hypothesize that those factors in the blue quadrant could be prioritized to help us find new medicines to cure these two leading killers.
Now our group has run these analyses on several thousand individuals. This work is still underway, but so far we've identified a list of about three dozen pathways that we do think should be prioritized. Now, time will tell if these work. If all of them work, if some, if any of them work. We just don't know. But I do want to show you a couple of examples that would suggest that we're on the right path. In the red quadrant, one of the factors we found relates to inflammation. And we often think of inflammation as being bad, but in reality, this is a process that our body evolved to help us recover from injury or to mount a fever to fight off an infection. But of course, there are always times where our body has too much of something. In this case, there's a rare genetic syndrome where children can be born with overactive inflammation, and they can have recurrent episodes of high fevers and rashes and other neurocognitive and developmental delays. Now in a triumph of science, investigators have pinpointed the exact molecule responsible for this, and they developed a drug that can block it. These children who have these rashes that I mentioned before can have a relatively remarkable improvement on these drugs and almost get back to a normal quality of life.
But relevant to today's talk, it turns out that there are a group of cardiologists who, for decades, have hypothesized that these same inflammatory factors may also be driving heart disease. They were able to convince the company that makes this drug to do a trial to look at the effect of this medicine in patients who had had a heart attack or a stroke in the past. And really, it was no surprise to many of us when the results of this trial were published. And they showed that, in fact, compared to a placebo, that this medicine could prevent recurrent cardiovascular events. But our algorithms predict that this drug should not only help prevent heart disease but also should be able to prevent cancer. And so this particular article gained a lot of attention because when they unblinded their results, the investigators were shocked to find that not only were the patients having fewer heart attacks but they were having a much lower rate of developing lung cancer and a much lower rate of even dying from cancer. In fact, these results were so surprising and powerful that I understand the company that makes this drug is now pivoting and prioritizing this as a cancer drug, because the effects were so significant.
How about another example from the blue quadrant this time? Well, here we come to one of my favorite cells in the body, which is an immune cell called the macrophage. Now, macrophage is from the Greek, meaning "big eater." And the role of this cell is to patrol the body, like a sentinel, and it looks for invading bacteria. When it sees them, it actually will eat them and remove them from our body before they can expand and cause an infection. But just like in the last example, there are oncologists who have hypothesized that these macrophages don't just have to eat bacteria, but they also have to look for and eat cancer cells and hopefully get rid of them before they can grow and metastasize. And so there's been a major initiative to develop medicines that can increase the appetite of these cells to help them go after those tumors. Now, this story is still in its early days, and it's unclear if this type of an approach will work. But some of the early studies would suggest that patients who have metastatic lymphoma, which you can see spread throughout this person's body on their CAT scan, that they may have a remarkable response to these types of drugs. And you can imagine here that the tumors are melting away as they're being eaten by these cells due to their increased appetite. But once again, what we found is that our algorithms predict that, yes, this drug should work for cancer, but we think it might also work for heart disease. And so we've now gone back and retrospectively analyzed the same CAT scans from the same cancer patients. But this time, instead of looking at the signal from their tumors, we can look at the signal in their blood vessels. And here I'm pointing with the arrow to the carotid artery. This is the artery that brings the blood to the brain, this is where cardiovascular disease will build up in patients before they have a stroke. And what we found is that while their cancer was melting away, it looks like their cardiovascular disease was melting away, too. And so, once again, these algorithms are predicting that we may be able to identify therapies that could be dual purposed to attack both conditions at the same time.
We don't yet know if any of these other pathways will have the same type of success. But what we do know for sure is the lesson that Galileo taught us almost four centuries ago, and that there is no such thing as settled science. We must challenge dogma, we must break down traditional silos. Because if we do, we may no longer be powerless against these leading killers, but may, in fact find ways to treat the world's two leading killers.
Thank you.
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