No, $75 Million Won’t Cure Heart Disease Or Reinvent Science

–Silicon Valley hype and hubris come to cardiology.

We may be close to peak hype and hubris in cardiology. This week some of the smartest people on the planet said that $75 million can help find new ways to prevent heart disease AND, as if that’s not enough, completely reinvent the way we do science.

On Wednesday Verily (Google’s life science venture), the American Heart Association, and AstraZeneca announced the award of a single $75 million grant for “One Brave Idea” to Calum MacRae, chief of cardiology at Brigham & Women’s Hospital. At an online press event Jessica Mega, chief medical officer of Verily (and, it probably should be noted, a former cardiologist at the Brigham) asked MacRae for his prediction of what he plans to achieve in 5 years.

”I believe that we will have identified significant new pathways in coronary disease. I believe we will be moving toward a cure for those pathways and preventative strategies that apply to those. And above all I believe we will have completely reinvented the way of doing science in this space and I think that will be a major advance in itself,” he responded.

Here’s how the One Brave Idea website describes his proposal:

“Dr. MacRae and his team plan to conduct a multi-phased research project to uncover new genetic, molecular and cellular markers associated with coronary heart disease (CHD) which could be used to screen the population at large to identify individuals at risk of developing CHD later in life.

“The project would start with a study to collect genomic information, lifestyle data (sleep, activity, stress), key public health data (environmental and economic factors) and responses from people with CHD their families. This data will be cross-referenced against data from the Framingham Heart Study and the Million Veterans Program to validate novel traits that may be associated with the onset of CHD.

In the next phase of the project, Dr. MacRae and his team would discover new screening approaches to identify individuals at an early age who may be at risk of developing CHD. In the final phase of the research, Dr. MacRae and his team will focus on developing novel preventative or pre-disease therapeutic strategies with the ultimate goal of reducing the burden of CHD.”

Nancy Brown, CEO of the AHA, described the project in somewhat plainer language:

“The One Brave Idea team’s first task will be setting up their ‘scavenger hunt’. That is, they must decide which areas will comprise the starting points for their quest.

“Investigations will begin with people whose family histories make them most likely to have coronary heart disease. Over time, researchers will expand what they screen for and whom they screen. The research will embrace cell biology, wearable devices and other modern tools, everything from geospatial mapping to social media.

“Answers are likely to come from a variety of places. It’s also likely that some areas they investigate yield no meaningful clues. That’s OK. Thomas Edison didn’t create the light bulb on his first try, either.”

It’s hard to know exactly how MacRae and his colleagues will be spending the $75 million or how they can hope to achieve their goals in 5 years. At the press announcement there was a lot of vague discussion about adopting the mentality of a startup company and learning to “fail fast.”

It’s worth wondering about why an enormous grant devoted to innovation is going to the heart of traditional biomedical research. As the chief of cardiology at the Brigham and a Harvard faculty member MacRae and his colleagues are the establishment. MacRae said he wants to change the paradigm for the way biomedical research is funded and performed compared to traditional “ivory tower research.” But of course he is a prominent occupant and defender of that same ivory tower.

Dinosaurs, it should be pointed out, don’t evolve into mammals. They go extinct.

It also seems fair to wonder if $75 million is really enough, since, as MacRae acknowledged, they are going to be sorting through “”almost an infinity of environmental exposures that we don’t really know about” and which may turn out to be important. MacRae said the project would “separate signal from noise” by adopting a “rapid cycle” from identifying a signal to then testing it in large populations. But he didn’t explain how his team— previously associated with traditional— and much slower— research, will be able to speed this process up.

Perhaps this project is just appropriating the language of Silicon Valley but really represents business as usual?

During the press conference MacRae and the sponsors all agreed that there would be many failures along the way. But they never acknowledged even the possibility that the entire project might fail, which I would define as the absence of solid actionable findings that will lead to practical and demonstrably beneficial measures to prevent the development of cardiovascular disease. Further, they never even mentioned the possibility that a discovery may have a harmful effect. (Think, for instance, of the negative impact of aggressive screening of student athletes, which can end athletic careers and turn previously healthy young students into heart patients for life. Or think about the negative impact of widespread screening for prostate cancer.)

$75 million seems like a lot, but compared to the NIH budget, or the Zuckerberg $3 billion gift to cure all disease by the end of the century (a perfect topic for another blog post), or the Obama/Biden cancer moonshot, it’s a drop in the ocean. But at least when it comes to hype it appears that Google, the AHA, and AstraZeneca got a lot of bang for their buck.

The announcement on Wednesday prompted a lot of interesting comments on Twitter. I invited two active participants in the discussion to elaborate on their comments.

Vinay Prasad is an hematologist-oncologist and Assistant Professor of Medicine at the Oregon Health and Sciences University.

The American Heart association, Google’s Verily and AstraZeneca have pooled 75 million dollars to fund a single researcher. What is the goal of this “one brave idea” Well, one Brave Idea, according to promotional video, is the idea that sizable funding of one “leader” can result in the “cure to cardiovascular disease”

Right off the bat, one would think that a single payment of 75 million is unlikely to accomplish what billions of dollars in sustained NIH funding for cardiovascular research for decades has not. One cannot also help but see the similarities to other recent donations. Mark Zuckerberg wants to cure all diseases in our children’s lifetime for 3 billion dollars. Well if one big idea can cure cardiovascular disease (a lion’s-share of global deaths) for 75 million— then I would say perhaps Mark Zuckerberg is overpaying. But, seriously, these sort of promises are unrealistic and frankly unhelpful for the public understanding of science. They are little more than a cheap PR stunt, which brings good press to the donors, but sets back the national discussion of sustainable, consistent funding. If the public thinks 75 million can seriously cure cardiovascular disease, then their desire to fight for federal funding may be diminished.

The AHA notes that submission was initially limited to “1 piece of paper”. Which seems odd. If you are going to do something so unprecedented, and collect such a large sum of money to a single researcher, you would think you should have fleshed the idea beyond a sheet of paper. Next time, why not a cocktail napkin?

The praise of the winning idea is as a “complete game changer”, which will “disrupt the way science is discovered”. These silicon valley buzzwords again are not very helpful to the public understanding of science.

Interestingly, 350 people submitted ideas, meaning that each submission could have gotten $215,000 instead. Not a bad deal!! But, we know so little about optimal research funding, it would have been wonderful if these sponsors would conduct a simple randomized study. 37.5 million (half the funds) could be given to 1 person, and 107,000 dollars could be given to each of the other 349 submissions. Then we could ask in a decade whether more breakthroughs came from the 1 team or the other 349 researchers. I hate to bet in cases like this, but if I were a betting man, I would put my money on the 349 researchers.

Turning to the actual idea, which is labeled as “one visionary idea.” First let me say, finding details about the “one brave idea” is challenging. The AHA seems committed to promoting one brave idea, providing details behind how this funding opportunity was created, but they seem to have much less interest in actually telling us what the one brave idea is exactly.

The goal of the project is to see what is the mix of genes and development and environment in early life that lead to coronary artery disease later, and how might this lead to new prevention and new cures. The plan will use “wearables on the wrist” to make measurements, and rely on the “gps on your phone” to measure your movements, and run a number of cell biology studies of these people. Then they will engage patients and families in “holistic ways” “We want to look early because we want to look where no one has looked. “Why can’t we look for cholesterol under the skin of a 5 year old?’— is a statement made by the PI.

I find it implausible that these measurements will amount to anything in the long run. Many of these wearables have not even shown they can even reliably measure the construct: i.e. do they even measure movement accurately? For 75 million, how big can the sample size be? Can’t be that big. I doubt big enough to find a signal in the massive noise. When you start to spend money on testing cholesterol under the skin of 5 year olds— how much will you have left?

Watching the PI discuss this problem is like watching a late night infomercial— full of rhetoric, empty of usable information/ facts.

It is almost as if they just scribbled “scalable/ big data science/ repurpose/ disruptive innovation/ game changer/ holistic/ dogma/ leadership/ focus/ transformative/ silos/ work together/predominant cause of death/ patient engagement/ partnership/ Verily/ AstraZeneca” all over 1 page and got 75 million in funding.

In short, awards like this make the press, but they pollute the public understanding of science, and fail to rigorously test whether the funds could have been spent better, as they lack a control arm.

…and don’t get me started about all the funding that the ‘team’ already receives from traditional sources.

Khurram Nasir is a cardiologist at Baptist Health South Florida:

While we all cherish the announcement of this exciting project, and though full details are not revealed, limited insights suggest we are chasing the same wine in a different bottle. In essence, the idea (looking for more risk factors and biomarkers) appears to involve recruiting a significant number of young individuals, aggregating a wide range of data from wearables, psychosocial/economic data, biomarkers and genetics, and ultimately using exceptional computational capacity to identify similar looking clusters.

This seems novel at first look but for a number of reasons I am skeptical that this project will provide any meaningful information above and beyond existing cohorts such as Framingham Heart Study or MESA.

First, the basic premise of the proposal that “half of patients with coronary heart disease have no known risk factor, such as high cholesterol” is clearly a myth, as it is well known that a majority (77-100%) of those presenting with CHD have established risk factors.

Second, we are increasingly growing to realize that at least one-third of those with extensive risk factors don’t develop atherosclerotic plaques. So the quest for new markers to expand the scope of those at risk is baffling.

Third, its is very unlikely that in the 5-year period there will be enough concrete endpoints to pinpoint the combined impact of the findings; that would require a very large sample size.

I would prefer we encourage more thoughtful ways to promote ideal cardiovascular health at an early age using well established methods to minimize disease burden and associated costs. For instance, a more pragmatic approach would be to pick out disparate risk groups such as those with low or risk factors and high actual disease burden (atherosclerotic plaque as with simple CAC testing) vs those with multiple risk factors and no disease and use all the proposed information in the right settings. In my my humble view, this study design would eventually shed more light on the underlying clusters of environmental/genetic/lifestyle factors forecasting those at actual risk of disease. Even more importantly, it would help us understand why those with traditionally high risk combinations (including family history) do not eventually develop disease.