“The staff who work with the enrollees have prioritized ensuring that their experience is positive and treating them as engaged participants. We’ve focused on that across all the institutions involved since day one as we’ve designed the workflows and the protocol, because we recognize we’re asking the participants to do a lot.”

McCue gives a glimpse of the testing participants undergo: “They get an extensive battery of tests: basic medical history and vitals, electrocardiogram, ankle-brachial index, some physical performance testing, cognitive testing, eye exam, echocardiogram and stress echocardiogram, X-ray, coronary artery scan, audiometry. We’re trying to get a comprehensive view of each person’s health.”

The Project Baseline study is no less than an ambitious effort to map human health. It came about as the result of discussions that began in 2013 between Drs. Sanjiv (Sam) Gambhir of Stanford, Robert Califf from Duke, and Andrew Conrad (then from Google X, now the chief executive officer of Verily Life Sciences).

Gambhir provides the background: “Google X was looking to undertake a landmark study in human health. I was initially contacted by Dr. Conrad due to my focus on early cancer detection and the potential for studying large cohorts of individuals at low and high risk for cancer. Dr. Califf was brought into the discussions due to his experience in running large cardiovascular trials at Duke. Over the course of many months and several discussions, the study evolved to what is now referred to as the Project Baseline study.”

The Project Baseline study is enrolling approximately 10,000 participants across the United States in an extraordinarily detailed, four-year examination of what it means to be healthy and to identify what happens during a transition to disease.

The leadership at Stanford includes Gambhir, MD, PhD, a professor and chairman of radiology; Kenneth Mahaffey, MD, a professor of cardiovascular medicine and director of the Stanford Center for Clinical Research (SCCR); and Rebecca McCue and Susan Spielman, who wear several hats in the School of Medicine.

Volunteers who elect to enroll are in for a comprehensive two days of tests, says McCue, who is the associate director of the SCCR and oversees site-based research in the Department of Medicine. “The staff who work with the enrollees have prioritized ensuring that their experience is positive and treating them as engaged participants. We’ve focused on that across all the institutions involved since day one as we’ve designed the workflows and the protocol, because we recognize we’re asking the participants to do a lot.”

McCue gives a glimpse of the testing participants undergo: “They get an extensive battery of tests: basic medical history and vitals, electrocardiogram, ankle-brachial index, some physical performance testing, cognitive testing, eye exam, echocardiogram and stress echocardiogram, X-ray, coronary artery scan, audiometry. We’re trying to get a comprehensive view of each person’s health.”

It doesn’t end after two days. Participants will return to their site of enrollment for a visit each year for four years. Some participants will be asked to return quarterly. All participants will receive tools to use, including an investigational study watch designed by Verily that tracks things like heart rate and activity level as well as a bed sensor that reports on quality of sleep. They will also have access via a mobile app to a portal where they will be able to respond to surveys and enter data of their own.

Every effort is being made to enroll a participant population that reflects the US population by age, ethnicity, health status, and other demographic variables, according to Spielman, director of strategic initiatives for radiology. She was involved in project discussions among the three principals from the beginning and currently co-leads Stanford’s strategy and development plans for the Project Baseline study with McCue.

She describes how the enrollment cohort came to be defined: “There’s a broad definition of who we’re targeting, so it allows for an easier recruitment process that is more inclusive and more realistic. Collecting information from a diverse group of people with different health histories is critical to the success of the study. Because it’s so difficult to recruit and retain in research, by redefining the cohort structures we’re able to bring in a bigger range of people more easily and enroll the diversity of the population that we need to be successful.”

Recruitment began in June 2017, and Stanford continues to enroll several new participants every day.

Most sponsors of clinical research studies provide the funding and are otherwise mostly silent partners. In the case of the Project Baseline study, it is the true partnership between academia and industry that makes the study possible, as Spielman explains:

“The mission of the study was developed collaboratively among Stanford, Verily, and Duke. Verily is developing many tools that are enabling us to perform the study as envisioned. As we are doing all these assessments to collect the data at each site, they are creating the necessary infrastructure that allows people to consent and enroll, developing the electronic data capture system for all the data to be entered, and implementing the software platforms for robust multi-dimensional data analyses at a later time.”

The intention is to make data available to anyone with an institutional review board-approved research study in accordance with guidelines established by a committee set up to handle such requests. It will be a tremendous resource for the whole global community.

Both Spielman and McCue express excitement about how well the study is going so far. Spielman recalls that “there were a lot of people who thought the scope was so big and the depth of the data being collected was so comprehensive that there would be many roadblocks. So the fact that we’ve been able to get started and are gaining momentum in enrollment is thrilling.”

McCue concurs, saying, “It’s remarkable how much effort has gone into this study from all sides. It took many years for the collaboration and the study protocol to come to fruition, through the efforts of a lot of dedicated individuals from Verily and Stanford and Duke. I’ve been really impressed by the intensity with which the faculty and everybody across the board have been engaged. What excites me most is seeing how motivated the teams are and how much people believe in the study and want to make something really good come of it.”

Sites at Stanford Medicine, the Duke University School of Medicine, and the California Health and Longevity Institute are currently enrolling. Additional sites may be added over time. Sometime in the coming years, when all approximately 10,000 participants have completed four years of tests and surveys and measurements, a vast treasure trove of data will have been amassed. It will be uniquely capable of answering questions about health and disease that have never been able to even be asked before.

It doesn’t end after two days. Participants will return to their site of enrollment for a visit each year for four years. Some participants will be asked to return quarterly. All participants will receive tools to use, including an investigational study watch designed by Verily that tracks things like heart rate and activity level as well as a bed sensor that reports on quality of sleep. They will also have access via a mobile app to a portal where they will be able to respond to surveys and enter data of their own.

Every effort is being made to enroll a participant population that reflects the US population by age, ethnicity, health status, and other demographic variables, according to Spielman, director of strategic initiatives for radiology. She was involved in project discussions among the three principals from the beginning and currently co-leads Stanford’s strategy and development plans for the Project Baseline study with McCue.

She describes how the enrollment cohort came to be defined: “There’s a broad definition of who we’re targeting, so it allows for an easier recruitment process that is more inclusive and more realistic. Collecting information from a diverse group of people with different health histories is critical to the success of the study. Because it’s so difficult to recruit and retain in research, by redefining the cohort structures we’re able to bring in a bigger range of people more easily and enroll the diversity of the population that we need to be successful.”

Recruitment began in June 2017, and Stanford continues to enroll several new participants every day.

Most sponsors of clinical research studies provide the funding and are otherwise mostly silent partners. In the case of the Project Baseline study, it is the true partnership between academia and industry that makes the study possible, as Spielman explains:

“The mission of the study was developed collaboratively among Stanford, Verily, and Duke. Verily is developing many tools that are enabling us to perform the study as envisioned. As we are doing all these assessments to collect the data at each site, they are creating the necessary infrastructure that allows people to consent and enroll, developing the electronic data capture system for all the data to be entered, and implementing the software platforms for robust multi-dimensional data analyses at a later time.”

The intention is to make data available to anyone with an institutional review board-approved research study in accordance with guidelines established by a committee set up to handle such requests. It will be a tremendous resource for the whole global community.

Both Spielman and McCue express excitement about how well the study is going so far. Spielman recalls that “there were a lot of people who thought the scope was so big and the depth of the data being collected was so comprehensive that there would be many roadblocks. So the fact that we’ve been able to get started and are gaining momentum in enrollment is thrilling.”

McCue concurs, saying, “It’s remarkable how much effort has gone into this study from all sides. It took many years for the collaboration and the study protocol to come to fruition, through the efforts of a lot of dedicated individuals from Verily and Stanford and Duke. I’ve been really impressed by the intensity with which the faculty and everybody across the board have been engaged. What excites me most is seeing how motivated the teams are and how much people believe in the study and want to make something really good come of it.”

Sites at Stanford Medicine, the Duke University School of Medicine, and the California Health and Longevity Institute are currently enrolling. Additional sites may be added over time. Sometime in the coming years, when all approximately 10,000 participants have completed four years of tests and surveys and measurements, a vast treasure trove of data will have been amassed. It will be uniquely capable of answering questions about health and disease that have never been able to even be asked before.

What led you to start the SPRC?
As an intern I had a patient in his 40s who died, and I had to comfort his widow. That led me to think of the potential for prevention because we were in the middle of an epidemic of post–World War II expansion of smoking, and of poor diet, and the beginning of a decrease in physical activity due to automation. After World War II we were the richest nation in the world, and the returning veterans were all feeling this post-war irrational exuberance. But smoking rates went up, and there was a return to an expansion of dietary intake of saturated fat from meat and dairy products with a disregard for some of the foundations of atherosclerosis.

There was a combination of increased smoking rates and cholesterol levels from diet along with decreased physical activity. We entered into an epidemic of preventable coronary disease, and I was a pioneer in that from my exposure to it during my residency training. It led me to write the book The American Way of Life Need Not Be Hazardous to Your Health.

The year 1927 was certainly noteworthy! In that year, nine decades ago, Werner Heisenberg described his uncertainty principle. Philo Farnsworth transmitted the first image from a television camera tube. Charles Lindbergh made the first solo non-stop trans-Atlantic flight. The success of The Jazz Singer marked the end of the silent film era. António Egas Moniz developed cerebral angiography.

It was also the year that a pioneer in preventive medicine, John W. “Jack” Farquhar, MD, was born. Among myriad accomplishments, Farquhar (with Nathan Maccoby) co-founded the Stanford Heart Disease Prevention Program to activate communities to change their lifestyle, preventing disease and improving health. As the scope of the organization widened to include multiple aspects of disease prevention and health promotion, its name changed to the Stanford Center for Research in Disease Prevention and later to the Stanford Prevention Research Center (SPRC). 

At 90, Farquhar, the C.F. Rehnborg Professor in Disease Prevention, emeritus, and professor of medicine and health research and policy, emeritus, attributes his longevity in part to practicing what he’s been preaching—paying attention to lifestyles that are relevant to successful aging. In a recent interview, he discussed how the SPRC got started, some of its seminal achievements, and where he’d like to see the SPRC in the future.

What brought you to Stanford originally?
Well, let’s see… I was at the Rockefeller Institute (now Rockefeller University) with Hal Holman, who was invited to Stanford to become its youngest ever chair of the Department of Medicine. At the time, there was a desire to bring what they hoped was a youthful figure into a rather elderly faculty, and he was part of that revolution. In 1962 he asked me to come here with several other eager young faculty who were research oriented rather than clinically oriented.

What led you to start the SPRC?
As an intern I had a patient in his 40s who died, and I had to comfort his widow. That led me to think of the potential for prevention because we were in the middle of an epidemic of post–World War II expansion of smoking, and of poor diet, and the beginning of a decrease in physical activity due to automation. After World War II we were the richest nation in the world, and the returning veterans were all feeling this post-war irrational exuberance. But smoking rates went up, and there was a return to an expansion of dietary intake of saturated fat from meat and dairy products with a disregard for some of the foundations of atherosclerosis.

There was a combination of increased smoking rates and cholesterol levels from diet along with decreased physical activity. We entered into an epidemic of preventable coronary disease, and I was a pioneer in that from my exposure to it during my residency training. It led me to write the book The American Way of Life Need Not Be Hazardous to Your Health.

It was a new way of thinking, but it was gaining momentum internationally. Within the United States, our colleagues at the University of Minnesota in particular were similarly inclined. We formed policy groups and became a pressure group to influence the National Institutes of Health to pay attention to the prevention side of cardiovascular disease.

There was a lot of attention on techniques like heart transplants, but I was convinced that saving people one by one was not the most effective way to address the problem. I realized the need to make permanent lifestyle changes to prevent cardiovascular disease by reaching people in the community where it was needed the most. That led me, with Henry Breitrose and Nathan Maccoby in the Stanford Department of Communication, to create a multimedia campaign to motivate and educate communities to undertake major lifestyle changes. That was really the beginning of the “total community” approach.

Can you name some achievements that came out of the SPRC?
The advent of the total community approach to prevention was really our invention. It was the idea that you could mobilize a community through a campaign using newspapers, radio, television, and medical authorities to provide information and training that people needed in order to change their lifestyle toward a healthier one that would prevent cardiovascular disease.

Peter Wood, Bill Haskell, and I were involved in showing that exercise increased the HDL fraction of blood lipoproteins. That particular discovery then was taken up throughout the world, and hundreds of papers came out about the role of HDL as the protective fraction and LDL as the harmful fraction of blood lipids. 

Another area of achievement was some of the methods for smoking cessation. The use of nicotine replacement was a new thing, and we were one of the first groups working on that. Later, a few of our people, including Tom Robinson, who happens to be a pediatrician, developed the methods for educating high school students on risk factors associated with smoking, poor diet, and lack of exercise. That was quite an important chapter, which I would call adolescent or youth education.

We took up the battle over obesity, too. The theme that runs through all this is prevention of disease through lifestyle issues. The whole lifestyle category would include smoking, exercise, and diet. And you could toss in stress management.

Today’s SPRC includes the WELL for Life initiative that is aimed at changing the global well-being landscape. There’s also a new master’s degree program in community health and prevention research.

Where would you like to see the center in the future?
I’d like the center to continue to grow in importance to the department and the university as a source of knowledge for methods to promote healthy living. And to have the School of Medicine and the university play an important part in the restoration of what should have been present 30 or 40 years ago—attention to the prevention side of the equation. In the last five years there has been increased attention to prevention within the medical school and the university.

I hope that the center remains important in developing methods of influencing policy and/or of educating society and people in positions of authority. I’d like to see a change in our training system so that people with higher degrees are cognizant of the principles of ecology, economics, and political science such that they can be participants in health policy change.

I want education to remain accepted as part of the equation to have optimal public health. Who you are educating and how they will influence public policy is all part of the dream to produce people who are smart, knowledgeable, and trained to tackle these problems.

It was a new way of thinking, but it was gaining momentum internationally. Within the United States, our colleagues at the University of Minnesota in particular were similarly inclined. We formed policy groups and became a pressure group to influence the National Institutes of Health to pay attention to the prevention side of cardiovascular disease.

There was a lot of attention on techniques like heart transplants, but I was convinced that saving people one by one was not the most effective way to address the problem. I realized the need to make permanent lifestyle changes to prevent cardiovascular disease by reaching people in the community where it was needed the most. That led me, with Henry Breitrose and Nathan Maccoby in the Stanford Department of Communication, to create a multimedia campaign to motivate and educate communities to undertake major lifestyle changes. That was really the beginning of the “total community” approach.

Can you name some achievements that came out of the SPRC?
The advent of the total community approach to prevention was really our invention. It was the idea that you could mobilize a community through a campaign using newspapers, radio, television, and medical authorities to provide information and training that people needed in order to change their lifestyle toward a healthier one that would prevent cardiovascular disease.

Peter Wood, Bill Haskell, and I were involved in showing that exercise increased the HDL fraction of blood lipoproteins. That particular discovery then was taken up throughout the world, and hundreds of papers came out about the role of HDL as the protective fraction and LDL as the harmful fraction of blood lipids. 

Another area of achievement was some of the methods for smoking cessation. The use of nicotine replacement was a new thing, and we were one of the first groups working on that. Later, a few of our people, including Tom Robinson, who happens to be a pediatrician, developed the methods for educating high school students on risk factors associated with smoking, poor diet, and lack of exercise. That was quite an important chapter, which I would call adolescent or youth education.

We took up the battle over obesity, too. The theme that runs through all this is prevention of disease through lifestyle issues. The whole lifestyle category would include smoking, exercise, and diet. And you could toss in stress management.

Today’s SPRC includes the WELL for Life initiative that is aimed at changing the global well-being landscape. There’s also a new master’s degree program in community health and prevention research.

Where would you like to see the center in the future?
I’d like the center to continue to grow in importance to the department and the university as a source of knowledge for methods to promote healthy living. And to have the School of Medicine and the university play an important part in the restoration of what should have been present 30 or 40 years ago—attention to the prevention side of the equation. In the last five years there has been increased attention to prevention within the medical school and the university.

I hope that the center remains important in developing methods of influencing policy and/or of educating society and people in positions of authority. I’d like to see a change in our training system so that people with higher degrees are cognizant of the principles of ecology, economics, and political science such that they can be participants in health policy change.

I want education to remain accepted as part of the equation to have optimal public health. Who you are educating and how they will influence public policy is all part of the dream to produce people who are smart, knowledgeable, and trained to tackle these problems.

During the past 10 years McLaughlin has been working out some of the details that make some overweight people more prone to insulin resistance than others. “It has to do more with the qualitative aspects of fat than the quantitative aspects,” she says.

McLaughlin has completed both metabolic phenotyping and radiologic measures of where fat is stored. She has also performed fat biopsies on over 600 human subjects. And she performed further research with Samuel W. Cushman, PhD, of the NIDDKD.

Based on that work, McLaughlin and Snyder now want to do even more in-depth studies of fat and blood from overweight and obese individuals who are subjected to a weight-challenge intervention.

Most Americans today have a body mass index (BMI) that, by definition, puts them somewhere in the range of overweight to obese. But those on the upper end of the BMI spectrum aren’t always the least healthy, even when it comes to diseases linked to weight. Someone whose BMI is barely in the “overweight” range may be plagued with diabetes, heart disease, fatty liver, and high blood pressure, while an obese individual may be metabolically healthy. It’s a conundrum that’s puzzled doctors in recent decades, even as the waistline of the average American has grown.

“We still don’t know what causes some people to get insulin resistance when they gain weight, while others seem to be protected,” says Tracey McLaughlin, MD, an associate professor in the Division of Endocrinology. But McLaughlin is on the hunt to find out.

She and Michael Snyder, PhD, a professor of genetics, received a $3.2 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). Their plan is to survey the molecular signatures of blood and fat cells in overweight and obese individuals in whom insulin resistance will be induced and then reversed by, respectively, dietary weight gain and loss.

Researchers know that, in general, insulin resistance—the first sign that the body isn’t processing blood glucose correctly—is linked to weight gain. In turn, insulin resistance can lead to prediabetes and type 2 diabetes, as well as high triglycerides, hypertension, heart disease, stroke, fatty liver disease, and many cancers. Weight loss, in most cases, reverses insulin resistance and prevents the development of metabolic syndrome and associated clinical morbidities.

During the past 10 years McLaughlin has been working out some of the details that make some overweight people more prone to insulin resistance than others. “It has to do more with the qualitative aspects of fat than the quantitative aspects,” she says.

McLaughlin has completed both metabolic phenotyping and radiologic measures of where fat is stored. She has also performed fat biopsies on over 600 human subjects. And she performed further research with Samuel W. Cushman, PhD, of the NIDDKD.

Based on that work, McLaughlin and Snyder now want to do even more in-depth studies of fat and blood from overweight and obese individuals who are subjected to a weight-challenge intervention. One goal is to find a biomolecular signature that can help tell clinicians which people are insulin resistant and at risk of developing metabolic syndrome; another goal is to find molecular pathways that link excess body fat to insulin resistance.

“Not all overweight and obese people are metabolically unhealthy. Only about half of them have insulin resistance, and the obesity-related health consequences are concentrated in this group,” says McLaughlin. “So it’s important to try to figure out who’s at risk for those diseases and focus resources on keeping them from gaining weight.”

Furthermore, she says, identifying the molecular pathways that link weight gain and insulin resistance may lead to new drugs.

As part of their studies, the researchers are taking blood, fat, and stool samples as participants gain and lose weight to study how levels of different molecules—from RNA to proteins, along with immune cells and the microbiome—change during weight perturbations. They’ve already collected data on 66 people and are recruiting more individuals toward their goal of 100 people for the study.

“Once we can identify people in this very early disease state, the first intervention is very easy and cost effective—it’s lifestyle changes,” McLaughlin points out.

One goal is to find a biomolecular signature that can help tell clinicians which people are insulin resistant and at risk of developing metabolic syndrome; another goal is to find molecular pathways that link excess body fat to insulin resistance.

“Not all overweight and obese people are metabolically unhealthy. Only about half of them have insulin resistance, and the obesity-related health consequences are concentrated in this group,” says McLaughlin. “So it’s important to try to figure out who’s at risk for those diseases and focus resources on keeping them from gaining weight.”

Furthermore, she says, identifying the molecular pathways that link weight gain and insulin resistance may lead to new drugs.

As part of their studies, the researchers are taking blood, fat, and stool samples as participants gain and lose weight to study how levels of different molecules—from RNA to proteins, along with immune cells and the microbiome—change during weight perturbations. They’ve already collected data on 66 people and are recruiting more individuals toward their goal of 100 people for the study.

“Once we can identify people in this very early disease state, the first intervention is very easy and cost effective—it’s lifestyle changes,” McLaughlin points out.