By Melissa Pandika
February 27, 2018 | The greatest challenge for biology and medicine is deciphering biological complexity, Leroy Hood, founder and director of the Institute for Systems Biology (ISB) and senior vice president and chief science officer at Providence St. Joseph Health, said during his plenary keynote address at the 25th annual Molecular Medicine Tri-Conference* in San Francisco.
Early in Hood's career, biologists approached biological complexity much like the six blind men in the Indian parable who tried to imagine an elephant by feeling different parts of it. They looked at a piece of the system—one gene or protein at a time—but couldn’t see the whole.
“Two things were missing: the way to talk about complexity, which became systems biology,” Hood said before a crowded auditorium at San Francisco’s Moscone South Convention Center on February 12, “and the second, if you were really to understand the elephant, you had to invent a lot of technologies to explore it.”
Hood has led several paradigm shifts in understanding this complexity. Since the 1970s, he helped develop a number of groundbreaking technologies, including automated DNA and peptide sequencers. Besides enabling the Human Genome Project, the automated DNA sequencer highlighted the importance of cross-disciplinary biology. In 2000, he co-founded the Institute for Systems Biology, a non-profit research institution in Seattle that uses an interdisciplinary approach to understand biological systems.
The systems biology pioneered by Hood highlights the complexity of the human body. To understand it, we need to amass huge amounts of data on numerous molecular networks over time for each individual—in other words, to create what Hood calls “personal, dense, dynamic data (PD3) clouds.” We also need to recognize the difference between healthy and disease-perturbed networks. When disease disrupts molecular networks, it often causes changes to the proteins that comprise them. By identifying these biomarkers, clinicians may be able to detect disease early, or even prevent it. This understanding of the complexity of wellness and disease lies at the heart of predictive, preventative, personalized and participatory medicine, or what Hood calls “P4 medicine.”
Hood and his colleagues applied this systems approach to developing a blood-based screen for malignant lung nodules. Computed tomography had detected millions of lung nodules a year, but clinicians could only determine whether they were benign or malignant after a biopsy. Half turned out to be benign, meaning many biopsies were unnecessary. Hood’s team used a mass spectrometry assay to eventually narrow a list of candidate biomarkers down to a panel of 13 proteins that were most effective in distinguishing malignant from benign nodule samples. Twelve mapped onto lung cancer disease-perturbed networks. Integrated Diagnostics, a company Hood co-founded, commercialized the panel in 2013, saving the healthcare system around $3.5 billion in unnecessary surgeries. The company honed this down to a two-protein panel in 2016.
Hood noted that the convergence of systems biology with digital health, big data and analytics, social networks, and scientific wellness—the use of measurements such as sleep patterns and immune cell activity to optimize health and prevent disease—is catalyzing the emergence P4 medicine. Hood’s team began introducing P4 to healthcare through the Pioneer 100 Wellness Project, an ISB pilot project that followed 108 participants, or pioneers, over nine months to create PD3 clouds that included their whole genome sequence, daily activity, blood samples, and other measurements. Using genome-wide association studies, they identified molecules correlated with genetic risk for 127 traits and diseases. Participants met with a behavioral coach every month to discuss so-called “actionable possibilities” based on their data to lower their risk.
“All 108 individuals had multiple actionable possibilities,” Hood said. “Most of you would find yourself at the bottom of the staircase of wellness. These actionable possibilities are what lifts you up those stairs.”
At the end of the study, ISB started a company, Arivale, with the goal to scale up to 100,000 pioneers by 2020. So far, Arivale has 3,500 pioneers. The idea is that PD3 clouds could be used to follow high-risk individuals, determine the earliest point at which they transition from wellness to disease, and identify biomarkers of this transition. These biomarkers could then be used to choose drug candidates or lifestyle changes to turn the tide, potentially even before symptoms appear.
Hood added that PD3 clouds could also allow researchers to run smaller trials, streamlining drug development. They could use PD3 clouds to identify biomarkers indicating the subtype of a disease someone has, and whether he or she will respond to a given drug. They can then use these biomarkers to select a group of only, say, 50 responders, and gain FDA approval because of the high levels of responsiveness. (Today, most people prescribed drugs don’t even respond to them.) Hood has begun applying this systems approach with his colleagues at Providence St. Joseph Health, creating a series of translational pillars, or clinical trials driven by scientific wellness and data clouds.
Chronic diseases account for 86% of healthcare costs, Hood said. Reversing these disease through P4 medicine could drastically reduce these costs. “This is going to create a scientific wellness industry, and transform our biotech, pharma, and diagnostic companies,” he said. “These benefits will only come about with systems-driven 21st century medicine.”
* The Molecular Medicine Tri-Conference; February 11-16, 2018; San Francisco. The Tri-Conference is produced by Cambridge Healthtech Institute, the parent company of Diagnostics World.