Revolutionizing Healthcare by Tracking and Understanding Human Cells During Disease

Seventeen years after its completion in 2001, the economic impact of the Human Genome Project can be estimated to be at least 50 dollars for every dollar invested. The scientific impact on the life sciences is beyond measure, as today one cannot imagine life science research without detailed genomic information for any well-studied organism. Genome sequence is often portrayed as “The book of life”. However, we cannot “read” from this book of life and understand the principles that underlie human biology. More precisely, we cannotbased on genomic sequences alonecompute predictive models for human phenotypes and disease. The sole interpreters of our book are our cells, and understanding how genomes function within cells, and how cells form tissues and dynamically remodel their activities when tissues progress towards disease is among the grand challenges in science and technology of our era. Moreover, although we can interrogate and manipulate many molecular mechanisms that control the life or death of cells, we generally cannot predict or cure diseases by analysing a patient’s tissues. This inability causes enormous suffering and a heavy, growing burden on our economy and ageing society.

However, recent disruptive technologies will, if further developed and integrated, induce a paradigm shift in basic and medical sciences by overcoming four fundamental shortcomings in our current approaches. (1) Resolving spatial cellular heterogeneity. Organs and tissues are composed of many different cells that communicate with each other to perform their specific functions. Each individual cell expresses a particular set of active genes and pathways, which is generally dependent on its environment and the activity of neighbouring cells. Therefore, we must understand, for each cell, how the genome controls its function within the tissue and how, vice versa, changes in the tissue and its environment influence the genomic activity of the cell. (2) Capturing cellular changes in time. A diseased organ has a specific history (i.e. onset and cause of the disease) and future (i.e. development of the disease, reaction to treatment). For example, inflammation may be normal and useful in the short term, but can lead to chronic diseases over longer time scales. To understand a patient’s current physiological state and its future course we must be able to reconstruct cellular histories and predict cellular trajectories (e.g. in the high dimensional space of gene expression) based on the molecular analysis of their tissues. (3) Establishing computational frameworks for understanding the cause and biology of disease. Current attempts to model human disease in the clinic often use limited parameters and lack the power required to integrate the many thousands of molecular phenotypes that can be acquired from patients. These models are missing the full power of modern machine learning. (4) Developing experimental systems that allow researchers to manipulate the genomes and cells from patient tissues. New technologies in genome manipulation and cell reprogramming are enabling the use of tissues in vitro and new models to advance precision medicine.

Overcoming these four technological barriers will empower us with the ability to profile the molecular makeup of thousands of single cells within a tissue (spatial context, 3D), capture and explain cellular changes as cells age and during disease progressions (4D), and derive and test models to infer causes, mechanisms, and treatment of diseases. In summary, we need to be able to track and decipher the book of life as it progresses through time— “LifeTime”. We must understand the forces (genome structure, epigenetics, gene regulation, cell-cell communication, etc.) that propel cells along trajectories in high dimensions and predict their future directions. LifeTime’s unifying goal is to quantify, model, and predict cell trajectories in tissues and whole organisms. This goal is a major step beyond the genomic revolution and will fundamentally transform our understanding of life and the practice of medicine. Ultimately LifeTime’s long-term vision is to make it possible for physicians to assess the molecular state of patient tissues in real time, leading to early diagnosis and effective interception of disease.