Precision Medicine and the Reinvention of Human Disease

Jules J. Berman

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128143933
• eBook ISBN: 9780128143940
• Topic: Medicine
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry

Despite what you may have read in the popular press and in social media, Precision Medicine is not devoted to finding unique treatments for individuals, based on analyzing their DNA. To the contrary, the goal of Precision Medicine is to find general treatments that are highly effective for large numbers of individuals who fall into precisely diagnosed groups.We now know that every disease develops over time, through a sequence of defined biological steps, and that these steps may differ among individuals, based on genetic and environmental conditions. We are currently developing rational therapies and preventive measures, based on our precise understanding of the steps leading to the clinical expression of diseases.Precision Medicine and the Reinvention of Human Disease explains the scientific breakthroughs that have changed the way that we understand diseases, and reveals how medical scientists are using this new knowledge to launch a medical revolution.- Clarifies the foundational concepts of Precision Medicine, distinguishing this field from its predecessors such as genomics, pharmacogenetics, and personalized medicine- Gathers the chief conceptual advances in the fields of genetics, pathology, and bioinformatics, and synthesizes a coherent narrative for the field of Precision Medicine- Delivers its message in plain language, and in a relaxed, conversational writing style, making it easy to understand the complex subject matter- Guides the reader through a coherent and logical narrative, gradually providing expertise and skills along the way- Covers the importance of data sharing in Precision Medicine, and the many data-related challenges that confront this fragile new field

Chapter 1

Introduction: Seriously, What is Precision Medicine?

Abstract

The concepts that will be developed through the book are: The reappraisal of disease causality in view of Precision Medicine's recognition of the multistep development of disease; Precision Medicine's emphasis on the classification of diseases according to the key pathways involved in the development of the disease; The rising influence of rare diseases on Precision Medicine's approach to the prevention, diagnosis, and treatment of the common diseases; The concept of disease convergence and how Precision Medicine research has elucidated converged pathways to disease expression, allowing us to find classes of convergent diseases that can be treated with the same strategy; The important role of proper methods for data collection, data annotation, and data sharing in Precision Medicine; Why data analysis is rapidly being eclipsed, in terms of advancements in the field of Precision Medicine, by data reanalysis.

Keywords

Convergence; Rare disease; Data annotation; Annotation; Data sharing; Reanalysis; Classification; Phenotype; Root cause

Outline

• Glossary
• References

I want to thank you for making this day necessary.

Yogi Berra

It's important, from the outset of this book, to discuss the definition of Precision Medicine. Or, more accurately, the definitions of Precision Medicine, as everyone you talk to seems to have a different opinion on the subject. From the US National Institutes of Health comes the following: “Precision Medicine is an emerging approach for disease prevention and treatment that takes into account people's individual variations in genes, environment, and lifestyle. The Precision Medicine Initiative will generate the scientific evidence needed to move the concept of Precision Medicine into clinical practice” [1,2]. An Advisory Committee to the NIH Director would include, under the mantle of Precision Medicine, “providing individual side-effect profiles of drugs, and preventative health care check-ups that include specific recommendations developed from interpreting an individual's genetic risk profile” [3].

Spin-off definitions seem to accept, as a simple fact, that physicians can account for the individual variability in genes, environment, and lifestyle for all their patients [4]. From the Engineering and Medicine group of the National Academies of Sciences came the following: “Every patient is unique, and the evolving field of Precision Medicine aims to ensure the delivery of the right treatment to the right patient at the right time” [5]. This is an uninformative and bombastic definition, implying that without Precision Medicine, doctors have provided the wrong medications at the wrong times, to the wrong patients.

Between the millions of interindividual variations in our genomes, the highly personalized lifestyle choices, and the differences in our environments, there seems to be plenty of uniqueness to spread around. It is easy to forget that our uniqueness as individuals often has much less to do with our diseases than does our sameness as members of the same species. Our sameness goes a long way toward explaining why humans seem to suffer from the same list of textbook diseases, regardless of their individualized genes and geography. Someone had to put the brakes on this epidemic of uniqueness. Much to their credit, the National Research Council of the US National Academies tacked on the following caveat to the definition of Precision Medicine: “It does not literally mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment” [6]. The Research Council wisely distinguished Personalized Medicine from Precision Medicine, by adding, “Although the term ‘Personalized Medicine’ is also used to convey this meaning, that term is sometimes misinterpreted as implying that unique treatments can be designed for each individual. For this reason, the Committee thinks that the term ‘Precision Medicine’ is preferable to ‘Personalized Medicine’” [6]. [Glossary Prognosis, Susceptibility, Uniqueness]

The National Research Council pointed out what should have been obvious from the start. We cannot provide individualized treatments, because treatments must be tested for safety and efficacy on groups of people. The best we can ever do is to assign patients to a group that has been fitted to a preapproved treatment. So where does this leave us?

Before we tackle a definition of Precision Medicine, let's stop a moment and consider our definition of disease. In earlier times, a disease was defined by its cause (e.g., influenza virus) and its pathological or clinical symptoms (e.g., fever, aches, chills). In the last few decades, there has been a profound change in the way we think about diseases. We recognize that every disease, even diseases whose root cause can be assigned to a single factor, such as a genetic mutation or an invasive microorganism, must develop in a sequence of steps, over time, before the disease is fully expressed. Advances in genetic analysis and molecular biology have permitted us to dissect some of those steps, in some diseases. What we are finding is that we can target specific events and pathways that lead to the development of disease, or that drive the clinical and pathological properties of a disease (it's so-called phenotype). [Glossary Phenotype, Root cause]

We can define Precision Medicine as an approach to the prevention, diagnosis, and treatment of disease that is based on a deep understanding of the sequence of biological events that lead to disease. With this approach we are learning: (1) that we can develop new drugs that target specific steps in the development of disease; (2) that drugs developed to interfere with a cellular event or pathway may serve as effective treatments for those individuals whose disease is driven by the pathway; and (3) that a treatment effective for a subtype of one disease may also be effective against other diseases that happen to be driven by the same pathway.

This approach, based on learning the steps that precede the development of disease, shifts the emphasis of Precision Medicine from finding unique treatments for unique individuals to finding general treatments that are effective against precisely identified biological processes, in whichever diseases those processes may occur. In the era of Precision Medicine, every disease has a biological history, and every event in the history of the disease is a possible target for prevention, diagnosis, or treatment. At this point, we can begin to see the thread of a story that will unfold throughout this book. We will need to explore our basic assumptions about disease development, and we will need to demonstrate how our approach to Precision Medicine is leading to a reduction in disease-related morbidity and mortality of diseases; otherwise, Precision Medicine would be just a waste of the time and money lavished on a scientific fad. Finally, the title of this book is Precision Medicine and the Reinvention of Human Disease. Somewhere in this narrative, we will need to demonstrate that our concepts of human disease are fundamentally changing, under the aegis of Precision Medicine. Our work is cut out for us, but the task may be somewhat simplified if we break it down into specific questions, as follows:

• – How can one be certain that diseases develop in steps?

This issue of the stepwise development of disease is a hard sell, perhaps because we often become aware of diseases suddenly, as though we first notice a disease at the moment of its inception. Even when we know that a period of time must pass between the cause of a biological condition and its eventual emergence, we tend to think in terms of a condition that begins fully formed, but too small to notice, until it has had a chance to grow into a clinically detectable result.

As an example, consider the growth and development of a zygote, in the womb. No so long ago, most everyone believed that at the moment of conception, a fully formed human was created—the so-called homunculus. During the nine months of pregnancy, the homunculus grew larger, without needing to change its shape or modify any of its internal organs, until it was ready to emerge through the birth canal. Of course, we now know that gestation is characterized by strict, sequential steps of development, through different biological stages and forms: zygote, blastula, blastocyst, embryo, and fetus. At each stage, certain crucial biological processes must occur for development to proceed.

Generations of medical students have been taught that cancer results from a mutation that confers the property of unregulated growth on the cell bearing the mutation. As the cell divides, it produces more cells, with the same cancer-causing mutation. Over time, the original mutated cell has produced a clonal population of sufficient size to be palpable, and to do damage to the host organism. We now know that this is not true. Although mutations are involved in the development of cancer, the first mutation occurs in a cell that does not suddenly acquire the morphological or biological properties of a cancer cell. In fact, a succession of cellular events, occurring in the descendants of the original mutated cell, must precede the fully developed cancer [7–12].

Biological functions develop as a sequence of events. This rule applies equally to complex processes, such as cell division and growth, and to simpler processes, such as blood coagulation and photoreception. In Section 2.2, “Why We Are Confident that Diseases Develop in Steps” we assemble the arguments that lead us to believe that diseases, like other biological processes, develop over time. [Glossary Host, Results]

• – Precision Medicine assumes that the steps leading to the development of diseases can be dissected and studied. What do we actually know about disease pathways, and why do we believe that we can learn all of the disease pathways for every disease that occurs in humans?

There are many questions that need answering here. What are these mysterious events and pathways that lead to disease? For that matter, what exactly is a pathway? How do we find disease pathways? Do disease pathways include the normal pathways responsible for cell maintenance? Can we inhibit these pathways without causing cell death? How can we develop drugs that specifically target individual disease pathways? Precision Medicine directs us to deconstruct diseases into sets of pathways, but how do we actually do this?

It turns out that we know a lot about the cellular pathways that lead to the disease, and that we have the tools to learn a lot more. Much of our knowledge on this subject comes from the study of rare, monogenic diseases, covered in Chapter 5. We will see that the rare monogenic diseases provide us with an opportunity to observe the effects of single-pathway disruptions. Furthermore, new treatments developed for the rare diseases are teaching us the general principles of pathway-directed therapeutics. [Glossary Rare disease, Pathway-driven disease, Druggable driver]

• – Precision Medicine assumes that the biological steps leading to any disease are characteristic of the disease (i.e., will lead to the diagnosis of the disease), crucial for the development of the disease (i.e., will result in the prevention of the disease, if the step is eliminated), and responsible for driving the expression of the developed disease (i.e., will result in the successful treatment of the disease, if targeted after the disease has expressed itself clinically).

How do we know that this is true? Before the advent of Precision Medicine, therapeutics was geared toward counteracting the symptoms of the patient's disease. Every healthcare worker of a certain age is familiar with the following clinical maxims.

• – If the patient has constipation, prescribe a laxative
• – If the patient has diarrhea, prescribe a drug that decreases gut motility
• – If the patient has a fever, prescribe an antipyretic
• – If the patient has insomnia, prescribe a CNS suppressant

Countless dermatologists have, knowingly or not, followed the all-embracing adage, “If the lesion is dry, make it wet. If the lesion is wet, make it dry.” Of course, nothing simplifies medicine better than the surgeon's motto, “When in doubt, cut it out!”

The past 50 years have witnessed a sophisticated change in the way that drugs are designed and developed. Most of the drugs that have reached the market in the past few decades have been small molecule drugs that were designed to spe...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Other Books by Jules J. Berman
• Dedication
• About the Author
• Preface
• Chapter 1: Introduction: Seriously, What is Precision Medicine?
• Chapter 2: Redefining Disease Causality
• Chapter 3: Genetics: Clues, Not Answers, to the Mysteries of Precision Medicine
• Chapter 4: Disease Convergence
• Chapter 5: The Precision of the Rare Diseases
• Chapter 6: Precision Organisms
• Chapter 7: Reinventing Diagnosis
• Chapter 8: Precision Data
• Chapter 9: The Alternate Futures of Precision Medicine
• Index