David B. Goldstein - The End of Genetics: Designing Humanitys DNA

THE END OF GENETICS

DESIGNING HUMANITYS DNA

David B. Goldstein

Copyright 2021 by David B. Goldstein

All rights reserved.

This book may not be reproduced, in whole or in part, including illustrations, in any form (beyond that copying permitted by Sections 107 and 108 of the US Copyright Law and except by reviewers for the public press), without written permission from the publishers.

Yale University Press books may be purchased in quantity for educational, business, or promotional use. For information, please e-mail (UK office).

Designed by Dustin Kilgore.

Set in Yale New and Alternate Gothic types by Integrated Publishing Solutions.

ISBN 978-0-300-21939-5 (hardcover : alk. paper)

Library of Congress Control Number: 2021939553

A catalogue record for this book is available from the British Library.

This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper).

Cover art: DNA double helix by Erzebet Prikel
http://fineartamerica.com/profiles/erzebet-prikel
www.redbubble.com/people/erzebetth

With apologies to John Legend for repurposing his lyrics, this book is dedicated to Arav, Maya, Aurora, Thomasina, Theodora, and Bernard, with love, for you and all your perfect imperfections.

It has become reflexive for authors to thank agents and publishers for their support and patience. But its being a reflex does not make it any less necessary or true, at least not in my case. Although writing has long been a private passion of mine, the technical writing my career requires did not teach me much about writing a general-interest science book. To the extent that I have learned something about how to tell a story that is both accurate and accessible, I have my agent of nearly twenty years, Georges Borchardt, to thank. And to the extent that my sometimes discursive storytelling has coalesced into something that looks, reads, and feels like a well-thought-out book, I have the guidance of Jean Thomson Black of Yale University Press to thank. For believing that my books, however many years delayed, will eventually arrive, when even I have had my doubts, I have both Georges and Jean to thank. For providing guidance and catching a few key inaccuracies in my descriptions of human reproductive biology I am grateful to Kate Stanley, and to Tatyana Russo for help with the figures and bibliography. Three anonymous reviewers caught a great many errors of both fact and tone, highlighted key issues to address, and made the book far more accurate and complete than it would otherwise have been.

THE END OF GENETICS

My career has been focused on identifying the genetic changes that cause disease in individual patients and on trying to use those genetic insights to develop effective treatments that target the precise causes of disease. Over the years this kind of work has been called personalized medicine or genomic medicine, and now increasingly is referred to as precision medicine. Whatever name weve given it, it has been both satisfying and frustrating. Genetics research has progressed more rapidly than many geneticists, myself included, had expected. As you will learn in the pages that follow, from devastating genetic diseases of childhood to later-onset and presumed more genetically complex diseases, such as amyotrophic lateral sclerosis (ALS), kidney disease, and heart failure, the mutations responsible for disease are being identified in ever increasing proportions of affected individuals. Treatments for these genetically resolved diseases, however, are lagging increasingly far behind the genetic discoveries. A recurrent theme has been waves of growing enthusiasm that new, precisely targeted treatments are just around the corner, then followed by crushing setbacks. We are currently in a period of renewed optimism about precision medicine, driven above all by stunning scientific advances in genomics, gene editing, stem cell biology, and pharmacology. But it is important to appreciate that we have been here before.

In the 1990s, many people thought that gene therapy was poised to dramatically improve the lives of a large number of patients suffering from genetic diseases, a lot of which had been newly diagnosed through our growing understanding of the human genome. Numerous trials were initiated in which viruses were used to introduce functional versions of genes that patients lacked because of inherited mutations.

One trial that was destined to change the field was initiated at the University of Pennsylvania and focused on a genetically transmitted disease caused by a deficiency of an enzyme called ornithine transcarbamylase (OTC). The disease is due to mutations in a gene on the X chromosome and affects mainly males, who have only one X chromosome. The mutations impair the function of the enzyme, which helps to break down nitrogen, and people with OTC deficiency can develop toxic levels of excess nitrogen in the body, in the form of ammonia.

In 1998 a young man with OTC deficiency, Jesse Gelsinger, enrolled in the trial and was treated with a modified cold virus. The modified virus was meant to introduce a functional version of the OTC gene to Jesses liver and therefore restore the normal processing of nitrogen, and thereby eliminate the toxic excess of ammonia. Instead, Jesses body mounted an unexpected immune reaction to the virus used to introduce the functional OTC gene. Within a day of the infusion of the virus, Jesse showed signs of jaundice, and progressed to multi-organ failure. Within five days he was dead. Later analyses suggested that the virus ended up being distributed much more broadly throughout Jesses body than expected and contributed to a devastating and ultimately fatal immune reaction. The rapid growth in gene therapy trials came to an immediate end, and it would take more than ten years for public trust and enthusiasm to be regained.

This reminder of the challenges in developing genetically targeted therapies is not intended to imply that the current enthusiasm about precision medicine is unjustified. Indeed, scientific progress in this area has been truly remarkable, and this scientific progress has led to increasingly important advances in treatments targeted to underlying causes of disease. Some of these you will learn about in the pages that follow, and some you will have read about in the news in recent years. But these advances are not coming anywhere close to keeping pace with our exploding knowledge of the underlying genetic causes of disease.

I have been concerned about the implications of this sharp discrepancy for many years. A decade ago, I wrote in Nature that the explosive growth in the identification of genes responsible for disease coupled with modest progress in developing treatments for those diseases would inevitably lead to increasing interest in ensuring that the genomes of children do not carry such mutations. Despite my being an enthusiastic advocate ofand, wherever possible, contributor toprecision medicine, the past decade has only added to my concerns about how limited our options remain to effectively treat genetic diseases. Not only do we lack effective treatments for most single-gene disorders; we now know that the challenge is even greater than finding a treatment that can undo the direct effects of the disease-causing mutations. The reason lies in the complexity of human biology.

Let us imagine the discovery of an entirely safe gene therapy treatment for a genetic disease. That is, we will envision a therapy that is capable of introducing a replacement for the faulty gene into exactly the cell types that need it. Let us further suppose that the replacement gene is expressed at the right times and in the right amounts and that no immune reaction is engendered. Unfortunately even this achievement, which is still very far away for most diseases, would not be sufficient in many cases. We now know that many human diseases have important developmental components. This means that the presence of the faulty gene early in life alters the developmental trajectory of the child, and even that of the fetus. For such diseases, even a completely effective replacement of the faulty gene post-natally would not represent a complete cure.