Breakthrough: The Quest for Life-Changing Medicines

Praise for Breakthrough

‘William Pao’s book vividly brings to life the people involved in medical research and development to find new ways to advance clinical outcomes for patients. The perseverance; intuition; iterations required to engineer that sweet spot are narrated in a very readable way.’

William ‘Bill’ Burns, Former CEO of Roche Pharma

‘Breakthrough reads like a mystery novel. It draws the reader in, first by describing the scientific discovery that provides key insight into a disease and then by weaving a tapestry of those who overcame almost unimaginable challenges to design and test the medicines we have today that cure, prevent, or vastly improve outcomes for those stricken with grievous illnesses… inspirational; a must read for anyone interested in or associated with drug discovery and development.’

Mace Rothenberg MD, President and Executive Director

of Museum of Medicine and Biomedical Discovery

‘An essential read for anyone interested in how basic science is translated for human benefit. Breakthrough: The Quest for Life-Changing Medicines delves into the fascinating and often surprising journey of drug discovery, unravelling the fascinating biology and convoluted research paths that lead to the development of new game-changing therapies. Authored by an acclaimed doctor, cancer scientist and drug developer; this book tells the captivating stories that bring the world of biomedical research and drug discovery to life.’

Dr Norman E. Sharpless, Former Director of the National Cancer Institute

and Former Acting Commissioner of the FDA

‘Dr William Pao has been a pivotal force in the field of cancer research for decades, channelling the tragedy of his father’s untimely death from cancer into a passion for scientific discovery. In Breakthrough, Dr Pao uses eight interesting vignettes to demonstrate that the process of discovery is complex, but that it exemplifies human ingenuity and the extraordinary power of team science.’

Margaret Foti, PhD, MD,

CEO of American Association for Cancer Research

‘A truly enlightening journey through many of the most important medical advances of the last few decades. The science underlying the discoveries blends seamlessly with personal insights into the researchers, physicians and patients who brought the work to life. All written in a style that will engage the curious lay person to those of us who were fortunate to witness some of these miracles firsthand.’

Howard A. ‘Skip’ Burris III, MD,

President, Sarah Cannon Research Institute (SCRI)

and Past President, American Society of Clinical Oncology (ASCO)

‘William Pao presents eight stories of biomedical achievement in a compelling, captivating, and remarkably complete fashion. These stories – and Pao’s own insights as both an accomplished physician-scientist and successful drug developer – capture the exhilarating process of discovery and the many individuals and teams that collectively contribute to the launching of successful medicines. Breakthrough: The Quest for Life-Changing Medicines is not just about chronicling a series of success stories; it is also about providing hope for much more of the same in the decades ahead.’

Tyler Jacks, Founding Director,

Koch Institute for Integrative Cancer Research;

President, Break Through Cancer

‘Pao traces seminal innovations from idea through challenge, setback, and risk, harnessing determination and luck to bring them to fruition. Breakthrough shares the excitement of bold discovery that captivates scientific researchers – motivated by the unyielding quest to save lives.’

Martha Liggett, Executive Director,

American Society of Haematology

To my dad, who died too young

Contents

Foreword

Introduction

Getting Started

1 The World’s Most Common Rare Disease

2 Lung Cancer in Never Smokers

3 The Universal Affliction

4 The Royal Disease

5 Therapy-Resistant Breast Cancer

6 The Virus That Stopped the World

7 The Dawn of Gene Editing

8 Viral Geometry

9 How to Innovate

Afterword

Acknowledgements

Glossary

List of Figures and Tables

Notes

Foreword

BY HAROLD VARMUS

The distressing symptoms and lethal consequences of disease are unwelcome commonalities of the human condition. Throughout history, various approaches – influenced by culture, religion, geography and social structures – have been pursued in efforts to ward off or reverse disease. Largely due to recent advances in science and technology, we (especially those of us in the most advanced economies) are living at a time of unprecedented power to prevent and treat human diseases. This is so because fundamental science is providing a deeper understanding of the biological mechanisms by which diseases develop and because novel technologies are allowing us to interfere with those mechanisms.

In this new book, William Pao – an accomplished physician, respected basic scientist and leader in the pharmaceutical industry – tells us eight fascinating stories about modern therapies that range widely from structurally designed chemicals to edited genes to enhanced antibodies. These stories reveal how new medical treatments arise from advances in many branches of science and medicine, including biochemistry, genetics, chemistry, structural biology, pharmacology, computational sciences and clinical trials. Happily, the stories are told in language that is accessible, without oversimplifying the science that has fuelled such remarkable progress.

While most of these stories do not yet end with the elimination or the cure of a disease, they are inspiring as adventures of the imagination, illustrations of human ingenuity, and demonstrations of how science can improve lives. In that sense, they have the potential to attract talented youth into the relevant fields of medical science, just as another book about discoveries of the principles of infectious diseases, Microbe Hunters by Paul de Kruif, was said to have done almost a century ago.

Comparison of these two books is an enlightening way to recognise the profound changes in medical science that have occurred during the past hundred years. De Kruif, an infectious disease expert who once worked at the Rockefeller Institute, wrote engaging, heroic tales of individuals – incidentally, but not surprisingly, all males – who discovered some of the first known microbes, mostly in the late nineteenth century; identified several of them as agents of terrible diseases (including tuberculosis, syphilis, malaria and yellow fever); and began to learn how such diseases might be controlled by our immune systems, by vaccines, or by chemicals found serendipitously to be toxic to the pathogens.

In the stories told here, only a few of the diseases are caused by invading microbes. The others are cancers or inherited disorders, affecting a variety of tissues and functions. And the heroes are not simply individuals. They are teams, composed of various kinds of people: scientists of several stripes, working in academia or industry; physicians caring for patients or conducting clinical trials; and others who support research as advocates, as funders, and as employees and leaders of public and private research facilities.

The teams may work synchronously to solve a problem. Or they may confront a series of difficulties sequentially, passing the baton from one set of experts to another. This intricate relay can happen in several stages: when a new disease, or new form of a known disease, is first identified and needs to be better understood; when the mechanism of a disease has been elucidated and its vulnerabilities need to be sought; when a potential target for therapeutic intervention is proposed and requires validation; or when a possible therapy needs to be manipulated chemically, evaluated in animal models, or subjected to definitive testing in human patients. The elaborate teamwork required to carry out these several complex steps may seem inherently different from the solitary actions taken by de Kruif’s heroic adventurers. But the rewards for patients and the public prove to be at least as great, and the stories at least as interesting and informative, as those told a century ago.

When readers of this book reach the middle of Chapter 2, they will learn that I know more about William Pao from direct experience than from hearsay and from reading this book. We worked together during the first stages of an exciting period of research on human lung cancer, when our findings and results from other labs drove rapid changes in the treatment of this common and frequently fatal disease. So I am well positioned to confirm that his skills as an investigator and clinician confer authenticity to his voice as a narrator of these tales – especially when supplemented by his extensive, more recent experiences as a leader in the pharmaceutical industry. Reader, you are in good hands – about to be told some remarkable stories by someone on the frontiers of medical science.

Harold Varmus, MD,

New York City, January 2024

Introduction

The Brazilian pit viper is a particularly lethal predator. It has long posed an occupational hazard for farmers in south-eastern Brazil who work in its natural habitat. Over the centuries, many witnessed the terrifying effects of its venom: one bite can cause a person to collapse on the spot. The venom is so potent that indigenous tribes used it to coat arrowheads to disable prey.

Back in the 1940s, the pit viper drew the interest of a Brazilian pharmacologist named Maurício Rocha e Silva. While much of the world was engulfed in war, Rocha e Silva was researching circulatory shock at the Biological Institute in São Paulo. His team sought to understand the toxicology of snake bites, unravelling how venom acted on the human body.

In 1948, they identified a previously unknown peptide that became elevated in blood plasma after animals were dosed with pit viper venom. (A peptide is a short chain of amino acids, the building blocks of proteins.) The mysterious molecule caused blood vessels to dilate: once a victim had been bitten, blood pressure dropped, sometimes catastrophically. Without sufficient pressure to force blood around the body, vital muscle, nerve and brain cells were starved of oxygen. Rocha e Silva and his team named this strange, havoc-wreaking peptide bradykinin.¹

Sérgio Ferreira was just fourteen at the time. Growing up in the state of São Paulo, he later applied to medical school with the ambition of becoming a psychiatrist. He changed his mind when confronted with the reality of his dream job: ‘Public psychiatry care in Brazil was rather poor, so I decided to become a scientist.’² He joined Rocha e Silva’s lab and was put to work investigating pit viper venom and bradykinin.

In 1964, for his PhD project, Ferreira showed that pit viper venom contains a substance, bradykinin-potentiating factor (BPF), that makes bradykinin much more active.³ Ferreira’s discovery further confirmed that pit vipers are lethal because they subvert the vital molecular system that regulates our blood pressure.

But the true medical breakthrough came when Ferreira moved to London to join the lab of another distinguished pharmacologist, John Vane. Ferreira took with him a vial of the pit viper BPF.

Vane, the grandson of Russian immigrants, was a self-described ‘experimentalist’. ‘At the age of twelve,’ he wrote, ‘my parents gave me a chemistry set for Christmas and experimentation soon became a consuming passion in my life.’ His first experiments made use of a Bunsen burner fed from his mother’s gas stove, but ‘a minor explosion involving hydrogen sulphide’ (a toxic and corrosive gas) stained the kitchen’s newly painted walls, and the precocious young scientist was banished to a shed.⁴

Vane was interested in high blood pressure, a primary driver of mortality worldwide. Hypertension is a major cause of strokes, heart attacks, and heart and kidney failure. At that time, millions of people were at risk of premature death because they had no reliable way to control their blood pressure. Our bodies must be able to raise or lower our blood pressure, depending on our physical activities, and we have a complex system of physiological and backup controls to keep our blood pressure at an appropriate level. Vane and his team were busy identifying some of the key components of that control system when Ferreira arrived. One key component is a blood pressure-raising peptide called angiotensin II. To make this peptide, we use an enzyme called angiotensin-converting enzyme (ACE).

‘Sérgio Ferreira brought this . . . brown goo,’ recalled Mick Bakhle when interviewed in 2016, laughing at the memory. Bakhle was another member of Vane’s team, assigned to investigate ACE at the time. On hearing of the effect of pit viper venom on blood pressure, Vane asked Bakhle in 1970 to test Ferreira’s BPF on ACE. ‘Brown goos are not very nice to work with, but we did have a look at it. And much to our surprise . . .’⁵

Ferreira’s brown goo turned out to inhibit ACE. It was an extraordinary discovery: an extract from a South American snake venom was shown to knock out the key enzyme that produced a critical blood pressure-raising peptide. Without ACE, there’s no angiotensin II; without angiotensin II, there might be no high blood pressure. ACE was also found to be the enzyme that inactivates bradykinin, meaning that without ACE, bradykinin would also remain around to lower blood pressure. This latter finding completed the pit viper puzzle.⁶

John Vane understood the potential medical significance of the ACE-inhibitor in pit viper venom immediately. But he also knew that Ferreira’s peptide, potent as it was, would make a lousy blood pressure drug. High blood pressure is a chronic condition that needs to be treated regularly over a long period of time, perhaps for an entire lifetime. It’s very hard to persuade most people to take a medicine repeatedly any other way than orally. But BPF could not be taken orally – the delicate molecule would be broken down in the stomach long before it reached the bloodstream. It could only be administered the way pit vipers do it – by injection.

What the world needed was an ACE-inhibitor that could withstand the human digestive system and be absorbed whole from the gut into the blood: a blood pressure treatment in a pill.

Such a pharmacological pearl was beyond the capability of an academic lab. But Vane had a side gig as a consultant to the American pharmaceutical company Squibb, and he suggested ACE-inhibitors as a potential research avenue. Two Squibb chemists, Dave Cushman and Miguel Ondetti, took up Vane’s lead. They mapped the molecular structure of Ferreira’s pit viper peptide and set about designing a more robust chemical cousin. It took them many years and multiple setbacks, but eventually they succeeded. The drug they came up with was named captopril. It was approved by the US Food and Drug Administration in 1981 and was the first reliably safe treatment for high blood pressure.

At first glance, captopril seems a modest kind of molecule made of commonplace components: nine carbon atoms, fifteen hydrogen, three oxygen, one sulphur and one nitrogen – that’s all. Yet, captopril was perhaps one of the most important innovations of the twentieth century in any field of scientific discovery. Aeroplanes opened up the world; semiconductors and the internet ushered in the digital age; but captopril and the other ACE inhibitors it inspired have given millions of us longer lives.

I’m an oncologist – a cancer doctor. I treated very sick patients for fourteen years. During that time, I prolonged the lives of many patients, but I also saw many others die or suffer protracted pain and incapacity. Each patient provided me with inspiration to improve on the status quo, but the biggest inspiration for my lifelong work has been my dad, who died prematurely from colon cancer in 1981.

Born in China in 1922, my dad set sail in May 1948 on the American President Lines’ U.S.S. General Meigs to the United States. He had no relatives in this new country, but with a degree in hand from the National Medical College of Shanghai,* he completed residency training in Ogden, Utah, on a stipend of $100 per month. After further training in Baltimore, Maryland, he got a job at Chestnut Lodge, a private psychiatric hospital in Rockville, Maryland. He eventually became Director of Psychotherapy.

Some of my best memories of him were from playing cards or Scrabble, hearing him sing Broadway tunes, and seeing him perform in Chinese operas. I also fondly recall that every four weeks, he and I would go and get our hair cut and have lunch together.

The first time Dad was admitted to the hospital, in 1979, I was eleven years old. I don’t remember being told that he had been diagnosed with cancer. I think he had found blood in his stool. Looking back, I suppose he had stage III colon cancer which was resected surgically.

Afterwards, he was put on what must have been 5-fluorouracil (5-FU), a chemotherapy drug that made his hair fall out and left him nauseated and vomiting. That was the end of our shared haircuts and lunches for a while. Following chemo, though, he bounced back and life seemed to return to normal.

About two years later, Dad returned to the hospital for exploratory surgery. The cancer had reappeared, and the doctors wanted to determine how far it had spread. (Radiographic imaging was not very advanced at that time.) He died on the operating table. The surgeon had found widespread liver metastases. After biopsying a lesion, he couldn’t stop the bleeding. Maybe this was a small mercy: my dad evaded the slow agony of cancer’s ravages.

For my family, the loss of our father was a cataclysmic shock. But our story is by no means unique. Cancer still claims a horrendous number of victims every day, too many of them young, too many of them leaving behind grieving family and friends. Around ten million people die of cancer worldwide each year – almost one in six of all deaths.⁷

My dad and my mom, also a physician, had always expected that my older sister and I would go into medicine. Our father’s death only reinforced that trajectory for both of us. After Dad died, I vowed that I would dedicate my life to making a difference for patients like him.

About twenty years later (after college, medical school, internship, residency, fellowship and post-doctoral training), I became a medical oncologist and translational science researcher – a cancer physician-scientist. I treated patients while at the same time running an academic translational research* lab to figure out at the molecular level why cancers grow, and ultimately to find ways to kill them.

Throughout that time, I collaborated with pharmaceutical companies to develop new medicines, including an important new lung cancer drug that is now prolonging the lives of many patients (see Chapter 2). In 2014, I left the world of academic medicine and transitioned to leadership roles in research and development in the pharmaceutical industry. I wanted to help create new therapeutic options directly, to make a bigger impact for millions of patients worldwide.

I’ve learned over the years that a great deal of creativity goes into making new medicines, most of it witnessed and appreciated by only a small handful of people. Across the wider pharmaceutical industry, amongst biotech firms and government labs, and throughout academia, thousands of scientists and experts are striving daily to create molecules that will save lives and help people feel or function better. They are trailblazing new areas of biology, inventing new tools and technologies to hit drug targets, and advancing our understanding of diseases. This is a community fuelled by innovation, a world of drug hunters charting new scientific territory every day of the year. Yet almost all of it remains invisible to the public.

To me, innovation is coming up with something that hasn’t been done before, showing that it’s possible, and having the courage to convince others that it’s worth doing. It’s something that many of us seek to do in all walks of life. We inevitably will look for ways to do things better – to add value through invention.

As a cancer physician, research scientist and drug developer, I have been witness to a vast field of innovation which is, at best, impenetrable to most people; at worst, it goes unnoticed. The men and women working on the next generation of medicines are undertaking some of the most extraordinary innovation ever seen. I want to lift the veil on some of that innovation and share stories from the front line of drug discovery.

It is not a straightforward ambition. The product of a Silicon Valley innovation story is often a super-branded and seemingly ubiquitous device or app that is intuitive to use. By contrast, the product of a pharmacological innovation story is a molecule too tiny to see, with an alien name and a mode of action that will often seem incomprehensible even to people with science degrees. That molecule may save thousands of lives, but if it’s a nightmare to pronounce, who’s going to talk about it?

And let’s face it: most people prefer not to take medicines if they can possibly help it; they learn about these drugs unwillingly – when they or their loved ones are struck by a disease. Furthermore, since everyone’s health is different, only a few medicines are widely known or taken.

As we glimpsed from the story of captopril, there is seldom just one hero or one team responsible for a new medicine. Hundreds of scientists, working across multiple organisations and decades, usually play a part in the innovation. Even the doctor who prescribes your medicine most likely will not know who invented it. That makes the stories of drug discovery both abstract and opaque compared to other examples of innovation.

But the toughest challenge may be the science itself. Rocket science is famously difficult, but the fundamental problems of space exploration are straightforward to communicate: how to ensure enough oxygen for the astronauts; how to withstand the cold in space, or the heat of re-entry; how to move in zero gravity. When it comes to treating cancer, however, the storyteller needs to start by explaining what cancer is at the cellular level, how it’s driven by molecular signalling pathways consisting of enzymes encoded by oncogenes and, by the way, what are all those things?

Nevertheless, I’m going to try to share some of the absolute awe I feel for the astounding innovation taking place in drug discovery labs around the world. These stories open a door to a more detailed and nuanced appreciation of what it takes to create something new and valuable that we trust to act on – and inside – our bodies. Medicine is one of the first technologies we encounter as children; we think it is normal to take a tablet to make us better. Yet, what a remarkable thing that is! As one of the scientists we shall meet later exclaimed, ‘Wow, oh my God! A serious disease can just disappear if a chemist builds the right molecule.’

To make a new drug we must decode nature – the biological secrets of life that have evolved over millions of years. We must identify and characterise a disease, understand scientifically why it happens, and then find a way to alter its course by giving a patient a particular molecule that will impact the disease without incurring significant side effects. The whole process is a triumph of human ingenuity, perseverance, collaboration and resilience. Reading these stories should fill you with hope for the potential of humankind to make the world a better place.

The science is challenging, it’s true, but it’s not impenetrable. In fact, I would argue it is fascinating, sometimes thrilling, occasionally revelatory. Once you’ve understood it, you’ll have a far better idea of how your own body works. You won’t need any scientific education to follow these stories, just a willingness to discover.

My hope is this book will serve as a bright, welcoming beacon for young people considering a career in the life sciences. Our mindsets, and therefore all the big decisions we make, are shaped by the stories we hear, and there are just too few stories about those who invent medicines.

If we want to encourage the next generation to join in the battle against cancer, to take on dementia, to be ready to respond to the next pandemic, we need to be unearthing and sharing the stories of exemplary scientific innovation by these unsung heroes.

So come with me on a deep dive into eight drug discovery adventures. We’ll find out why paracetamol, one of the world’s most popular drugs, was left unused for decades after its discovery. The extraordinary tenacity of a sick child’s mother will illustrate how innovation can depend on the determination and drive of a few individuals. A cunningly modified part of the immune system will be the breakthrough that frees people with haemophilia from the tyranny of near-daily injections. A type of blood we normally see only inside the womb will be resurrected in adults to treat sickle cell disease. A passion for the geometry of cones will lead to the discovery of a new HIV treatment. A worldwide pandemic will spur the discovery of an antiviral in record time. And the lives of patients with cancer will be prolonged by new therapies against specific genetic targets.

Along the way, we’ll discover where the big ideas come from, how the best scientists overcome obstacle after obstacle, how diverse teams work together in pursuit of a common goal, how innovators make the most of serendipity, how breakthroughs depend on a foundation of deep, seemingly unconnected knowledge, how even the smartest scientists depend on trial and error to make progress, and how personal curiosity and commitment keep people going.

Drug discovery shows that seemingly impossible breakthroughs can be achieved, given time, dedication, skill, collaboration and a dash of luck. I hope the dogged determination and wondrous creativity shown by these drug developers inspires you to innovate in the field of your choice, and even change people’s lives, as they have.

* The National Medical College of Shanghai later became the Shanghai Medical Universi-ty; in 2001 it was integrated into Fudan University.

* Translational medicine seeks to convert laboratory discoveries into practical medical applications and to discover the molecular mechanisms underlying clinical phenomena observed in patients.

Getting Started

Medical science is a complex topic. To ease that complexity, here’s a quick briefing on some key biological concepts and an outline of the drug development process. These introductory notes are here if you find yourself getting lost in amino acid chains or pre-clinical toxicology reviews further down the road. You can also consult the glossary at the back.

A Crash Course in Biology

To understand how drugs work, we must go deep into the science of cells, biochemical systems and ultimately molecules – the actual targets of the drugs.

We can start simply. Our bodies are made up of the things we eat and drink: water, sugars, fats, proteins and minerals. For drug hunters, it is the protein that is of the greatest interest. Proteins come in a dazzling array of forms. They make most of the important stuff happen in the body – catalysing, signalling, metabolising – and so we generally seek to activate or inhibit proteins. That’s what most medicines do: they encourage particular proteins to do something, or they prevent proteins from doing something.

One category of key proteins for the drug hunter is enzymes. An enzyme is a protein that catalyses some kind of change. That change happens when the enzyme binds to one or more other molecules. That means every enzyme has at least one binding site, a physical docking bay where small natural molecules – or drugs – can bind.

Proteins are built from blueprints encoded in genes. Our genes contain manufacturing instructions written in strands of DNA. Each gene encodes a specific protein. DNA is first ‘transcribed’ into messenger RNA (mRNA), and then mRNA is ‘translated’ into protein.

Confusingly, the protein and gene often have the same name. You can tell the difference in print because the gene is italicised. So, EGFR is the gene for EGFR protein. I’ll try to make it clear when I’m talking about a gene or a protein.

Proteins are made up of chains of amino acids.* These are very simple molecules, usually consisting of a few atoms of carbon, hydrogen, nitrogen and oxygen. Different proteins have different sequences of amino acids, and these sequences determine the protein’s unique structure, which in turn determines its biochemical properties – how it behaves in the body. When individual amino acids come together in a chain, they undergo a slight chemical change; the resulting links in the chain are known as amino acid residues.

Biological molecules and systems, by their nature, are often complex and unpredictable. Living things evolved over hundreds of millions of years, and we just don’t understand everything about them yet. So, when we intervene in a biological system with a new potential drug, we may encounter surprises. Drug discovery might be summed up as designing molecules to manipulate biology – but biology is not always so easily manipulated.

How Medicines Are Made

Drug discovery and development is the process of inventing and testing a new medicine to treat a particular condition or disease. At the heart of a medicine is usually a single active ingredient that affects a specific target and does the work of treating cancer, fighting infection, and so on. There may be other components that help the medicine get to the right part of the body and do its job effectively. The active ingredient is a unique molecule – a collection of atoms arranged in a particular way. This may be a small molecule (generally under 1,000 atomic mass units), a chemical typically created and synthesised by chemists that can often be taken orally in tablet form. Or it may be a large molecule (generally over 150,000 atomic mass units), a biologic such as an antibody, created by protein engineers and produced in living cells. Due to their large molecular size and other intrinsic properties, biologics are usually injected. The type of molecule selected for a particular medicine depends upon the specific target of interest.

When we want to make a new medicine for a disease for which there is still an unmet medical need, we start by