How we know what we know about medicine - A review of The Drug Hunters by Drs. Donald Kirsch and Ogi Ogas
A rose of death
In 1941, British citizen Albert Alexander pricked his face on a rose thorn. A malignant bacteria on the rose made its way into the cut, and the infection spread rapidly. Alexander’s face, scalp, and eyes became severely swollen within a few days. To stop the spread of the bacteria to his brain, doctors removed Alexander’s eye, but this did not stop the infection. With Alexander facing certain death, Howard Florey and Ernst Boris Chain, a pair of immigrant scientists, decided to test a new fungal strain on him. The scientists injected him with penicillin. The first lab-developed antibiotic. In less than a day, the infection went into remission. Penicillin was working. But being such a new drug, the scientists had used their entire supply, which was not enough, the infection relapsed and Alexander died after a few days.
If Alexander had pricked his face two years later, he probably would have survived. The major pharma companies scaled up production of the fungal strain rapidly, and penicillin accompanied the allied forces on D-Day, and has since saved countless lives up to the present day. The Drug Hunters, by Donald Kirsch and Ogi Ogas, is a book about the drug discovery process. The authors highlight the discovery of drugs like penicillin, as well as the contraceptive pill, reliable anaesthesia, beta blockers for treating hypertension, the use of insulin to treat type 1 diabetes, and a vaccine for syphilis, just to name a few. They also explain the mechanisms of drug testing and the critical role of financing. By humanizing the idiosyncratic nature of drug discovery, the authors make the material approachable. And while these stories should be lauded, I was disappointed that the authors framed mental health disorders, namely depression, as a medical problem, in want solely of an appropriate medicine. This side steps a broad literature on a diverse set of available treatments for depression.
To be clear, this book does a brilliant job at illuminating how we make new effective drugs. The historical scope of this book clearly shows how much progress we have made, while still conveying to the reader how much more we stand to discover. Author Donald Kirsch is a veteran in the pharma industry, and his insider perspective was insightful. His description of the financial stakes involved in drug production today was sobering. He writes “it costs an average of $1.5 billion, and 14 years to manufacture a new drug.” Some low-ball estimates put the cost just under $1 billion to develop single medication. And that is because “only 5% of proposals get funding by management, and only 2% get FDA approval.”
Due to the high cost of drug development, we learn, there is a disincentive for pharma companies to invest in drugs that are only taken once, like antibiotics. 15 out of the major 18 pharma companies have given up researching how to make the next antibiotic, despite the growing global resistance to existing antibiotics.
Pushing pharmacological frontiers
One of the most illuminating and inspiring histories in the book is the invention of the pill. Its invention is an excellent case of science being directed for ethical aims. By 1951, Margaret Sanger, the septuagenarian feminist and founder of what is now Planned Parenthood, had approached every major pharma company, and failed to persuade a single one that there was merit to developing the world’s first oral contraceptive. Afterall, contraception was illegal, and “why would women want to take a pill every single day just to control conception?” one exec asked her.
Sanger partnered with her multi-millionaire friend, Katharine McKormick, and they approached Gregory Pincus, an outcast Jewish chemist, with the proposal to fund his work if he developed the Pill. In short, their plan worked, and they eventually convinced a pharma company to manufacture it. A critical lesson from the invention of the Pill, is that major pharma companies can respond to popular opinion. Or in this case, a few individuals.
Many of us, myself included, take for granted the discoveries of medicine that were laboriously, and sometimes painstakingly developed. One clear case is the length of time it took for drugs to be standardized. The discovery that ether could be used as an anaesthesia (not just laughing gas) was, itself, a miracle of science. For most of history, due in part to its horrific nature, surgery was restricted only to life-saving operations (the removal of gangrenous limbs). For decades after its discovery, the potency of ether was “fantastically variable.” Private apothecaries manufactured it, and third party sellers sometimes diluted it, so quality varied. Too strong a dose, and a surgery patient could die. Too weak a dose, and they could wake up during surgery, only too conscious. It took almost a decade before Edward Squibb discovered a standardized method for production in 1854.
It was fascinating to witness the human motivations at play in those working in the field of pharma research. Frederick Banting, who discovered insulin can treat type 1 diabetes, had a huge ego, and was extremely reluctant to share any credit, even when it was due. On the other hand, Paul Ehrlich, who discovered the cure for syphilis, was much more humble, referring to his discovery as “a moment of luck” after “seven years of misfortune.”
Medicine fake news
A disturbingly common theme throughout the book is that the mainstream dogma in the medical profession can be wrong, and even resistant to new discoveries. In an experiment in the 1840s, Ignaz Semmelweis showed that hand-washing can reduce infant mortality from 18% to 2%. Since this contradicted the prevailing miasma theory of infections (vapours associated with environments were thought to be the true cause of infection, and hospitals were thought of as clean, so not able to cause infection) Semmelweis was roundly ridiculed, turned to alcoholism, and was eventually locked up in an insane asylum where he was beat to death by the guards. And members of the medical profession continued to stick their fingers in cadavers before delivering babies for decades.
John Snow helped put to rest the miasma and depravity theories of epidemiology by making a map of the sites where people in Soho, London were contracting cholera. He showed that certain contaminated wells were causing the outbreak of the disease. Not people’s moral behaviour.
In 1747, James Lind showed in a controlled experiment, that providing limes to sailors helped prevent scurvy. Unfortunately, his ideas did not catch up and sailors continued to suffer the symptoms of scurvy: losing teeth, respiratory issues, skin as black as ink, ulcers, rictus of the limbs, and abominable breath. It wasn’t until 1795, half a century later, that the British navy made lemons and limes standard issue at sea.
Depression is framed too narrowly
Dogmas are often slow to yield to new approaches. And that brings me to my main criticism of the book; that is, the authors have nothing critical to say about a prevailing dogma within the pharma industry today: that depression starts with a chemical imbalance.
I bring up this criticism because the authors discuss the accidental discovery of the selective serotonin reuptake inhibitor (SSRI) class of drugs. The ones that boost serotonin in the brain. The authors plainly state that increasing serotonin in the brain decreases depression for reasons we do not know, mentioning its discoverers “merely got lucky that there were more positive changes than negative ones.” That statement does not reflect the diversity of opinions on mental health.
Professor David Healy argues that the link between serotonin and depression has not been established, arguing in the British Medical Journal that this is the “marketing of a myth.” Professor Joanna Moncrieff from the University College of London, argues “the disease-model, [implying a chemical imbalance], is ultimately not helpful, as well as being unfounded.”
For a select number of people, the roots of depression may be tied to genetics. And critics and proponents of the pharma approach to treating depression all agree that you should consult your doctor before quitting antidepressants. Medication for depression can work for some people, as a recent systematic review suggests. But as Harvard professor of placebo studies, Irving Kirsch, points out, “Almost half of the clinical trials sponsored by the drug companies have not been published.” And antidepressants do not come without negative side effects. A new study suggests that drugs to treat depression may drastically raise the risk of mortality.
In addition to negative side effects that accompany antidepressants, a narrow focus on chemical solutions to depression ignores the vast body of research that suggests depression is a problem with many causes. The World Health Organization, the leading medical body in the world, said in 2011, that “mental health is produced socially. And the presence or absence of mental health is above all a social indicator and therefore requires social, as well as individual solutions.” That is the official opinion of the United Nations too. And Tom Insol, the former director of the National Institute of Mental Health until 2015, said that mental health treatment is “so broken,” and that the “field is extremely reluctant to try new approaches.
If depression is a chemical imbalance, that is the proximate cause, but typically not the ultimate cause. That is the central argument in Johann Hari’s new book Lost Connections. The ultimate cause of depression is highly dependent on environmental factors, Hari argues. The author travelled around the world, interviewing experts in the field, and in his book he outlines seven factors we know contribute to depression, ranging from lack of meaningful work, lack of exposure to nature, improper sleep and diet, to, as the book title suggests, a diminishing number of meaningful connections in our increasingly busy lives. One study he references points out that in 1985, most respondents in a study said they had three close friends. In 2004, the most common answer was zero. The list Hari offers is far from comprehensive, as he points out. But he effectively shows that if we want to cure depression, we need to take a less narrow, and much broader approach than the one funded by the major pharma companies.
While The Drug Hunters discusses the steady pressure major pharma companies face (high executive churn, and demand for quarterly profits), I feel the authors could have addressed a seeming conflict of interest posed by major pharma companies’ marketing model for antidepressants. The treatment of depression is an expensive industry, and it should not focus disproportionately on chemical imbalances in the brain. Summarizing the allocation of resources for scientific inquiry on mental health, Hari writes “You could fill an aircraft carrier with studies on the brains of people with depression. You could fill an aircraft with studies on the social causes of depression. And you could fill a toy plane with studies on reconnection.”
I would like it if the authors of The Drug Hunters discussed some of the limitations major pharma companies face for treating mental health. Once again, this is not to deny that antidepressants help some people. But for many others, the side effects and dependency can cause their own host of problems.
The most invaluable insight from The Drug Hunters is that we can update our misconceptions about medicine. We make mistakes, sometimes we get things right by accident, sometimes theories have remarkable predictive power and we nail solutions. We are lucky to enjoy the cumulative benefits of former drug hunters. But our theories always stand to be updated and integrated. As philosopher of science and physicist David Deutsch argues, our best theories are always misconceptions at best. You don’t know what you don’t know. This book shows the human story of how we came to know some of what we do know.
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