A little perspective…

by Wells

While often we are quick to bemoan the molasses-like pace of medical discovery – perhaps especially those of us who work in the biomedical sciences – sometimes a little perspective is healthy.

The Guardian recently re-printed an article originally written in 1846 on the “most perfect success” of the use of ether as an anesthetic, the very concept of which was still quite novel to physicians at the time. While analgesics like laudanum had been available to Western physicians as early as the 15th century, the ability  to induce unconsciousness in patients on demand was  groundbreaking. Prior to ether – which, as it turned out, saw prolific use as an anesthetic for nearly a century after its inception – patients had a nasty habit of kicking, screaming, and being generally unhappy during painful surgeries. Not only did ether keep the patient still and motionless during procedures – a definite advantage from the surgeon’s perspective –  but it also afforded them some respite from the nightmarish pain that accompanied the procedure itself,  which some suggest may even help to reduce the psychological trauma associated with grievous injury and suffering.


The first successful human kidney transplant, performed at Brigham Hospital in Boston, MA. A triumph of modern medicine that would have been completely impossible without nearly fifty years of dosing people haphazardly with ether. Photo: Harvard Medical School

While we can now enjoy a smug chuckle at the disturbingly crude technologies available to the surgeons of the Victorian era, consider how much of medical progress would have been impossible without these initial arbitrary and likely dangerous applications of ether in the operating room. Some of the most magnificent life-saving interventions of the modern era, including organ transplantation and cardiac bypass surgery, would have been nothing but pipe dreams without the development of anesthesia and the field of anesthesiology that would later follow. That said, it was nearly fifty years before Alice Magaw, a nurse at what would later become Mayo Clinic, developed a consistent and reproducible method of dosing patients with ether prior to surgery. That’s fifty years before the medical establishment came up with a method better than “winging it” for the administration of a highly flammable organic solvent to human beings. Yet, without that half-century spent wandering in the woods with little better than a clumsy intuition of how to use ether, we would never have progressed to where we are today.

The truth is, a lot of modern medical practice still has yet to find their Alice Magaw. The disease that I study – Polycystic Kidney Disease – currently has no FDA approved therapy . Patients with the dominant disease are born with mostly normal kidneys that, over the course of many years, develop large fluid filled cysts that eventually destroy the architecture of the renal tubules and cause kidney failure by the 5th decade of life. It is a very common illness, affecting approximately 1 in 1000 individuals, and represents the most common genetic cause of kidney failure and the third most common cause of kidney failure overall. Currently, the only treatment available is supportive care for pain as the cysts expand, and dialysis and transplantation when the disease has progressed to end stage renal failure. It is a cruel and ugly disease – exactly the sort of affliction to which it is the mission of the biomedical sciences to find response.

Kidneys removed from a patient of Polycystic Kidney Disease. Combined, they weighed 22kg - almost 50lbs. Photo: the New England Journal of Medicine

Kidneys removed from a patient of Polycystic Kidney Disease. Combined, they weighed 22kg – almost 50lbs. Photo: New England Journal of Medicine

Physicians and patients alike were disappointed to learn that the first drug proven to successfully slow kidney growth and protect kidney function in patients with PKD, tolvaptan, was not recommended for approval by the FDA advisory committee for use in the treatment of Polycystic Kidney Disease. Despite its promise in clinical studies, the committee believed that the adverse events reported during the study were not worth what they perceived to be marginal improvements afforded by the drug. While the story of Tolvaptan is not yet over – indeed, there are many issues with the FDA’s evaluation of success, including how to effectively measure the performance of a drug in the treatment of a disease that takes nearly half a century to progress to the point of measurably impacting kidney function – it was a serious disappointment to a community of patients who are currently afforded no other hope by the medical establishment.

This place of frustration is one that is familiar to countless patients of a great many diseases, and to those who have made it their life’s work to treat them. Many diagnoses – like lupus , cystic fibrosis, and Huntington’s disease, to name just a few – bring with them little in the way of hope. For such diseases, just as is the case with Polycystic Kidney Disease, the therapies available are primarily supportive in nature and do nothing to address the root dysfunction that is behind the disease itself.

Indeed, the concept of addressing the specific molecular dysfunction behind the disease in a given patient (as tolvaptan is intended to for patients with PKD) is actually a fairly novel concept, and one that is the cornerstone of personalized medicine (a topic I plan to cover in future posts). It is a concept that was first brought to life by Linus Pauling in his seminal paper on the cause of sickle cell anemia. In it, Pauling and coauthors describe how the “sickling” of red blood cells in patients of the disease is caused by a defect in hemoglobin, the molecule present in red blood cells responsible for ferrying oxygen from the lungs to the various other tissues in the body. The notion that diseases have their roots in molecular dysfunction inspired the obvious question – what can we do to fix them?

TIME Magazine's coverage of the approval of imatinib for the treatment of chronic myelogenous leukemia.

TIME Magazine‘s coverage of the approval of imatinib for the treatment of chronic myelogenous leukemia.

It took fifty years before medical science found an answer. In 2001, the FDA approved imatinib (Gleevec) for use in patients with chronic myelogenous leukemia (CML). It was the first drug of its kind – unlike traditional chemotherapeutics, which act to inhibit  division or induce  death in a variety of rapidly dividing cells in the human body, imatinib’s activity was completely specific to the diseased tissues. This specificity comes from the mechanism of the drug’s action – it works by inhibiting an enzyme that is produced aberrantly in the cancerous cells, and which is also behind the progression of the disease itself.  Not only does this specificity spare the patient’s body from the devastating side effects that accompany traditional chemotherapy, but it also is behind the drug’s remarkable efficacy. Nearly 90% of patients with CML treated with imatinib were disease-free at 60 months – a rate of remission that can only be described as miraculous.

While imatinib is effective against only a small fraction of cancers, the proof of concept revolutionized the biomedical sciences. Indeed, the clinical trials of tolvaptan for patients with PKD could be considered its spiritual successors; like imatinib, tolvaptan’s action is specific for the sites of cyst growth in patients with the disease, and works by addressing a dysfunction that is believed to be at the root of the pathogenesis of the disease itself. Unfortunately, unlike imatinib, finding the right target will not be so easy. The molecular dysfunction behind PKD is far more complex and still poorly understood, as is the case with many diseases which are being actively researched in labs across the world.  Today, a wide variety of molecular therapeutics are being investigated for use in cancer, Alzheimer’s disease, and spinal muscular atrophy, just to name a few.

So, while many of us are frustrated with the inadequacy of available therapies for a variety of awful diseases that continue to take a terrible toll on patients across the globe, it is worth considering where we started and how far we have come. It took Dr. Brian Druker – the physician from the Oregon Health and Sciences University who championed the development of imatinib – nearly 10 years from the date of its patent to secure FDA approval for its use in patients with CML. This of course does not include the years and years of research that preceded the development of the drug, without which imatinib would never have seen the light of day. Given that it took nearly half a century to come up with a standardized method of administering ether, the pace of medical science today seems reasonable in comparison. With 2014 barely a day old, I look forward to going back to work with renewed vigor and enthusiasm for the tasks ahead of me. While the pace of medical discovery may be slow, it is most assuredly steady. That, I hear, is what wins the race.


Koch E. Alice Magaw and the great secret of open drop anesthesia.  AANA J. 1999; 67(1): 33-4.

Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. New England Journal of Medicine. 2012;367(25):2407-2418.

Pauling L, Itano HA, Singer J, Wells IC. Sickle Cell Anemia, a Molecular Disease. Science. 1949; 110 (2865): 543-548.

Pray L. Gleevec: The Breakthrough in Cancer Treatment. Nature Education. 2008; 1(1):37.