We are proud to practice medicine in the modern era: the 21st-century heirs to Hippocrates. Along the way we have abandoned a materia medica of bizarre and unusual therapies like mummy powder and eye of newt. Our pharmaceuticals are lined up in bottles and bags with clearly marked expiration dates. It’s a far cry from the witches in Macbeth, standing around the fire chanting:
Round about the cauldron go;
In the poison’d entrails throw.
Toad, that under cold stone
Days and nights has thirty-one
Swelter’d venom sleeping got,
Boil thou first i’ the charmed pot.
Double, double toil and trouble;
Fire burn and cauldron bubble.
Or have things really changed? We would shake our heads at the remedies of Shakespeare’s son-in-law, Dr. John Hall, who used spider webs, poultry larynx, and animal excreta as part of his materia medica. But wait: Perhaps we should think twice before condemning him. Perhaps we are less different then we think. We just use similar products that have been sanitized.
Some modern medicines retain their strong biotherapeutic flavor. The field of organotherapy led to the extraction of active elements from the glands of mammals and eventually insulin, thyroid extract, growth hormone, testosterone, and adrenaline. The modern forms of these drugs are just a few steps removed from their origins, but somehow don’t strike one as unusual. Read on to see how we use such non-mammalian biotherapeutic exotica as lizard spit, salmon sperm, and leech saliva as part of the most modern pharmaceutical armamentarium.
How unlikely would it seem, but all too true, that the newest weapon in the fight against diabetes is derived from lizard spit? The lizards in question are Heloderma horridum and Heloderma suspectum (aka the Mexican beaded lizard and the Gila monster).
This strange tale begins in the Bronx, N.Y., not renowned (aside from the Bronx Zoo) as a home for Sonoran lizards. Cockroaches and rats may be the dominant fauna there. Dr. John Eng, an endocrinologist, was hunting for new hormones. In the venom of the beaded lizard he discovered a vasoactive hormone he named exendin-3. In the venom of the Gila monster he found the less vasoactive exendin-4, which seemed to have an interesting effect on beta cells.
Dr. John Eng eventually patented exendin-4, and now we have the newest drug on the market for the treatment of diabetes. The first of class of incretin mimetics, synthetic exendin-4, is also known as exanatide and marketed as Byetta. Administered as a twice-daily injection, exanatide stimulates beta cells, via a specific receptor, to secrete insulin in a glucose-dependent fashion, suppresses glucagon overproduction, slows gastric emptying, and improves satiety. The net result is that most patients experience improvement of glucose control and weight loss. The most common side effects are nausea, which tends to be moderate, self limited, and a result of hypoglycemia. As with any new drug, side effects may still be determined over time. As of yet there have been no reports of reptilian metamorphosis
The sperm of salmon is worth mentioning here as a bridge between diabetes and the treatment of coagulation disorders. An important step in the biotherapy of insulin depended on salmon sperm. Salmon sperm contains protamines, which are small arginine-rich nuclear proteins that stabilize DNA. Salmon sperm was used because it is more easily obtained than some mammalian alternatives.
When we write prescriptions for NPH insulin, how often do we contemplate what those initials represent? The acronym stands for neutral protamine Hagedorn. In 1923 Hans Christian Hagedorn (a Danish physician, 1888-1971) and August Steenberg Krogh (a Nobel-prize winning physiologist, 1874-1949) obtained the rights from Sir Frederick Grant Banting (1891-1941) and Charles Best (1899-1941), who had first isolated insulin, and formed a company called Nordisk Insulinlaboratorium to produce insulin for Scandinavians. Krogh’s wife, Marie, was diabetic.
Ten years later Hagedorn and Jensen discovered that injection of insulin would have a prolonged effect if mixed with protamine-rich salmon sperm. The necessity of a pH of 7 for activation made the handling of insulin difficult. Zinc was added to the mix as a stabilizer. By 1946, an easier-to-use crystallized form was developed, and it was marketed by 1950 as NPH insulin.
When a patient is overdosed with heparin, excessive bleeding can be a problem. Protamine sulfate is a valuable medication used for reversal of heparin. Protamine is a strongly basic substance that combines with the strongly acidic heparin to form a stable complex. The protamine-heparin complex is not an anticoagulant; protamine causes a dissociation of the heparin-antithrombin III complex, resulting in loss of heparin’s anticoagulant activity. Given too quickly it may cause hypotension or anaphylaxis and may cause allergic reactions to patients with fish hypersensitivity.
From the anticoagulant effect of salmon sperm, we move to the world of Annelida. More than any other creature, the leech stands out as the epitome of biotherapy. Its name alone, Hirudo medicinalis, emphasizes its medical nature. Used by many ancient societies, the leech reached its zenith in mid-19th century France. Leeches were the fashion, women’s dresses were decorated with faux leeches, and cosmetics were applied to give that “healthy pale look” sometimes attained by being bled with leeches.
In 1833 more than 40 million leeches were imported into France. However, the leech’s days were numbered. The biggest blow was when Pierre Louis made his name as the father of medical statistics by proving leeches led to a worse outcome in treating pneumonia. The death of the leech was the birth of evidence-based medicine.
But all is not lost for the leech lover. The use of the leech as an anticoagulant was recognized in 1884. In its modern chemical form, recombinant leech saliva marketed under names such as lepirudin, is indicated for coronary thrombolysis, unstable angina hemodialysis, heparin-induced thrombocytopenia, and DVT prophylaxis. Recombinant hirudin, a man-made chemical similar to leech saliva, is manufactured in large quantities and is much easier to obtain than “milking” leeches. The mechanism of action is direct inhibition of thrombin. Leeches are making a comeback in the treatment of skin grafts, however. A mechanical leech has also been designed.
The argument for the protection of our planet’s biodiversity could not be more obvious. A new treatment for diabetes comes from Gila monsters. What novel substances lurk in the ever-shrinking rain forests? Whether from lizard or leech, the day of biotherapy is not yet done. Despite all this, I’m not cornering the market on synthetic eye of newt. TH
Jamie Newman, MD, FACP, is the physician editor of The Hospitalist, consultant, Hospital Internal Medicine, and assistant professor of internal medicine and medical history, Mayo Clinic College of Medicine, Rochester, Minn.