We just finished discussing the antibiotics revolution, which allowed physicians to
successfully treat many of the infections that had killed billions of people over the millennia.
Bacterial infections, once the number one world killer, have now more or less disappeared from
the top-ten list of killer diseases, at least in the developed world. In this top-ten list,
we now find conditions such as heart disease, stroke, chronic obstructive pulmonary disease,
cancer, and so forth. As we discussed in the introduction to this series, the average human
life span increased dramatically in the 20th century, specifically due to our newfound
ability to combat pathogens with antibiotics and a booming immunization program. But with
infectious diseases sharply reduced in severity, these other conditions now present themselves as
more difficult to tackle, because they are not due to an invading pathogen, but rather to the
intrinsic limitations of human biology and the aging process. For the rest of the series, we will
focus mainly on the ways that mankind has been approaching the treatment of these conditions,
and we will start with diabetes mellitus. Although diabetes was described in ancient times,
it was probably not a very common condition. There was no effective treatment against it
until the 20th century, so a diabetes diagnosis was a death sentence. Today, diabetes affects
about 300 million people worldwide, and seems to be, at least in part, the product of an unhealthy
lifestyle. Luckily, many effective treatments are available, and most patients are able to live a
normal life with a drug-based management protocol. The story of diabetes begins in ancient Egypt,
with the first documentation of the condition and the first attempts at a cure. Earlier we
mentioned German Egyptologist Georg Ebers, who acquired the famous papyrus that bears his name
in 1872. The Ebers Papyrus is one of the most important early documents of the ancient practice
of medicine. Written around 1550 BCE, it was probably copied from much older documents. The
Ebers Papyrus describes diabetes as a condition in which patients eliminate plentiful urine,
a hallmark of diabetes we now call polyuria. The following mixture was prescribed as treatment:
“a measuring glass filled with water from the bird pond, elderberry, fibres of the Asit plant,
fresh milk, beer-swill, flower of the cucumber, and green dates”. There are no modern studies
to confirm or refute this treatment, perhaps in part due to the difficulty of collecting these
unusual ingredients. However, it is reasonable to speculate that this bizarre concoction did not do
much to address the underlying causes of diabetes. The Egyptian tradition had a strong influence on
ancient Greek medicine. Although Hippocrates, the “father of medicine”, did not use the word
“diabetes”, there are references in his work to “excessive urinary flow with wasting of
the body”. Hippocrates must be credited with the concept of preventive medicine.
He stressed the influence of diet and exercise on good health, and this is still one of the
most important tools in preventing metabolic diseases like diabetes. In the Roman empire,
Galen and Aretaeus introduced the term “diabetes” from the Greek word for “syphon”. They described
the rare disease as a “melting down of the flesh and limbs into urine”, and noted that the urine
tasted sweet. There were actually urine tasters in those days, specializing in diagnosing the
condition and its severity. The Hindus had noted this phenomenon much earlier than the Greeks and
had named the condition “honey urine”. Upon noticing the attraction of ants to the urine
of diabetic patients, they used ant attraction to urine as a qualitative test for diabetes.
No progress was made regarding the cause of the disease during the Middle Ages. Maimonides,
in the 12th century, proposed that diabetes was caused by “the sweet waters of the Nile and the
resulting heat that spread over the kidneys”. We have already discussed Paracelsus and the
Renaissance period as one in which speculative medical knowledge was rejected, and a movement
was born to introduce experiment-based medicine. Thomas Willis, an English physician, was the first
to propose, in the 17th century, that diabetes originated in the blood and not the kidneys,
as diabetes patients had elevated glucose levels in the blood as well. However, the conclusive
experimental phase did not begin until the 19th century. At the close of the 19th century,
German physiologist Oscar Minkowski demonstrated conclusively that removal of the pancreas from
a dog resulted in the sudden onset of diabetes, followed rapidly by death. In 1869, 22-year old
German biologist Paul Langerhans discovered the site in the pancreas which was responsible for
glucose control, and his work was presented as his doctoral dissertation at the University of
Berlin. In his honor, this key region of the pancreas is now named “islets of Langerhans”.
So at the turn of the 20th century, it became clear that a mysterious substance, probably a
hormone, was secreted by a known region of the pancreas, and that the hormone, which we named
insulin, after the islets where it was produced, was responsible for controlling glucose levels
in the blood. We now know that Type 1 diabetes is caused by the inability of the pancreas to
produce insulin, and Type 2 diabetes is caused by the resistance of an organism to insulin action.
Unfortunately, all attempts to extract insulin from pancreas cells only led to the hydrolysis
of insulin by the enzymes in the pancreas. The hormone was apparently a peptide, and it took a
few decades before a group of Canadian scientists, working at the University of Toronto, succeeded in
the long-sought isolation. In 1921, young Canadian medical researcher Frederick Banting, working in
the laboratory of Professor J. J. MacLeod, decided to extract the pancreas from dogs,
but he added a procedure called pancreatic duct ligation, which effectively destroys the cells
responsible for secreting trypsin, the enzyme responsible for degrading insulin. Without the
trypsin-secreting cells, insulin remained stable and could be isolated. Injecting this hormone into
sick animals, and then diabetes patients, had dramatic effects. Insulin’s ability to
restore health was so dramatic that its effects were described in colorful terms, such as ‘‘the
raising of the dead.’’ Two years later, in 1923, Banting and MacLeod were awarded the Nobel Prize
for Medicine, a year after Banting had received his MD degree. Banting was also knighted by King
George V in 1934, and received an annuity from the Canadian government to continue his research.
Insulin was generally extracted from the pancreas of animals such as pigs and cows in order to treat
patients. The hormone was administered by injection because it was not stable enough
for oral administration. In 1926, insulin was crystallized, and this allowed the preparation
of a much purer product. It was another 30 years before the amino acid sequence was determined.
In 1951, British biochemist Frederick Sanger unveiled the structure of insulin, for which
he was awarded the Nobel Prize in Chemistry in 1958. He was one of only two chemists to
receive the Nobel Prize twice, the second time for his contributions to nucleic acid chemistry.
The human insulin protein is composed of 51 amino acids. It is a heterodimer,
composed of two chains: an A-chain and a B-chain, which are linked by two disulfide bridges. A
third disulfide bridge is located within the A chain. Upon isolation of insulin from animals,
it became clear that the sequence varies slightly between species. Insulin from pigs is especially
close to the human version, as it differs only by replacement of the C-terminal amino acid of the
B chain, which is threonine in humans and alanine in pigs. Insulin from cows differs by three amino
acid substitutions. Their biological activity in humans is very similar but not identical.
In the 1960s, insulin was also prepared by total synthesis, and its 3-dimensional structure was
elucidated via X-ray crystallography by Dorothy Hodgkin. With the advent of recombinant DNA
technology, pharmaceutical companies introduced human insulin produced by bacterial fermentation
of genetically engineered E. coli, which is still the most practical and cost-effective way
of producing insulin. Large scale-production of insulin to treat diabetic patients is now heralded
as one of the greatest scientific accomplishments of the 20th century, which suddenly enabled
many patients to live a relatively normal life. We should not forget, however, that in the 1980s
there was a violent backlash by anti-science groups against recombinant DNA technology,
and the production of human proteins by bacterial fermentation. Oddly, the anti-science lobby seemed
to prefer seeing cows and pigs slaughtered and chopped up, rather than to allow the “unnatural”
insertion of a foreign human gene into a bacterium, which is now a routine practice.
The same political forces and activists aligned against GMOs today were already at work back then.
One of the main actors was senator Ted Kennedy. In 1975, he called for hearings to tightly regulate
recombinant DNA research, and he proposed that any federally-funded scientist who did not obey
his regulations should lose their NIH grant. This so-called “high-risk research” was actually banned
at Harvard and MIT, until the scientists installed a number of strict security measures. In 1982,
Eli Lilly & Co. submitted a New Drug Application for recombinant human insulin, or Humulin,
using a GMO. It was immediately approved. Human insulin is now readily available,
despite the anti-science backlash. In spite of its successful applications,
insulin is not a panacea against diabetes. People with diabetes are at increased risk
for the long-term development of complications like blindness, kidney failure, heart disease,
and stroke. The severity of these conditions is tightly related to the duration of episodes
of uncontrolled high blood glucose levels. However, when diabetes is treated with newer
formulations of insulin, designed for controlled delivery, or with the use of modern devices,
which sense the level of glucose and meter the exact amount of insulin to keep glycaemia
within a narrow range, the side effects of high blood glucose can be successfully mitigated.
Chemists have also been hard at work to improve the properties of insulin by modifying its
structure. One example is insulin glargine, developed by the company Sanofi-Aventis,
and marketed under the trade name Lantus. Insulin glargine differs from human insulin
by the presence of a glycine residue instead of asparagine at position 21 of the A-chain,
and by extension of the carboxy-terminus by two additional arginine residues. This does not alter
the biological properties of insulin, but shifts the isoelectric point from a pH of 5.4 to 6.7,
imparting more desirable solubility properties to the molecule. This allows for the subcutaneous
injection of a clear solution, with a desirably slow absorption from the
site of injection without peaks and troughs for about 24 hours, resulting in a superior product.
Today there are many other options for the management of diabetes,
and some of these will be discussed over in the pharmacology series. But thanks to this progress,
diabetes is often considered a minor ailment, treatable to the point that many patients do not
approach their condition with the attention it requires and suffer the often dreadful
consequences. It is quite easy to forget that, until 100 years ago, a diabetes diagnosis was a
death sentence. This situation persisted till Banting’s and MacLeod’s isolation of insulin,
an event of extraordinary importance in the history of medicine and science in general.