Microbes at Work
Written by Arushi Singh
The last century has witnessed an unprecedented advancement of medical breakthroughs, especially in drug discovery and design. This talk by Dr. Jennifer Kerr of Notre Dame of Maryland University took a historic look at how biopharmaceuticals started, focusing on origin stories of antibiotics and insulin.
Antibiotics were an instrumental discovery in the world of science because they kill bacteria and thus can combat infections. Alexander Fleming is nicknamed the “father of antibiotics”, but there were some key predecessors, like Paul Ehrlich and Gerhard Domagk, who aided in their discovery. Fleming is credited for this discovery due to an accidental finding. One night, he left a petri dish of bacteria open in his lab space. Inadvertently, mold grew and contaminated the sample. Fleming noticed a “zone of inhibition”, or area of no bacterial growth, around where the mold had overtaken. This suggested the mold was creating a substance inhibiting bacterial growth. It did so through a mechanism of action that targets the bacterial cell wall and prevents repair. Fleming ultimately isolated this compound and discovered Penicillin in 1928.
Notably, Penicillin production stalled until the 1940s and there still were hiccups in mass production of the drug. In anticipation of the mass casualties expected in World War II, the UK and USA collaborated on the mass production process and stabilization of Penicillin. Oxford scientists, Dr. Ethel Florey and Margaret Jennings, were instrumental in Penicillin production and purification clinical trials leading up to D-Day. The company Pfizer was involved as well and developed deep citric acid fermentation tanks for large-scale antibiotic production. These initiatives not only aided in the war effort, but also increased antibiotic production and overall yield harvesting substantially. So much so that by 1945 anyone could receive Penicillin, not just the military.
However, antibiotic resistance followed shortly after. Professor Mary Barber was one of the first to detect microbes becoming resistant to Penicillin. Luckily Dr. Selman Waskman and Elizabeth Bugie were hard at work looking for other sources of antibiotics. They systematically screened soil cultures and determined zones of inhibition specifically for pathogenic bacteria and landed upon the antibiotic Streptomycin. Importantly, Streptomycin killed bacteria that were shown to be resistant to Penicillin. The compound was derived from the genus Streptomyces which nowadays supplies half of the global antibiotic supply.
The 1950s became known as the golden age of antibiotic discovery, but unfortunately, scientific advancement has weaned off in recent decades. Antibiotic resistance, on the other hand, has been on the rise, as has antibiotic misuse. In recent years, the WHO has labeled antimicrobial resistance (AMR) an ever-pressing problem for science. Low trial passage, long drug discovery to approval pipeline, and decreased pharmaceutical incentive for profit have hindered development as well. Dr. Kerr also demoed a PEW research model which highlighted the bleak outlook of antibiotic production over the upcoming years.
The seminar switched gears to discuss the role of microbes in another health area. Diabetes occurs when the pancreas cannot create enough insulin to adequately control blood sugar. Sugar in the blood can cause damage across the body in addition to adverse symptoms like frequent urination, excessive thirst, and feeling lethargic. There are variations of the disease. Type 1 diabetics don’t have the necessary cells to produce enough insulin on their own, while Type 2 occurs when the body has developed a resistance to heightened levels of insulin over time.
In the past, Type 1 diabetes was a death sentence early on in life because no one knew the true origin of the disease or how to cure it. Dr. Frederick Banting, John MacLeod, Charles Best, and Gladys Boyd were true pioneers in this regard. In 1921, their research team determined the use of the pancreas in experiments with dogs and began insulin treatment in humans. They found that dogs died shortly after the removal of their pancreas. However, the researchers were still able to keep the animal alive by supplementing it with a pancreatic extract. This pointed them to treatment in human diabetic patients. Nevertheless, insulin harvesting and purification from animal pancreas were extremely inefficient. To get one pound of insulin, the pancreases of 23,500 animals were needed. That totaled 56 million pancreases per year.
It wasn’t until the 1980s that pharmaceuticals searched for a new mechanism of insulin creation using recombinant DNA methods. Recombinant DNA combines DNA between different organisms for expression in a non-originating host species. A modified vector is then put into the host cell. However, the DNA sequence for insulin was not yet discovered, though the 51 amino acid sequence had been determined, courtesy of Dr. Frederick Sanger. Dr. Rosalyn Yalow, Keiichi Itakura, Arthur Riggs, and Herbert Boyer then used immunoassay to detect insulin amounts and reverse engineered the DNA sequence. In addition to DNA expression there was further complex assembly required to fully create active insulin. Finally, Humulin R was developed in 1982. There were further refinements and tweaks to the process which drove down costs.
However, in recent years, different patents and variations of insulin, such as fast/slow acting or different periods of activity, have made insulin prices unattainable for many. This has led to calls for a price cap for insulin and other life-saving drugs. Further discussion occurred at the end of the seminar session regarding what can be done about this. Dr. Kerr suggested getting involved and having general awareness about what’s going on in your community. She also plugged the BUGSS Open Insulin initiative, which aims to create safe insulin as an affordable alternative to what’s on the market. Learn more about Open Insulin at BUGSS here: https://bugssonline.org/