HPS is pleased to present a clinical paper independently prepared by one of its key business partners. The views expressed in this article are those of the authors and do not necessarily reflect any opinion or view by HPS or its network of Pharmacies.

Biological medicines are agents manufactured in, extracted from, or semi-synthesized from biological sources and can be composed of sugars, proteins, nucleic acids or even living cells and tissue.1 Biological products encompass a vast array of vaccines, blood and blood derivatives, allergenic patch tests and extracts, HIV and hepatitis tests, gene therapy products, cells and tissues for transplantation, and new treatments for cancers, arthritis and other serious diseases.

The discovery, development and uses of biologicals are disease-genetic information dependent. In this review article we will look at the rag to riches evolution of biologicals.

The modern day concept of vaccination goes back to Edward Jenner, the English physician who in the late 1790’s noticed milkmaids were generally immune to smallpox. Jenner postulated that the pus in the blisters that milkmaids received from cowpox protected them from small pox which had a mortality rate of about 20%. Based on this observation he began small pox vaccination (a term he coined from Latin: vacca, a cow) by scraping pus from cowpox blisters onto the hands of children.2 In 1980, as a result of Jenner’s discovery and widespread success of vaccination, the World Health Assembly officially declared the world and its peoples free from endemic smallpox.

However, the history of antitoxins derived from the blood serum of animals used to treat certain diseases was not always that rewarding. In 1901, 13 children tragically died of tetanus when diphtheria patients routinely treated with antitoxin derived from the blood serum of horses contained tainted serum from the blood of a tetanus-infected retired milk wagon horse named Jim.3

In the 1950’s, the use of two batches of Jonas Salk’s killed polio vaccine led to 260 people contracting polio. This unfortunate occurrence, known as the “Cutter Incident”, was the result of live polio viruses being found in batches manufactured by Cutter Labs. Prior to this incident, the killed polio vaccine was deemed safe and efficacious after being tested in over 1.8 million children in what is the largest clinical trial of a drug or vaccine in medical history.4 By the late 1950’s, Albert Sabin theorized that a weakened, live-virus polio vaccine would provide longer lasting immunity. His vaccine was tested in field trials in the Soviet Union between 1957 and 1959, and was licensed in the US by 1962.5

The extraction and use of hormones and other biologicals from animals to treat human diseases goes back to the early 1920’s when a group of Canadian researchers: Prof. John James Macleod, Dr Frederic Grant Banting and two medical students, Charles Best and Clark Noble proved that diabetes is a disease of insulin deficiency.6 This led to the production of purified insulin from ox pancreas, and Eli Lilly in 1923 became the first insulin manufacturer.

The early 1920’s also saw the discovery and extraction of heparin from dog’s liver in the US by Jay McLean and William H. Howell. Yet it was not until 1936 when the Swedish company Vitrum AB launched heparin purified from beef lung for intravenous use.7

In 1937, Harvard physicians Arthur Patek and FHL Taylor published a paper describing anti-haemophilia globulin found in plasma. It could decrease clotting time in patients with haemophilia.8 Yet it wasn’t until 1964 when Robert Macfarlane, a British hematologist, described in detail the clotting process and paved the way for Judith Graham Pool, a researcher at Stanford University to isolate factor VIII from the cryoprecipitate left behind after thawing plasma. Such discovery opened the way for blood banks to produce and store the factor VIII, making emergency surgery and elective procedures for patients with haemophilia much more manageable.9

The 1950’s saw the extraction of growth hormone from the pituitary glands of cadavers to treat children with growth disorders.10 The dawn of the new age of modern medicine came about in the 1950’s when the pioneering work of James Watson and Francis Crick in unfolding bare the DNA molecular structure opened the doors of science to human gene therapy. Within twenty years of discovering DNA, work on recombinant DNA (r-DNA) began.11

In the early 1980’s, hepatitis and HIV were perhaps the most feared risks associated with blood transfusions, and Creutzfeldt-Jakob disease was the most feared risk associated with the use of growth hormone from cadavers. Thankfully, r-DNA and highly sensitive and specific nucleic acid-based tests allowed the presence of hepatitis and HIV to be detected rapidly. In June 1984, the Pasteur Institute identified HTLV-III virus as the likely cause of AIDS, and by the mid 1980’s the FDA licensed the first commercial blood test, ELISA, to detect antibodies to HIV in the blood. Blood banks begin screening blood supply.12 Licensing of the first r-DNA vaccine, Hepatitis B, the first recombinant human insulin, human growth hormone and human clotting factor VIII followed suit.

The last thirty-years has seen the accelerated development of various vaccines to protect against significantly virulent viruses such as hepatitis, human papillomavirus (HPV), and even chickenpox. But one virus still remains elusive to those seeking to create a vaccine to guard against it: HIV.

In parallel with the evolution of r-DNA, we also witness significant evolution in the development of monoclonal antibodies as well as their dramatic transformation from scientific tools to powerful human therapeutics.

Never was so much owed by so many to so few: the work by Georges Köhler & Caesar Milstein in producing monoclonal antibody using hybridoma technology13 and the elegant work by Niels Jerne discovering a plaque assay demonstrating a visual representation of antibody producing B cells14 changed medicine forever! The laboratory production of monoclonal antibodies involves the creation and culture of a hybrid cell in a selection media with the fusing of two cells: a B lymphocyte with specific antibody producing capability and a myeloma cancer cell which has the ability to grow indefinitely at a faster rate than normal cells to produce monoclonal antibodies at a large scale.

Muromonab-CD3 (orthoclone OKT3 by Janssen-Cilag) was the first monoclonal antibody approved by the FDA in 1986 as an immunosuppressant to reduce acute rejection in patients with organ transplants.

To date, the number of approved or in the process of being approved therapeutic, diagnostic and preventive monoclonal antibodies has surpassed 350, covering the treatment of numerous diseases such as rheumatoid arthritis, osteoarthritis, cancer, macular degeneration, multiple sclerosis and numerous infections including rabies.

All cellular organisms depend on stem cells for their developmental growth and survival. There are two basic types of stem cells: embryonic (or immature) and adult stem cells, and both have characteristic capabilities in organisms that include multicellularity, coloniality, and regeneration.15 Over the last thirty years adult stem cell research have played a pivotal role in the evolving medicine of bone marrow transplant and the treatment of refractory haematological cancers and immune disorders.

In conclusion, The German philosopher Immanuel Kant (1724–1804) has been credited with the following quote “Science is organized knowledge”. However, in research there are no final answers, only insights that allow one to formulate new questions for further research, even across generation gaps. This is beautifully illustrated by the joint award of the 2012 Nobel Prize in Physiology or Medicine to John B. Gurdon and Shinya Yamanaka for their discovery that mature cells can be reprogrammed to become pluripotent.

In 1962 developmental biologist J. B. Gurdon replaced the immature cell nucleus in an egg cell of a frog with the nucleus from a mature intestinal cell. The modified egg cell developed into a normal tadpole. The DNA of the mature cell still had all the information needed to develop all cells in the frog.16 More than forty years later, and armed with this knowledge, stem cell researcher S. Yamanaka conducted his brilliant 2006 experiment of introducing only a few genes, he could reprogram mature cells to become pluripotent stem -i.e. immature cells that are able to develop into all types of cells in the body.17 This observation has fuelled research over the last decade in the area of regenerative medicine.

Back to the future: Is reverse aging perhaps tomorrow’s reality?

References:

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  2. Hopkins, Donald R. The greatest killer: smallpox in history, with a new introduction. Chicago: University of Chicago Press. (2002). p. 80.
  3. Food and Drug Administration. 100 Years of biologics regulation. Silver Spring: Food and Drug Administration; 2009.
  4. Michael Fitzpatrick The Cutter Incident: How America’s First Polio Vaccine Led to a Growing Vaccine Crisis J R Soc Med. 2006 Mar; 99(3): 156.
  5. Lee Hampton Albert Sabin and the Coalition to Eliminate Polio Americas Am J Public Health. 2009 January; 99(1): 34–44.
  6. Krishnamurthy K. Pioneers in scientific discoveries (2002). Mittal Publications p.266.
  7. Barrowcliffe TW History of heparin Handb Exp Pharmacol. 2012;(207):3-22.
  8. Arthur Patek and FHL Taylor HEMOPHILIA. II. SOME PROPERTIES OF A SUBSTANCE OBTAINED FROM NORMAL HUMAN PLASMA EFFECTIVE IN ACCELERATING THE COAGULATION OF HEMOPHILIC BLOOD J Clin Invest. 1937 Jan; 16(1): 113–124.
  9. National Hemophilia Foundation. History of bleeding disorders. New York: National Hemophilia Foundation; 2013.
  10. Beck JC, Mcgarry EE, Dyrenfurth I, Venning EH Metabolic effects of human and monkey growth hormone in man. Science May 1957: 125 (3253): 884–5.
  11. Jackson, D.; Symons, R.; Berg, P. Biochemical method for inserting new genetic information into DNA of Simian Virus 40: Circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli Proceedings of the National Academy of Sciences of the United States of America (1972)69 (10): 2904–09.
  12. AIDS.gov. A timeline of AIDS. Washington: US Department of Health and Human Services, 2012.
  13. Köhler G, Milstein C Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7.
  14. NK Jerne. The somatic generation of immune recognition. Eur J Immunol. 1971-1-1-9.
  15. Chiranjib Chakraborty and Govindasamy Agoramoorthy Stem cells in the light of evolution Indian J Med Res. 2012 Jun; 135(6): 813–19.
  16. GURDON JB Adult frogs derived from the nuclei of single somatic cells. Dev Biol. 1962 Apr;4:256-73.
  17. Takahashi, K.; Yamanaka, S. Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell 2006 126 (4): 663–76.

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