A vaccine is made of either the whole or part of bacteria that causes a disease or virus. Thus, they come from biological organisms. Due to their living sources, the vaccines are classified by the FDA as part of a larger category known as biologics. Biologics encompass far more than vaccines and differ from traditional pharmaceuticals, in that biologics are proteins that can either trigger a similar response or directly attack the medical defect. This category includes everything from blood transfusion products to cellular and genetic therapy technology.
History of Biologics: Rural Origins of a Booming Industry
Smallpox was once one of the most widespread and dangerous diseases to ever afflict humanity. Today, however, smallpox has been eradicated and is now discussed more as a potential biological weapon. This transition is important to medicine because smallpox vaccination is the first documented use of biologics  (Fig. 1).
The first recorded research in biologics began in the 1770's, when a doctor in rural England researched the use of viruses to prevent against related diseases. Dr. Edward Jenner exposed a test subject to the cowpox virus. After allowing the eight-year-old boy's immune system enough time to process the contaminant and build antibodies to fight it, Jenner then exposed him to smallpox. As the boy did not contract smallpox from his exposure to the virus, Jenner discovered the first use of a biologic treatment in the form of a vaccine .
More recently, the world of biologics has produced numerous vaccines and has expanded to include novel therapeutics to directly combat medical disorders. Founded in 1976 in San Francisco, the first modern biologics company was Genentech. This new step in biotherapeutics proved that genetically altered bacterial cells could produce the necessary proteins for biologic treatments .
How Biologics Work: Mechanics of the Medicine
Development of a biologic product begins with the identification of a protein which, when inserted into the body, will help to correct a medical disorder. Subsequently, the DNA that codes for this protein must be separated from the rest of the DNA strand .
This feat is accomplished by utilizing enzymatic proteins known as nucleases, which cleave the double-stranded DNA molecules at specific sites. Once these gene coding segments have been separated, their genes can be expressed and studied to determine which segment codes for the desired protein .
After isolating the desired gene, the DNA segment must be inserted into a cell where it can be expressed and the protein produced. This is performed by a process known as DNA cloning. To clone a segment of DNA, plasmid vectors (small circular DNA molecules) are cut by a nuclease and the desired gene is inserted. Host bacterial cells are subsequently transformed by the insertion of the DNA plasmid vectors into the cells .
With the gene coding for the desired protein successfully integrated into host bacteria, the next steps of biologic formation are fairly straightforward. The genetically engineered bacterial cells are grown on a nutrient-rich medium, which enables them to proliferate and produce the desired protein. Once the bacterial colonies have reached a sufficient size, the cells are split open (lysis) and the protein to be used for treatment is isolated, properly stored, and distributed to physicians .
The biologic is then ready to be put to use in the patient. In the case of a vaccine, the injected protein is a mild form of the disease-causing antigen. In this case, the biologic stimulates production of antibodies, the proteins that bind antigens, and macrophages, the cells that destroy antigens. Although their numbers gradually dwindle, these soldiers of the immune system remain in the body indefinitely, which ensures a rapid response should the patient ever be infected by the full-strength antigen .
In other cases, the biologic proteins directly attack the problem at hand. As seen in the treatment of diabetes, the administered insulin proteins immediately fill the void caused by the lack of naturally occurring insulin and reduce the amount of glucose in the blood .
Manufacturing: Producing the Proteins
By relying on biologically cultured organisms to produce biologic treatments, the manufacturing of these therapies differs greatly from the traditional small molecule chemical medicines of the pharmaceutical industry.
Traditional chemical medicines are produced very simply; laboratory technicians conduct chemical reactions followed by purification techniques to produce the desired product. Although these laboratory procedures have the potential to be quite complex, the principle behind pharmaceutical manufacturing is simply to combine the necessary chemicals. In contrast, biologics production is far more complex.
As previously noted, biologics are protein-based treatments that must be grown in living cells and subsequently purified. Small-scale production of desired proteins is common practice in collegiate biology labs, but to produce the quantities necessary for widespread treatment, the production techniques must be modified drastically.
A manufacturing plant on the scale of Amgen's Longmont, CO, manufacturing facility cannot use small Petri dishes to produce its whole supply of biologics. To remedy this problem, the scale of protein production is gradually increased. Laboratory technicians produce the first colonies of modified cells through traditional laboratory techniques, incubating the cells to promote reproduction. These initial colonies are repeatedly inbred to ensure they will maintain purity of the colonies. Subsequently, the colonies are transferred to immense vats for large-scale fermentation. Here, the cultures grow for approximately two weeks to ensure sufficient quantities are produced .
Extensive research and experimentation must be conducted to determine the proper conditions for culture fermentation. Bioengineers, molecular biologists, and other scientists must work to determine the proper nutrient media, correct acidity, precise temperature, and the length of time necessary for the cultures to grow to the requisite density for harvesting. Without this detailed research and testing, the cell cultures may not reach the proper state of maturity at which the protein in question has been generated in the necessary levels .
After the cell cultures are extracted from the fermentation vats, the protein desired for the biologic therapeutic must be purified from the rest of the cells. These processes are the same as those used in simple laboratory exercises, only on a much larger scale. Chromatography, discussed above, is the most common form of purification .
The technology of biologics production is continually developing. ATMI LifeSciences and DCI-Biolafitte are set to debut their joint effort to advance the manufacturing of biologics at the upcoming biotechnology trade show in Philadelphia .
Future of the Field: The Next Generation
In looking to the future of biologics, it would be easy to delve into the world of science fiction and fantasy and picture a cornucopia of natural cures for every known disease. This cannot be the case, but biologics do appear to be the fastest growing sector of the medical industry.
Since the incorporation of Genentech in the 1970's, the proportionately small scope of biological products has expanded greatly. The product range of biologics now includes treatments for such widespread ailments as hepatitis C, arthritis, and breast cancer. With this growing platform of biologic medicines and the several hundred potential therapies currently being researched, even insurance companies have realized the growing importance of biologics and are adapting their policies accordingly .
New developments in biologics are leading to more focused cancer treatments that target specific cancerous cells, as well as treatments custom-tailored to each patient. Novel therapies for cancer are desperately needed as the fight against life-threatening mutations continues daily with little hope of a cure in many cases. If the individually designed treatments currently being researched prove applicable, the survival rates of many currently debilitating ailments could skyrocket.
Thus, as the field of biotechnology grows and matures, it promises the development of biological medicines with the potential to drastically alter the course of modern medicine and its future.
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