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Biopharmaceuticals
The vast majority of pharmaceutical products are compounds derived either from synthetic
chemical processes, from naturally sources (plants, microorganisms), or combinations of both. Such
compounds are used to regulate essential bodily functions or to combat disease-causing microorganisms.
Limited quantities of some of these have historically been derived from organs of animals and from
blood. Now genetic engineering helps to produce some of these molecules in unlimited quantities. In
practice this involves inserting the necessary human-derived gene into suitable host microorganism that
will further produce the therapeutic protein (biopharmaceutical) in quantities related to the scale of
operation.
The first human gene sequences encoding important therapeutic proteins, cloned into
microorganisms, were insulin, human growth hormone (somatostatin) and the interferons.
Thus, there are millions of people in the world who need regular intakes of insulin to overcome the
lethal effects of diabetes. Insulin extracted from pigs and cattle has long been the source of worldwide
usage, and some unfortunate side-effects have occurred due to additional contaminating compounds
presented in the animal insulin. Recombinant human insulin has not such problems and now has the
largest market share of sales.
The growth hormone, somatostatin, has been extremely difficult to isolate from animals; half a
million sheep brains were required to yield 0,005 g of pure somatostatin. By cloning the human gene for
somatostatin into a bacterium, the same amount of hormone can be produced from 9 litres of a transgenic
bacterial fermentation. One child of 5000 suffers from hypopituitary dwarfism resulting from growth
hormone deficiency and easy availability of this biopharmaceutical will be of immense benefit to these
child sufferers. The annual world market is estimated at $US 100 million.
In 1957 two British researchers discovered substances produced within the body that could act
against viruses by making cells resistant to virus attack. Most vertebrate animals can produce these
substances, known as interferons, and many animal viruses can induce their in vitro synthesis and become
sensitive to them. However, only small amounts of interferon are produced within cells, and it is very
difficult to extract and separate them from other cellular proteins.
Human interferons are glycoproteins (proteins with attached sugar molecules) and they control
many types of viral infection, including cancer. They attack the cancer cells by inhibiting their growth,
and they can also stimulate the body’s natural immune defences against the cancer cell.
There are many different types of interferon characteristic of individual species of animals; mouse
interferon will respond to mouse cells but not human cells, and vice versa. Furthermore, different tissues
from the same species produce different interferons. Thus, interferon for human studies must be derived
from human cells (primarily, using leukocytes from blood).
Two sources of interferon are currently available. The first is from human diploid fibroblasts
growing attached to a suitable surface. The second source is from bacteria in which the gene for human
fibroblast interferon has been inserted into a plasmid in such a manner that interferon is synthesised and
then extracted and purified.
Lymphokines are proteins produced by lymphocytes (part of the body’s immune system) and are
important to immune reactions. They have a capability of restoring the capacity of the immune system to
fight infectious diseases or cancer. Interleukin-2 at present offers the greatest potential and is now
produced by genetic engineering.
At present, all biopharmaceuticals are produced by way of genetically engineered mammalian cell
or microbial fermentations. However, with the development of transgenic animals (Chapter 10) it has
become possible to produce certain human proteins of biopharmaceutical potential, including tissue
plasminogen activator, blood clotting factors, etc. In the lactating glands of several animal species, such
as mouse, cow and pig. These products can then be more easily extracted and purified.
An American company can now produce human haemoglobin in the blood of transgenic pigs that
could therefore serve as a human blood substitute. This transgenic haemoglobin is free from human
pathogens such as HIV and it does not need matching before transfusion because it is not composed of
red blood cells.