Friday, December 9, 2016
EVOLUTION AND PHARMACEUTICALS
Evolution and Pharmaceuticals
During the course of the evolution of life on earth, species were faced with many challenges. Over time, a mold tailored a chemical to a point where it prevented bacteria from interfering with its growth. Alexander Fleming noted that inhibition of bacterial colonies on a petri dish around a fungus that contaminated the culture. The happy accident and his observation of the effect of penicillin led to many searches for other fungi that might be producing other antibiotics.
We have a more versatile bacteriafighting method in our immune system. It can even fight against toxins, given the right circumstances. We can induce other mammals to produce antivenoms in their serum to combat potentially lethal snakebites when injected after a bite. Are there other marvels of nature waiting to be discovered by our pharmaceutical industry?
Groups, especially sponges, that are attached to the sea sediments or rocks, have an evolutionary history of over half a billion years. Their major defense against microorganisms such as bacteria may include physical barriers, such as mucus secretion, but there has been a wide assortment of toxic materials, some of which provide protection against predators and others probably against microorganisms. It seems such knowledge could provide a wealth of useful products. I think the major thrust has been to look for anticancer activity in such products.
EVOLUTION: CONTROL OF SPEED AND DIRECTION
Control or lack thereof
The hereditary changes determining the speed and direction of evolution are not subject to control nor are they controlled by some foreseen outcome of the process of natural selection. Many possible random events producing changes in the DNA produce a range of possible variations in individuals. The survival value may be valuable in one habitat, but detrimental in another. When the habitats occur in different parts of the range, the one species may become two or more species as accumulations of differences become great enough that the extremes can no longer interbreed successfully with each other.
The survival or death of a variant may be due to chance meeting with a predator. A falling rock may select traits by eliminating those of individuals too slow to see and escape, but its selective action would be random for traits not involving sensing its approach and facilitating rapid evasion.
In the billion years animals have existed, and the millions of species present now and during many of those billion years, there have been uncountable selective events resulting in compounds useful for survival, and far greater numbers of events that were useless or harmful. But the harmful ones reduce the chances of their bearers surviving. The result - many millions of possible useful substances still to be discovered are out there in nature.
Speed of evolutionary change
Early in the evolutionary lineage of groups of related organisms change was probably quite rapid as compared to groups that have not radiated into all available habitats. Well adapted species may change very little. This is evident in the fossil record. One of the more astounding ones is Lingula, a brachiopod living today, whose shell is much the same, except for size, as a Pre-Cambrian fossil brachiopod shell.
The speed of evolution of things affecting survival can be quite rapid when there are great differences in survival value involved. Most fish are well streamlined, so little drag enables easy progress through the water. Birds are also streamlined, but their streamlining is of most value at high air speeds. Natural selection maintains the streamlining for both fish and birds.
Direction of evolutionary change
Different species of the same group may be evolving in different directions. For example, most mammalian groups, such as rodents, carnivores, and primates have radiated into different sizes. Those particular examples have mostly started from relatively small ancestors. But several vertebrate groups show the largest species are only known from fossils. Direction is not typically linear. The long ancestral line from early life to us and most higher animals went through a regression from annelids to the pogonophorans before advancing to the groups leading to the vertebrates.
The genetic basis of the above
Most inherited characteristics of animals are multifactorial, that is multiple locations on the DNA may affect the expression of the characteristic. Some may have one locus that may have an all or none effect on the expression of a characteristic. Other characteristics may have more complicated inheritance. All aspects of a species are subject to evolution; besides physical and physiological features, life style, life cycle, and other features evolve, sometimes independently, but often in conjunction with other features. Improvement in one aspect of our physiology can have far reaching effects in many systems. Conversely, diseases are often characterized by many symptoms.
Sickle cell anemia is an example where the substitution for one particular amino acid in a long hemoglobin chain modifies the structure of the hemoglobin molecule. Heterozygous individuals have less expression of the gene into the fibrous form, but their red cells have enough to provide protection against growth of malaria parasites. So natural selection maintains the disease in areas where malaria kills many without the gene, and the disease kills many homozygous for the gene (i.e., inheriting it from both parents). But in areas where malaria is not present, the frequency of the gene is expected to diminish due to higher mortality of those with the disease.
Environmental control of gene expression
One of the examples of environmental control are the two color-phases of animals in arctic and subarctic locations. In summer, several species of mammals and birds have fur or feathers of darker colors than the white shown in the winter. It is protective coloration for prey species with the seasonal change, as well as enabling predators to have greater success in getting closer to prey before they are alarmed. Apparently, the colder temperatures prevent expression of the pigmentation genes.
I suspect my white hair is a result of lower activity resulting in skin temperature needed to make the melanin for my long-gone youthful dark hair; the benefit is many young people holding the door for me.
EVOLUTION AND PHARMACEUTICAL COMPANIES
Quasi-genetic control of gene expression
The existence of introns and exons suggest a possible mechanism of graded responses of genes since so much of the DNA is not serving as a template for RNA producing the physiological and/or structural biochemical actions of the genome. Think how the length of the “inactive” space between genes may moderate or accelerate reaction to an adjacent promoter or inhibitor gene.
The enzymes acting are usually proteins with an active site held in appropriate form by seemingly inactive parts of the molecule. The inactive parts have parts that can undergo substitutions of minor portions that may not have much effect on action. Hormones may have similar flexibility.
Drug manufacturers take advantage of such flexibility to produce new versions of medications that can then be patented to replace the original that is going off patent. Some molecules receiving such modification may have changed effectiveness in unpredictable fashion with no change, bad changes, or good changes. Toxicity, solubility, and other factors make it nearly as big a screening problem with pre-clinical and clinical testing before marketing. But the economics of keeping it on patent and high priced is important to them and makes it profitable.
Physical chemistry and computers have become capable of visualizing three dimensional structures of molecules. Knowing the structure of some significant portion of a bio-molecule makes it simpler to design chemical molecules that will bind to the site and bring desired structure to the rest of the molecule. There seems to be no end to the possible applications. I doubt that the computer will be able to do all the thinking and evaluation that a competent research team can bring to complement the task.
A great drug company, The Upjohn Corporation, was started by a local physician who developed the friable pill. They were an excellent employer and blessing to the community. Several mergers later, they are now Pfizer. Along the way research teams were disbanded in downsizing the merged research effort. The emphasis is now on buying up small innovative companies to stock their new-drug pipeline. I don’t know of any successes of the computer-driven drug designing, although I am sure it has yielded some benefits at the cost of losing possible greater benefits from the old research teams.
Now and then there are hints of and actual spin-offs of businesses. The drug company business types and corporate boards can now reward themselves outrageously like many other businesses do. Shareholders, employees, and communities suffer with the shenanigans. Short term rewards imperil future benefits. The vast majority of executives are honorable and hard-working, but one persuasive senior executive can do a lot of damage in their grasp for material success. Make a big deal of the mergers or downsizings achieved and get a big bonus in dollars or shares at everyone else’s expense. Pfizer is still a good company.
Joseph G. Engemann Emeritus Professor of Biology, Western Michigan University, Kalamazoo
December 9, 2016