The Doctor Weighs In

By Dov Michaeli MD, Ph.D

One of the more fascinating aspects of evolution is the continuous “battle of the species”; one species trying to fend off the attack of another, parasitic species. It is a classic warfare of measure/counter-measure, not unlike modern warfare. But unlike human warfare, a successful parasite is not the one that kills its host—that would spell  the demise of the parasite; that would be self defeating, won't it? Success is defined as the capacity to live off the host, and efficiently spread to other individuals. The host, on the other hand, is successful if it can avoid being killed by the attack and keep the attacker in check. And so we can see a battle of adaptations: a parasite honing its “skills” so as to attack, but not kill, just colonize; the host, adapting to the presence of the parasite, but keeping the damage to a minimum. You might say that both warring species arrived at an arrangement of co-habitation, or détente.

How can a species adapt?

Answer: by natural selection. Again, the example of warfare is most instructive. Imagine an enemy invading another country. As long as the invader can enjoy the abundant food and shelter the country provides—its chances of conquering this country are quite good. And if it doesn’t kill off the farmers who produce the food—it will continue to thrive in the conquered country. The British Empire is a perfect example of such “enlightened” colonization. But consider Napoleon in Russia, or Hitler in the USSR. The invaders’ brutality on the one hand, and the response of “scorched earth” strategy on the other, were ultimately responsible for the ignominious defeat of the invaders. Likewise, HIV or the Ebola virus are pretty lousy parasites: they kill their hosts. On the other hand, parasites like leeches are quite successful; nobody dies. The host may become weakened, and the leach “knows” to fall off when it is engorged with blood—but both sides survive to live another day.

Co-evolution

Now here is a truly interesting twist on the war between the species. Back to our warfare analogy. What if the conqueror conscripts all able bodied farmers to work the land to supply it with food, but spares the infirm? Wouldn’t that favor the survival of the infirm? If the conditions of labor under the conqueror are especially harsh and even deadly—then, of course, the spared sick people would constitute an increasing part of the population. So here is selection, albeit not quite natural, in action. Similarly, what would happen if a parasite infected a person with some genetic mutation that affected the parasite’s ability to survive? Obviously, the parasite would not survive, and the mutation, albeit deleterious, would confer a survival advantage on the person who carries it. And this is how a parasite that evolved to infect humans, can in turn cause a change in the human genome. If the infection is deadly enough, the individuals who possess the mutation would slowly constitute an increasing proportion of the population.

Malaria—the quintessential human parasite

Malaria, a tremendously successful pathogen that is responsible for more than 300 million cases and 1 million deaths annually, has had a large impact on the shape of the human genome. Malaria-selected mutations in human genes promote survival in areas where malaria is endemic. The parasite's substantive effect on the human genome is due to its high prevalence in areas where it is endemic and its long history of co-evolution with humans. Stop and think for a moment: we all came out of Africa at one point or another. So this lowly parasite had a hand in shaping our genome! Indeed, not only this one. We can find the fingerprints of hundreds of viruses and bacteria in our genome. What a perfect demonstration of the influence of the environment on our genes.

Several mutations that confer resistance to malaria have been identified. Interestingly, all of them interfere with the energy metabolism or with the synthesis of proteins of red blood cells. Why is this particular cell so important? Because the malaria parasite (Plasmodium falciparum) spends a phase of its life cycle in red blood cells, before moving on to the liver. Unsurprisingly, these mutations are prevalent only in areas were malaria is endemic. For instance, sickle cell anemia is prevalent in Africans and African Americans. Two other conditions, known as α and β Thalasemias are most prevalent in Africans and Mediterraneans. And yet another, known as G6PD deficiency, is prevalent among Jews and Saudis (could that form a basis for understanding between the warring neighbors?). All of these mutations inflict pain and misery on its carriers; but there is silver lining—they are all resistant to malaria.

A recent paper in the New England Journal of Medicine added another mutation to the roster: an enzyme known as PK (pyruvate kinase) which is important in, you guessed it, the energy metabolism of the red blood cell. The paper provides us with additional insight into the subtleties of “the war of the species”. We have two copies of each gene (each copy is known as an allele). If the mutation is in only one allele (the other is non-mutated, or wild type), the individual is quite healthy, and acquires moderate resistance to the parasite. But if the mutation is in both alleles, the resistance to malaria is absolute—but the person suffers from severe anemia. A medical case of “no free lunch”.

The subtleties of the struggle between invader and victim don’t end there. In addition to mutations affecting red blood cells, we have an immune response that jumps into action when confronted with the foreign invader. Furthermore, the immune response can differ between individuals in the variety of mechanisms that are employed (such as antibodies, blood cells called macrophages, other blood cells called lymphocytes). And this is just a small sampling of the variability ( called polymorphism) between individuals. But the invader doesn’t just give up and goes home. The malaria parasite evolved as a response to human polymorphism marked genetic diversity (polymorphism) of its own, which allows it to maximally adapt to the various defenses the host throws up against it, and continue transmission. As you can appreciate, co-evolution is an unending battle, where each side deploys new weapons, only to be countered but even newer weapons.

Why is it important?

Does anybody require a more compelling demonstration of evolution and natural selection in action? Or for that matter, let’s not forget the measure/counter measure war between bacteria and antibiotics. But let’s not get sidetracked by the bizarre politics of science in America. The rest of the world has accepted natural selection as a fact of life as we know it. I am sure we’ll catch up one day.

Why is the study of pathogen-selected host polymorphisms useful? Because it provides insight into naturally occurring mechanisms of host defense, which could be used to develop therapeutic agents to combat disease. The fight against malaria has been long and frustrating. Attempts to develop vaccines against the malaria organism all ended up in failure. A deeper understanding of the rules of war between us and the parasite, the measures and counter measures employed but the combatants, will give us a clue were the vulnerabilities of the enemy lie—and allow us to defeat it.

By Dov Michaeli MD, Ph.D

In 1796 Dr. Edward Jenner performed an experiment that today would have got him expelled from his Medical Society, and maybe even landed them in jail. He vaccinated a boy against smallpox by pricking his arms with pus taken from the sores of a milkmaid with cowpox, a closely related but milder disease. He based this audacious experiment on his astute observation that milkmaids, who had been exposed to cowpox, never contracted smallpox. Let’s not forget what smallpox meant in those days—it meant an almost 100% chance of death. Could anybody have guessed that this observation would become the first harbinger of the field of Immunology?

It took over 200 years before another vaccine was created; in 1914 a vaccine against whooping cough was introduced. But then, the pace picked up: in 1928 a vaccine against diphtheria, in 1933 against tetanus, and so on. Five years ago a vaccine against varicella, causing chickenpox and shingles was approved. Last year a vaccine against human papilloma virus (HPV) was introduced. This virus causes endometrial (lining of the uterus) cancer, and immunization of prepubertal girls should protect them for life. This is the first successful vaccine against cancer.

The two most important facts about all these vaccines are that they are essentially 100% effective, and they don’t cause the emergence of resistant strains. So why don’t we have more of them?

The advent of antibiotics

Many ancient cultures, including the ancient Greeks and ancient India , already used molds and other plants to treat infection. This worked because some molds produce antibiotic substances. However, they couldn’t distinguish or distill the active component in the molds.

Sir Alexander Fleming (6 August 1881- 13 March 1955) was a Scottish biologist and pharmacologist. Fleming published many articles on bacteriology, immunology, and chemotherapy. His best-known achievements are the discovery of the enzyme lysozyme in 1922 and isolation of the antibiotic substance penicillin from the fungus Penicillium notatum in 1928, for which he shared the Nobel prize in Physilogy and Medicine in 1945 with Flory and Chain.

Here is an incredible but true story of a lucky accident, coupled with an astute observation. Fleming was the first to notice the antibiotic properties of molds and fungi. By 1928, he was investigating the properties of staphylococci. He was already well-known from his earlier work, and had developed a reputation as a brilliant researcher, but quite careless lab technician; cultures that he worked on he often forgot, and his lab in general was usually in chaos. After returning from a long holiday, Fleming noticed that many of his culture dishes were contaminated with a fungus and he threw the dishes in disinfectant. But on one occasion, he had to show a visitor what he had been researching, and so he retrieved some of the unsubmerged dishes that he would have otherwise discarded, when he then noticed a zone around an invading fungus where the bacteria could not seem to grow. Fleming proceeded to isolate an extract from the mold, correctly identified it as being from the Penicillium family, and therefore named the agent penicillin.

He investigated its positive anti-bacterial effect on many organisms, and noticed that it affected bacteria such as staphylococci, and indeed all Gram-positive pathogens (scarlet fever, pneumonia, gonorrhea, meningitis, diphtheria) but unfortunately not typhoid or paratyphoid, for which he was seeking a cure at the time.

Fleming published his discovery in 1929 in the British Journal of Experimental Pathology, but little attention was paid to his article. It was only in 1940 that Flory organized his whole department of biochemistry at Oxford to solve the problem of stabilizing the drug and scale up and production that a useful drug was produced in 1945.

Fleming's accidental discovery and isolation of penicillin in September 1928 marks the start of modern antibiotics.

Fleming also discovered very early that bacteria developed antibiotic resistance whenever too little penicillin was used or when it was used for too short a period.

Fleming cautioned about the use of penicillin in his many speeches around the world. He cautioned not to use penicillin unless there was a properly diagnosed reason for it to be used, and that if it were used, never to use too little, or for too short a period, since these are the circumstances under which bacterial resistance to antibiotics develops.

Fleming was prophetic

Indeed, an avalanche of discoveries of new antibiotics followed, and one by one they fell victim to the phenomenon of resistance.

How did that happen? Exacly as Fleming predicted: by inappropriate use and by under dosing. But there is another reason for resistance to antibiotics that Fleming could not have foreseen: widespread use in farm animals in order to prevent disease to ensure larger and healthier animals (and profits). Together with the slaughtered cattle, pigs and poultry we get the antibiotics that they had been fed, in low doses and for a long duration—the “ Fleming recipe” for resistance.

MRSA—a case study

Staphylococcus aureus is a bacteria that we host quite happily on our skin without much trouble. Every once in a while the bacteria will penetrate a cut or a wound and cause an abscess. An abscess can be drained, with excellent long-term results. But “to be on the safe side” physicians prescribe a course of antibiotic therapy. This led in the 1970s to the emergence of a strain of S. aureus that was resistant to many broad specificity antibiotics, called Methicillin-resistant Staph Aureus, or MRSA. This strain was restricted by and large to hospitals, until a few years ago what we feared happened: the resistance spilled over to the community. MRSA can still be treated with vancomycin or linezolid—but not for long. Strains of S. aureus resistant to vancomycin are already emerging. Brace youreself for appearance of the new superbug. What are we doing about it? Physicians are already adopting the practice of abscess drainage without antibiotics. Why haven’t we heeded Fleming’s warnings in the first place?

Back to vaccines

None of the vaccines we have been using for many decades has produced resistance. Their track record is superb. The CDC is reporting that of 13 diseases that children are routinely vaccinated against the death rates for nine diseases have fallen by more than 90% since the vaccines were approved. Before the discovery of the polio vaccine the death rate is estimated to be over 3000 a year, not to mention the tens of thousands of children who became paralyzed and had to live for many years in iron lungs. Smallpox, Jenner’s first feat of immunization, has now been declared completely eradicated. No antibiotic can claim that.

Why weren’t more vaccines developed?

The reasons are many, but the most important ones are:

• Companies that developed vaccines were under constant threat of litigation, mostly for unfounded reasons. A prime example is the latest crusade by true believers that the mercury preservative used in many vaccines is responsible for an epidemic of ADHD and bipolar disorders in children. The evidence for these claims is bad science, pure and simple. Some excellent studies definitively debunked those beliefs, and showed no relationship of mercury in vaccines and disease of any kind. In any event, vaccines are now available without mercury, using alternative preservatives.
• Pharmaceutical companies are populated be chemists, not by biologists. The little biotech company I worked for had more immunologists in its staff than a giant like Pfizer. Such a culture is not conducive to biological thinking. Only recently, with the advent of molecular biology, did the wind of biology begin to blow in the laboratories and board rooms of these companies.
• Vaccines are cheap, and the profit margins are razor-thin. This is a prime reason why most of the manufacturers of the flu vaccines exited the field.

The future

MRSA is not an isolated case. More pathogens are on their way to becoming multi-drug resistant. We are slowly but surely losing the race; the pharmaceutical pipeline is essentially empty. The answer to this impending emergency is recognition on the part of industry and government that each of us is in possession of a powerful tool called the immune response. Vaccination against all bacteria and most viruses is feasible, and the immune response has done an infinitely better job than the pharmaceutical chemists. Why not get back to what works?

Dov Michaeli MD, Ph.D is in the biotech industry