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Connections

I have a friend who’s an artist and he’s some times taken a view which I don’t agree with very well. He’ll hold up a flower and say, “look how beautiful it is,” and I’ll agree, I think. And he says, “you see, I as an artist can see how beautiful this is, but you as a scientist, oh, take this all apart and it becomes a dull thing.” And I think he’s kind of nutty.First of all, the beauty that he sees is available to other people and to me, too, I believe, although I might not be quite as refined aesthetically as he is. But I can appreciate the beauty of a flower.

At the same time, I see much more about the flower that he sees. I could imagine the cells in there, the complicated actions inside which also have a beauty. I mean, it’s not just beauty at this dimension of one centimeter: there is also beauty at a smaller dimension, the inner structure…also the processes.

The fact that the colors in the flower are evolved in order to attract insects to pollinate it is interesting – it means that insects can see the color.

It adds a question – does this aesthetic sense also exist in the lower forms that are…why is it aesthetic, all kinds of interesting questions which a science knowledge only adds to the excitement and mystery and the awe of a flower.

It only adds. I don’t understand how it subtracts.

Taken from Richard Feynman:  What Do You Care What Other People Think?

One of the primary influences in my outlook on life, besides the movie Duck Soup, was the TV show Connections by James Burke from 1978. I was 21 when it was broadcast; I remember the impact of that series more than any science related book or show.

The show took various scientific advances and demonstrated how seemingly unrelated events were actually interconnected and how these unexpected connections led to the wonders of modern society. Burke took the usual linearity of events that is taught as history and went on what seemed like endless tangents to get to an end result.

“Burke begins each episode with a particular event or innovation in the past (usually Ancient or Medieval times) and traces the path from that event through a series of seemingly unrelated connections to a fundamental and essential aspect of the modern world. For example, the program traces the invention of plastics from the development of the fluyt, a type of Dutch cargo ship (Wikipedia).”

The show gave me, for the first time, an understanding of the complexity of scientific advances and history. Connections resulted in one of the few epiphanies in my life (5), and have informed my approach to medicine and science. Understanding and looking for connections, both obvious and hidden, leads to understanding in medicine and often to finding unusual etiologies for diseases.

An example from my practice: an elderly female with acute bloody diarrhea. Cultures of the stool grew Aeromonas hydrophilia, a fresh water organism. Chatting with her led to the discovery that each day she drank a tittle of holy water. She had brought home a jug of the water from a shrine, which was in Mexico. We cultured the water and it grew Aeromonas. Turns out that holy water is a common source for Aeromonas (6). It’s a long way from a Mexican shine to American diarrhea, but if you look for connections you can find them.

The are many connections in medicine: through time, through space, and through scale (1). Anyone who has spent any time listening to me pontificate at the hospital knows that not only do I think Infectious Disease is the coolest specialty in medicine, it is the only specialty in medicine that encompasses not only all of medicine but all of human experience (2).

Let’s wander through an example of the connections in an ID case.

A patient presents with what looks like a boil on the leg.

It’s probably methicillin resistant Staphylococcus aureus, the dread MRSA (7). MRSA is rampant in the USA, with a new strain of MRSA, the USA 300 strain, that has become the predominant strain in the US this century. In my neck of the woods, 65% of community acquired Staph infections are MRSA. When I started practice in 1990, only 2% of Staph were MRSA and the infections were virtually always acquired from hospitals and nursing homes. It has been an interesting change.

At the level of the patient, I have to ask, is it MRSA? Are there connections that lead to another diagnosis? A hot tub associated infection? Or a mycobacterium or fungus from the environment? A few quick questions can exclude these possibilities. No environmental or other exposures to lead to other etiologies. No connections. No odd exposures to make me think it’s not MRSA, and I am going to lance the boil and send it for culture to make sure. But it will take 48 hours to get the culture back.

Again, connections at the level of the patient: any needle use or skin conditions that increase or decrease the likelihood it is Staph? Nope.

Step up to connections in the patient’s local environment: family who might be carriers of Staph? Pets? Hobbies? Is he a wrestler? Fresh from prison? Any connections to the local environment that leads to an exposure to Staph? No connections.

Step up to the city, the US, the world. What is the carriage rate for Staph (it’s about 1 in 3)? What is the MRSA rate (about 1.5% as of 2004). Rates are increasing for uncertain reasons. It has always been thought that antibiotic resistant strains are less fit in an antibiotic free environment. Why is the MRSA increasing? It should be less fit unless there are compensatory mutations that make up for the decreased fitness of being antibiotic resistant. Doesn’t appear to be a connection at the larger level. Certainly some diseases are increasing from global warming such as dengue and malaria, while others are decreasing, such as RSV. MRSA doesn’t appear to have a connection with global climate change.

Back to the patient.

Nothing in the environment or the US to worry about with a connection to this patient.

Is there a reason this patient has an MRSA infection? Bad luck? Probably. Nothing by history to suggest there is a reason to suspect an immune defect I can diagnose.

That being said, there is increasing data to suggest a wide variety of polymorphisms in a variety of systems are associated with increased or decreased susceptibility to infections.

Polymorphisms are the natural variations in the genes that code for proteins.

Your DNA codes for a tyrosine where I code for a glycine. As a result of a simple amino acid substitution in protein, you may have a increased likelihood of dying or getting an infection.

There is a wing of the immune system that in humans is called the toll like receptors. The toll receptors were first discovered in fruit flies (8) but have subsequently been found in virtually every living animal and are one of the oldest parts of the immune system.

While the toll like receptors cannot be boosted, they can certainly have mutations, and these mutations, these variations, are polymorphisms.

If you have one variant in your DNA, then there may be an increased risk for infection. There are many toll mutations that lead to increased risks for a variety of infections. There is no firm connection as of yet with MRSA and a toll like receptor mutation, but there is a suggestion that TLR2 Arg753Gln polymorphism (that toll like receptor 2 arginine substitution at location 753) may increase risk for Staph infections (3).

And there are other mutations that are connected with Staph infections. Perhaps the patient is colonized with Staph and get boils due to other variations in the immune system.

Variations in interleukin, C reactive protein and complement factor H are all associated with Staphylococcus colonization and boils:

“The IL4 −524 C/C host genotype was associated with an increased risk of persistent S. aureus carriage, irrespective of S. aureus AFLP genotype. The CRP haplotype 1184C; 2042C; 2911C was over represented in individuals who were not colonized . In individuals with boils, carriers of the CFH Tyr402 variant, and the CRP 2911 C/C genotype were over represented (4)”

Translated: variations in common proteins can lead to increased susceptibility to MRSA.

So even without classic risks for S. aureus, the answer for why one patient gets disease and why it runs in the family may be bad luck. Or it may be in the genes. It may be that the fault, dear Brutus, lies not in our stars, but in ourselves.

There are also the connections at the level of the organism. Staphylococcus aureus makes dozens of proteins whose sole purpose, apparently, is to kill us. The current MRSA frequently has a protein called the Panton Valentine leukocidin (PVL) that dissolves human cells. The presence of the PVL in part is why the current MRSA is such a problem. It liquifies the local tissues, dissolving the immune system and surrounding tissues into the bloody pus so commonly found in the boils when they are lanced. PVL may be one of the compensatory changes that allow MRSA to prosper.

PVL is but one of many toxins, many of which enhance the virulence of S. aureus. I have often wondered what the real function of some bacterial toxins is. What good is botulism toxin? I can’t see how it promotes the spread of the organism in humans. Many virulence factors are probably epiphenomena of their real function, what ever that may be. What is the connection to bacterial evolution of these toxins? I don’t know.

Then there is the level of antibiotic resistance. Is the infection located where I can deliver an antibiotic? Is it resistant to what I am going to choose? I have knowledge of current resistance patterns in my community, but it is a moving target.

Doxycycline is effective, as is trimethoprim-sulfamethsoxazole. The problem with both agents is the development of resistance is easy, and the pus environment is potentially antagonistic for tmp-sulfa. The only other oral agent is linazolid, but it costs 50 dollars a pill, so a 10 day course often runs 1200 dollars or more. With 1 in 5 people with no health care, that brings into play the biopolitical connection between the ability to provide health care and the ability of the patient to pay. A quick check: no insurance (9).

I could use intravenous vancomycin, but the use of vancomycin not only drives vancomycin resistance in Staph, but leads to increased incidence of vancomycin resistant enterococcus. In the few cases of vancomycin resistant S. aureus, the resistance genes have jumped from enterococcus to Staph. If I go with vancomycin, I be will be contributing, in my own small way, to local and world wide resistance to vancomycin (10).

There are also the multitudinous ways organisms become resistant to antibiotics and how those resistance genes can jump, again by a variety of means, from organism to organism and then world wide. The local ecology can increase the development of resistance in one bacteria; that resistance can jump to other species, and then spread.

The penicillin resistance of S. pneumoniae, for example, occurred when a few strains acquired resistance genes from other bacteria and then spread across the world, taking with it resistance to many of the common and inexpensive antibiotics.

Think globally, act locally. It is ID in action.

To understand ID is to understand evolution and ecology. ID is applied evolution of people and pathogens. There may be, oh, I don’t know, say a neurosurgeon somewhere that doesn’t understand the connections of evolution with infectious diseases, but I would be shocked if there was an ID doc who was an evolution denier. I wonder if there has been enough genetic change in the MRSA of today to say it is a different species as the S. aureus of 30 years ago. A rough estimation makes 30 years of bacterial replication the same as 6 million years of human replication. Humans have had a reasonable number of changes in 6 million years. I wonder what has occurred to S. aureus. The connections between evolution and the ecology that drive antibiotic resistance provide deep understanding of the treatment of infectious diseases.

If the patient is unlucky enough to require IV antibiotics, I have to wonder what the best therapy is, and I know that the MIC to vancomycin, the mean inhibitory concentration, the amount of antibiotic it takes to stop growth, is increasing for Staph. While it used to be 0.5, increasingly I am seeing 1 or 2 for an MIC. As the MIC increases, due to simple amino acid substitutions in the cell wall, the efficacy of vancomycin decreases. Even susceptible organisms may not be, and if I push the vancomycin, I may be increasing the toxicity, No good deed ever goes unpunished. And I will not wander into the swamp of drug drug interactions.

Is he sick enough for IV, but not hospitalization? Payment and coordination of care and the lack of a health care system again enter into the picture.

And should I treat his fever? (No). The evolution of fever is topic for another time.

In the end, the boil is lanced, the patient is sent home on doxycycline and he and his family are decolonized. If he is lucky, that will be the end of it.

So many connections, and I only covered a few of them:

The biology, anatomy, physiology of the infection.
The chemistry and epidemiology of the infection.
The chemistry of the antibiotics.
The history, evolution and ecology of organisms and the host.
The finances of the the medical industrial complex.

Up and down scale, space and time. Every time with every patient.

How does this relate to the topics on this blog?

I understand medicine from the level of the individual molecules interacting to cause disease to the world as it alters the risks of infection. From the atom to the bacteria to the human to the city to the planet, extending back to the beginning of human evolution.

I have, dare I say it (dare, dare) a holistic approach. A real holistic approach. The panoply of medicine as I see it is rich with understanding from connections from the level of the human DNA to global climate change and many things in between. It is what makes Infectious Diseases just so damn cool.

Where in all this understanding does acupuncture, as one example, fit? How do the alternative practices connect with the known world? They don’t. Homeopathy, acupuncture, chiropractic, energy therapies exist in their own isolated universe with no connection to natural reality.

There is no chi, there are no genes that code for meridians. There are no polymorphisms that render one patient susceptible to acupuncture and another not. Acupuncture has no connections to anatomy, physiology, chemistry, genetics, evolution, physics, biochemistry, developmental biology etc etc. What do they add to the understanding of the world at any level beyond the psychology of deception? Or any other alt med? Alt med is like a god of the gaps, but there are no gaps, at least no gaps that need to be filled with any of the interventions studied by the NCCAM.

Alt med’s are intellectual dead ends that add nothing to understanding of biology or history or ecology or evolution or anatomy or anything. They have no connections.

I know, I know, I know. I am a closed minded reductionist. There is more in heaven and earth than is dreamt of in my philosophy. Right?

Unlike alt med, in science and medicine I see connections, endless, amazing, incredible, connections. A beauty and understanding of the world that is absent in alt med.

“I am among those who think that science has great beauty. A scientist in his laboratory is not only a technician: he is also a child placed before natural phenomena which impress him like a fairy tale.”

Marie Curie (1867 – 1934)

Marie would not find beauty in alt med.

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References and Snotty Comments

1) http://micro.magnet.fsu.edu/primer/java/scienceopticsu/powersof10/

2) For the record, not only is Infectious disease the best part of medicine, and ID docs the smartest docs the following are also superior: Mac OS, French Bordeaux’s, Oregon IPA’s and ESB’s, and my wife and sons. Just saying.

(3) A novel polymorphism in the toll-like receptor 2 gene and its potential association with Staphylococcal infection. Infection and Immunity.
2000, vol. 68, no11, pp. 6398-6401.

(4) The Journal of Infectious Diseases 2008;197:1244–1253.
Host Polymorphisms in Interleukin 4, Complement Factor H, and C-Reactive Protein Associated with Nasal Carriage of Staphylococcus aureus and Occurrence of Boils.

(4) Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis.2008-Feb; vol 46 (issue 4) : pp 584-93

(5) The other being a meal at St. Estephe’s in Manhattan Beach, California, my first gourmet meal; more memorable, I am afraid to say, than my first kiss.

(6) Holy water fonts are reservoirs of pathogenic bacteria
Environmental Microbiology 4 (10) , 617–620 I suppose that Louis Pasteur went to hell, otherwise he would have insured that holy water was pasteurized water.

(7) M-R-S-A, not mursa.

(8) “Their name derives from Christiane Nüsslein-Volhard’s 1985 exclamation, “Das war ja toll!” The exclamation, which translates as “That’s weird!”, was in reference to the underdeveloped posterior portion of a fruit fly larva.” Wikipedia.

(9) Health care in the US is second to none. Its because we rank 27th. One does get what one pays for.

(10) In infectious disease, its use it and lose it.

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