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Monday, February 18, 2013

Bacteriophage therapy, biome reconstitution, heparin--potential scientific breakthroughs plagued by un-coolness

During the last year I have been paying particular attention to lesser known and under appreciated miracles in medicine. It is a mystery why miracles of any sort would be under appreciated, but it is so very human to ignore things in plain sight which disrupt our deeply held belief systems or even are simply not what we are looking for.

For those readers who don't believe that they could actually ignore something that is both true and in plain sight, I refer to this YouTube video, a classic experiment in selective attention. If that is not enough, there is a study in the journal Psychological Science (just reported in the popular press yesterday) which shows that radiologists looking for cancer failed to see a very obvious and ridiculous image on a chest x-ray.

I would propose, also, that we are even more likely to ignore information if that information is uncool. Things that are cool make us feel indestructible and things that are uncool make us feel weak or embarrassed or out of place. Olympic snow boarders, action movie heroes and dancing flawlessly in high heels are cool. Sexually transmitted diseases, urinary incontinence and broccoli between the teeth are uncool. In medicine, heart transplants, miracle drugs and prosthetic joints are cool. Here are a few things that we really do not hear much about at all, despite the fact that they are inspiring, potentially paradigm changing and have been around for years.

Bacteriophage Therapy:
Researchers have been aware of tiny viruses which kill bacteria since the late 1800's. Early on it was not clear that these elements were alive, and it was not proven until decades later that they were, in fact, viruses. In any environment where bacteria naturally grow, bacteriophage live as well, and they can be separated from the bacteria experimentally by using a fine porcelain filter. The water we drink contains phages, since purification is not designed to remove them and they are innocuous. When phages are deliberately grown with bacteria, we can isolate them in concentrations that can be used to treat bacterial infections. In the 1940's, before antibiotics were commercially available, phages were produced in the US by the Eli Lilly company. As early as  1919 phages were used to treat children with severe dysentery, and in the 1920's thousands of people with cholera were treated with it. When antibiotics became more widely available, phage therapy dwindled in popularity. A scientific paper written in 1934 questioning its utility was another nail in the coffin. Reviewing this paper in the light of what is known now, it is clear that its negative conclusions were heavily based on weak science. Phage research and therapy has continued to be actively pursued in Poland and the Republic of Georgia, but the kind of science we like in the US, the double blind placebo controlled trials, have not been done. There are papers comparing antibiotics to phages, which are compelling and generally show phages to be significantly more effective. Phages have been given orally, topically, intravenously, in the eye, intraperitoneally, in large doses, to humans and to laboratory animals with essentially no toxicity. Producing phages is easy, since they can be isolated from a bacterial broth with a filter which is not much different from what we backpackers use to pump safe water from mountain streams. When bacteria become resistant to a phage it is simple to create another phage that is effective for that bacteria. Phages and bacteria evolve constantly in nature in just that way.

It is clear that now that broad spectrum antibiotics are losing the war against resistant bacteria and that their overuse is creating huge problems for us, not to mention their expense and myriad side effects, we need to look seriously at using bacteriophages therapeutically. The US is not, however, geared up to do this at all. Drug companies are not interested, since they don't have the equipment and, since phages are living organisms, they can't get exclusive rights to market them. Universities and research institutions could take up the ball, and there are bacteriophage projects ongoing, but they are hardly able to bring this to full production capability. It is at least theoretically an advantage to use a mixture of phages to treat infection. It would be very difficult to accurately characterize a diverse population of phages which would hamper approval processes.

Also, bacteriophages are quintessentially uncool. The main research institutions which produce phages are the Eliava Institute in Georgia and the Hirszfeld Institute in Poland. Much of the research was done by the former Soviet Union. Eastern Europe is, at least to scientists, basically uncool. We don't understand their language, we don't trust their methods, we are uncomfortable with their culture. A major source of therapeutic and experimental bacteriophage isolated at the Eliava Institute is the polluted river which runs through Tbilisi, the capitol of Georgia. Sewage is uncool. Phages have been around for years and still we don't use them. Obviously they must not be effective. We worry that we might be duped into believing that something is effective when it is not, which would be very uncool. Scads of research, though not scrupulously done, strongly suggests that bacteriophage therapy works. (See link for an excellent review article.)

Biome reconstitution and fecal transplant:
I have written several times about fecal transplant, most recently after the publication in the New England Journal of Medicine of an article out of the Netherlands showing a clear superiority of instilling healthy donor stool in the intestines of patients over use of antibiotics for Clostridium Difficile colitis. Various ailments of the colon, and possibly even obesity may be caused by alterations in the flora of the lower intestines and may be effectively treated by adding an appropriate bacteriological community. The use of healthy poop to cure disease of the colon is probably ancient, and has been in our medical literature since the 1950's. Research has shown it to be staggeringly effective, working within days and resulting in long lasting effectiveness with only one treatment.

In the first decade of this millenium, good research out of Duke University suggested that losing helminths (worms) from our guts due to improved sanitation has been responsible for various diseases of autoimmunity, including allergies, inflammatory bowel disease and maybe multiple sclerosis. There is even a possible connection with autism. There is some good research showing improvements in Crohn's disease and Ulcerative Colitis by reintroducing helminths.

I would suggest that giving people worms and introducing poop soup into the intestines by way of a tube is icky and uncool, which may be why we are so very hesitant to take up this kind of therapy even though it appears to be cheap, elegant and effective. Fecal bacteria and intestinal worms are unlikely to be heavily marketed by drug companies, upon whom we have often depended for the impetus to make major therapeutic changes. These are not things which will make anybody much money, which means that researchers, physicians, hospitals and patients will have to push for them.

The very expression "fecal transplant" is at least giggle, if not gag inducing. The term "biome reconstitution" is much cooler and should probably be the term we use, so perhaps we can get past being grossed out and move forward towards helping sick people get well.

Heparin for burns and wounds:
I have written about this at least a couple of times after being introduced to the concept about a year ago. Heparin is a naturally occurring biological molecule released from mast cells at the site of vascular injury. It is isolated naturally from the livers of pigs or cows and is used to prevent clotting. It is in every hospital formulary and has been a mainstay of therapy for clotting disorders for decades. It has anti-inflammatory and healing properties as well, which are undoubtedly relevant naturally and can be useful therapeutically. One of its main proponents in its use to treat burns and skin ulcers is Dr. Michael Saliba who first did animal experiments with it for this purpose over 40 years ago. Although articles have been published on its efficacy, it has never taken hold in the US for burn treatment, despite the fact that it dramatically reduces pain and scarring. There is quite a bit of research showing that it is effective, but it is difficult to do controlled trials since the caregivers treating the patients can pretty easily tell if their patients are not having pain. I did some little experiments using it for wounds and now have it in any first aid kit because it works so much better than anything else I've used. I, however, am not in any position to do controlled trials.

Heparin will never make anyone any money, since it has been around forever and works just fine in the 1:5000 concentration vials that are easily and cheaply available at any hospitals. Its main proponents are Dr. Saliba who is a family practitioner with an interest in burns and a very cool research project as a medical student, and many burn doctors who are non-English speakers and don't publish in our most prestigious journals. Protocols for its use are at his website which is very user friendly but looks hokey and makes a person think that there is some proprietary aspect to heparin for burns and that maybe its effectiveness is overstated. Heparin for burns is probably awesome, effective and inexpensive and failed to catch on because it will not financially benefit anyone and for various reasons it suffers the stigma of uncoolness.

Over centuries, though, many uncool concepts have eventually found enough support to become commonly believed truth. Copernicus (whose birthday is today) proposed that the sun held still and the earth and planets revolved around it. His idea was so unthinkable that he delayed publishing it for years and was even hesitant to discuss it with other scholars. It took over a hundred years for heliocentrism to be commonly accepted. It took only 5 years from the time a mother of two children with acute arthritis in Lyme Connecticut contacted her health department with concerns about a possible infectious cause until an effective antibiotic was found for Lyme disease in 1980.  Dr. Robin Warren first saw helicobacter pylori in stomachs in 1979, established its role in causing stomach ulcers with his colleague Dr. Barry Marshall, was ridiculed for years and won the Nobel Prize for his work in 2005.

Researchers and clinicians will eventually legitimize good, effective treatments for terrible diseases even if those treatments are presently not adequately sexy to receive notice. The "truth will out" as they say. It is presently frustrating, though, to watch the glacially slow speed with which this is happening.




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