Double agents in medicine

My ongoing research of allergy and autoimmune disease has uncovered a long history of medical manipulations that defy logic. Even my seasonal allergies have been quelled with homeopathic dilutions of dust, mold, and pollen. Allergy immunotherapy is intriguingly similar, exposing us to daily, increasing amounts of allergens that slowly reprogram our immune system. In any case, it is mind-boggling to find out that certain harmful substances can be carefully controlled to benefit our health. And it is time for our minds to unboggle. This concept is a critical piece in the puzzle of human health.

Biotherapy buzz

Biotherapy may be the most bizarre type of tweaking we’ve ever done in medicine. This broad approach makes use of living organisms, and many of these organisms are perceived as dangerous to human health. The use of honey bee products or apitherapy has been used for thousands of years, dating back to Egyptians, Hippocrates and ancient religious texts. While we know there are antibacterial, antifungal, antitumor, and antiinflammatory agents in honey and bee propolis, the use of bee venom is more complex. It is known to trigger intense pain, swelling, and anaphylactic shock but can improve certain autoimmune and inflammatory disorders such as multiple sclerosis, arthritis, eczema, psoriasis, bacterial and viral infections. Chinese researchers also observed significant benefits in adding bee acupuncture to treatment of ankylosing spondylitis. The FDA has approved a purified form of bee venom that is used for injection, though there are obvious risks for this treatment.

According to a new reference book Biotherapy – History, Principles and Practice, other unusual sources of biotherapy include organisms like leeches, worms and bacteriophages. Medicinal leeches can consume excess blood that has pooled and caused uncomfortable swelling, but the primary benefits of hirudotherapy are the anticoagulants and vasodilating compounds in their saliva. Leech bites can bleed for about six hours, essentially purifying and restoring the tissues around them.

Equally amusing is the medicinal use of parasitic worms or helminth therapy that may benefit some cases of inflammatory bowel disease (IBD) by suppressing inflammation. Scientists point out that helminths – infecting one-third of the world – have shaped our genetics to favor survival for both worm and host. Without them, developed societies appear to be experiencing unprecedented rates of allergy and autoimmune conditions. While a new immune paradigm is rapidly forming around missing enemies like helminths, therapy may only be helpful for prevention rather than treatment.

Dr. Jim Olson’s “tumor paint” makes use of chlorotoxin, the primary toxin in scorpion venom. Chlorotoxin attaches to malignant cells and can be illuminated in order to identify tumors and prevent removal of healthy tissue during cancer surgery.

Phage therapy is the use of naturally-occuring viruses called bacteriophages to infect and eradicate specific bacteria. Antibiotics have stolen the spotlight since phage therapy was popular in the 1930s, but recent antibiotic resistance has rekindled interest. The first controlled clinical trial for the effectiveness of phage therapy was published in 2009, and there have been over 500 different bacteriophages identified for numerous bacteria such as E. coli, Salmonella enteritidis, and Staphylococcus aureus. Phage therapy has appeared safe and effective, yet growth is sadly limited by lack of research and financial incentives for companies that cannot obtain patents for phage products.

Similarly, oncolytic viruses – a major contributor to some cervical and liver cancers – can inhibit tumor growth and show great potential as an alternative to toxic, life-threatening cancer treatment. Viruses such as herpes simplex, adenovirus, and vaccinia viruses can be genetically modified to enhance their Trojan horsepower after injection into tumors. Other viruses such as Reovirus and Seneca Valley virus replicates within tumor cells without modification. A recent study even used macrophages to discreetly deliver the virus and eradicate tumors in mice with prostate cancer.

Simply speaking, the forced viral “infection” allows tumor cells to be identified and attacked by the immune system rather than grow discreetly. There are obvious challenges when we try to manipulate the immune system, particularly when adding chemotherapy drugs without knowing how each individual will respond. But we are making new progress in working with our enemies.

Tolerance by toxin

Much more basic “toxic” elements and compounds have been used to alter our physical response and tolerance, primarily to reduce reactivity to foreign substances as well as our own cells and tissues. Our immune system must constantly draw a fine line of tolerance in order to maintain balance and health, and this plasticity can drastically change between early life and old age. Though tolerance has not been in focus for most of medical history, the recent rise in autoimmune disease has forced a closer a look at tolerance to pollen, food, and even pancreatic beta cells (type 1 diabetes).

Mithridatism

The practice of mithridatism has roots in ancient Persion history around 120 BC. Mithridates VI, the king of Pontus, allegedly consumed minute, regular doses of poisons, arsenic and other unknown ingredients to achieve immunity or tolerance to poison. Mithridatism appears to be the term once used for unscientific and very dangerous attempts to develop tolerance to biological toxins. This approach was successful for disciplined researchers like snake handler Bill Haast who self-injected snake venom for most of his life (and lived to reach 100).

Allergen immunotherapy and tolerance

Allergen-specific immunotherapy involves consuming or injecting dilutions of the offending allergen, gradually increasing dosage over time until long-term desensitization or tolerance is achieved. Defining tolerance is rather tricky in terms of immunity. Tolerance generally refers to a more permanent state of resistance – a lack of symptoms when exposed to a particular substance. Desensitization refers to an ability to avoid symptoms with ongoing treatment or avoidance of the substance.

Current research has revealed that our tolerance levels are affected by a little protein called Foxp3 that marks Treg cells – immune T cells that keep us from overreacting to invaders or even our own tissue. Deficiency of Treg cells and genetic mutations of Foxp3 are believed to play major roles in the development of autoimmune disease. Allergen immunotherapy creates T cell tolerance, increasing allergen-specific Treg cells that help control allergic inflammation.

Yet tolerance can work against us in the case of certain cancers. Research has revealed that tumors can create immune suppression and tolerance that prevents the body from eliminating cancerous cells. More specifically, tumors appear to cripple the surveillance of our natural killer cells, promoting breast cancer and melanoma. A thorough search did not reveal any substantial studies discussing cancer risk in allergy immunotherapy patients, and more research is necessary to determine the long-term impact of this type of forced tolerance.

It is not surprising that allergy-related conditions tend to show inverse associations with brain cancer, colorectal cancer, pancreatic cancer, and others based on gender. In fact, the autoimmune skin condition vitiligo has been induced as an experimental method of treatment for melanoma cancer.

On the other hand, certain highly inflammatory, chronic autoimmune diseases like celiac, inflammatory bowel disease, rheumatoid arthritis, and lupus strongly associate with certain types of cancer – particularly in the associated inflamed organs. Considering these connections, it is interesting to consider the development of allergy as a possible cancer defense mechanism, eventually promoting autoimmune and inflammatory conditions if internal and external irritants remain.

Sleight stimulation

The pendulums in health practice typically push toward gentle controlled stimulation. The various modalities of medicine approach this in a variety of ways; traditional Chinese medicine promotes the flow of vital energy (Qi) and anticancer activity through acupuncture; chiropractors unblock nerve energy and subluxation through adjustments; nutritionists increase natural killer cell activity and reduce inflammation through dietary astaxanthin; and public health clinics provoke immune memory and disease prevention through vaccination. Some of the stimulating therapies involve substances known to be toxic in higher doses, creating controversy and confusion.

Heavy metals in Chinese herbal medicine

Arsenic and other heavy metals have been a part of of Chinese medicine recipes for at least 2,000 years. According to Sun’s book Biological Chemistry of Arsenic, Antimony and Bismuth, realgar and other arsenic-based minerals have been used to improve the effectiveness of many Chinese herbal remedies.

Indeed, we did not realize that arsenic trioxide handily suppresses certain types of cancer cell growth, including a form of leukemia. It is thought that arsenic trioxide influences the genetic activity surrounding this type of cancer. Scientists are trying to clarify how “poison” like arsenic has contributed to Chinese medicine and new types of cancer therapy.

On the other hand, inorganic arsenic exposure from drinking water is associated with kidney cancer, bladder cancer, lung cancer, and skin cancer. Rice is also a major source of inorganic arsenic and even 1/2 cup could easily take us past the maximum contaminant limit. It appears that arsenic may contribute to harmful symptoms by altering genetic expression, though individual genetics play a major role in disease susceptibility. High concentrations of inorganic arsenic are found in certain Chinese herbal medicines like Chrysanthemum.

Levels of other heavy metals like mercury, cadmium, and lead can be dangerously high in certain Chinese and Indian medicine, posing toxic threats to unsuspecting consumers. It is not clear if higher levels of these metals are a result of intentional therapeutic addition, agricultural conditions, or improper manufacturing. Unlike arsenic, mercury (cinnabar) and other metals have been used in both Indian and Chinese medicine but not given any therapeutic consideration in Western medicine.

Chinese researchers report that both realgar (arsenic sulfide) and cinnabar (mercury sulfide) are less toxic than sodium arsenate and mercuric chloride. As with all chemicals, the form or compound dramatically changes its impact on the body, and each body has a unique response at any given time. Without studying the effects of all variations, we are dismissing important clues in how our body reacts to environment and potentially powerful medicine.

Coal tar therapy

Despite carcinogenicity in high amounts, low concentrations of coal tar in topical products have been historically effective for psoriasis and atopic dermatitis. Researchers found that coal tar activates an aryl hydrocarbon receptor (AHR) to work its magic, reducing inflammation and swelling and restoring skin with poor barrier function. AHR is an important protein in our bodies that detoxifies drugs or pollutants that enter the body.

To date, we have neglected to understand the power of coal tar and other AHR ligands by dismissing them as entirely toxic. Only recently, researchers discovered that tetrachlorodibenzo-p-dioxin, the primary contaminant in Agent Orange, actually suppresses peanut allergy in mice. This and other AHR ligands appear to dramatically impact our immune system by interfering with genes and cell differentiation.

Phototherapy

The use of light for healing dates back several thousands of years. Heliotherapy has improved health by exposing skin to direct sunlight, fighting bacteria like tuberculosis and improving autoimmune conditions like psoriasis. Sanitariums were popular health resorts around the turn of the 20th century where visitors experienced holistic treatments that included heliotherapy .

Yet we can be harmed by excessive or chronic exposure to the sun’s UVA, UVB, and UVC wavelengths. UVB light, among other environmental influences, instigates gene mutations that lead to skin cancer, while UVA increases oxidative stress that indirectly promotes skin cancer. Our exposure to natural ratios of UVA and UVB light is dramatically altered under glass that filters out UVB. Fortunately we are protected from almost all deadly UVC radiation by the ozone in our upper atmosphere.

It is important to note that each type of UV light plays a different role in each type of skin cancer, and they appear both harmful and protective. In fact, rates of the deadliest melanoma cancer are actually increased where people are exposed to less UVB. When our skin is exposed to UVB light, it creates vitamin D which appears to help suppress skin cancer. Studies continue to find inverse correlations between UVB and 15 types types of cancer. UVA also promotes the formation of nitric oxide in the skin that plays a role in healing and immune defense, though animal research hints that males may not benefit from UVA as much as females.

Heliotherapy has evolved into modern-day phototherapy where wavelengths of light are controlled and delivered to improve specific conditions. Benefits of UV therapy are outlined in a recent paper published in Dermato-Endocrinology. Blue and red light, applied with LED devices, has safely improved different cases of acne and other infectious bacteria. Low level laser therapy uses red and near-infrared light to successfully treat pain, swelling, inflammation, and other hurdles to healing. Even UVC radiation has been suggested as a possible treatment for brain cancer, pancreatic cancer, ovarian cancer, and wound infections.

Homeopathy

One of the most notorious examples of duality in medicine is homeopathy. This formal, individualized approach to curing multiple systems was delineated by Samuel Hahnemann at the end of the 18th century. Dilution remedies are elaborately crafted from single substances that, in larger amounts, would cause symptoms similar to those in the affected individual. While some clinical remedies like Arnica may work for the average muscle strain, other constitutional remedies are tailored for the person’s entire set of physical and psychological symptoms. Some of these substances include deadly poisons like arsenic trioxide, poison ivy, and belladonna – diluted to the amount of less than a molecule that’s impossible to measure or document.

A disturbing dearth of thorough research in homeopathy inhibits our complete understanding of human health. It is difficult for scientists to analyze homeopathy without an ability to explain the effects. The confusion breeds pervasive criticism and contempt. To make matters worse, popular culture has started to blur the lines between “homeopathy” and natural remedies. Fortunately, veterinary medicine has been less inhibited by the negative stigma, using homeopathy for difficult conditions such as dermatitis, viral warts, arthritis, and urinary/renal conditions in cats and dogs.

Although the goal of classic homeopathy is achieving long-term health of the entire body, symptom-oriented success has been documented for various allergy conditions. Homeopathic remedies including dilutions of histamine behave similarly to modern immunotherapy, reducing IgE levels and mast cell degranulation. In the case of typhoid infection, researchers suggest that the homeopathic remedy Baptisia works through the formation of similar antibodies much like a vaccine.

Inoculation, vaccination, and immunotherapy

The idea of inoculation – infecting ourselves with disease to boost our immunity – is thought to date back to ancient India as well as 10th century China. Eastern inoculation involved snuffing up smallpox scabs, and Western inoculation involved exposing scratched skin to pus from a mild case of smallpox. Jenner’s first vaccine for smallpox proved safer than these methods, injecting nonfatal cowpox virus to achieve immunity and centuries of fame.

Vaccines originated around the same time that Hahnemann was honing homeopathy. Different types of vaccines expose us to live or weakened viruses, inactivated organisms, inactivated toxins, or segments of the organism. Few of us are aware that these vaccines do not work without some poorly understood ingredients called adjuvants. These dirty little secrets help stimulate the immune response and prolong the immune programming period so that the vaccine is theoretically more effective.

Though adjuvants have been used since the 1920s, we have little knowledge about their mechanisms. Recent studies have implicated adjuvants in immune diseases such as silicosis and Gulf war syndrome. Aluminum salts have been the adjuvant of choice and trigger a complex cascade of immune activity, though recent work is questioning the necessity of this response. Oil-in-water adjuvants have been used for flu vaccines and appear to only work as a complete formula, further complicating the adjuvant enigma.

Vaccines are generally delivered by injection because their antigens can be degraded by the gastrointestinal tract. New techniques could improve oral vaccines, including the use of certain probiotics as vehicles of delivery. Vaccines are now being used in cancer treatment to boost the body’s immune response and program it for long-term tumor destruction.

Scientists have also been exploring the use of vaccines in allergen-specific immunotherapy to prevent allergy. This novel approach could prevent allergies by stimulating the immune system and provoking immune programming long before allergy and the need for tolerance arise.

The hormetic mechanism

It seems counterintuitive that small bits of disease or disease-causing substances could benefit us at all. An explanation to this madness is encapsulated in the concept of hormesis, first defined in the late 1800s by a scientist examining how yeast was stimulated by minute amounts of poison. While we have assumed that all common toxins can affect us in a linear fashion, new studies show that we have missed an important detail in living systems.

“…these data confirm that hormesis is common to many – if not all – living systems, including bacteria; they underline the relevance of a deepened knowledge of both the effects and the possible consequences of exposure to low doses of contaminants.” –Dose Response, 2013

Hormesis begins to quantify the misunderstood power of homeopathy, describing a biphasic “J or U-shaped” dose response that has appeared in 9000 substances (per the hormesis data set in 2011). The fascinating effect extends to temperature, exercise, diet, and light therapy. We may be most familiar with the example of diet and exercise, where health benefits are gained from moderate amounts of exercise and caloric restriction. The leading researcher in hormesis is Professor Edward Calabrese who has written countless papers explaining the phenomena that we have tragically overlooked.

It is believed that mild oxidative stress may contribute to some of the benefits in hormetic substances. Other studies propose that some form of immune tolerance might be activated, as low doses of glutamate helped protect brain cells from exposure to toxic levels of glutamate. The concept of preconditioning ischemia is another internal example of protection from a typically harmful experience; short periods of ischemia (lack of blood supply) can create a type of tolerance in heart or brain cells that protect them from more fatal strokes or heart attacks. The most dramatic example of hormesis may be the recent discovery of decreased cancer mortality in atomic bomb survivors exposed to intermediate doses of radiation.

Yes, radiation appears to reduce certain cancer risks in adults in very low doses. This might explain why some cancer rates are lower with exposure to sunlight. It is notable that low dose ionizing radiation associated with genetic mutations in animal studies (even more in male offspring), yet these changes were reduced with antioxidants. The hormetic cancer benefits of radiation may not come without a price; population studies of low levels of ionizing radiation showed  an increase in circulatory disease. We urgently need ways to determine risk factors such as age, genetics, cumulative exposure or consumption, and antioxidant consumption to better harness the power of hormetic substances and life forces.

Controversy of contradictions

Governments and industry are already debating how hormesis will impact health regulations. We have relied on a linear no-threshold model to estimate the toxicity of carcinogens – a striking contrast to the U or J shape model featured with hormesis. If our model changes, many industries with toxic emissions hope to be exonerated from the blame for increased cancer or mortality. More likely we will find that smaller doses can be even more detrimental to long-term disease risk.

If the eye-opening model of hormesis changes anything, it will help us realize that we cannot make gross assumptions about the harmful or beneficial effects of substances around us. Oversimplified thinking may conclude that we can have too much of a “good” thing, or maybe not enough of a “bad” thing. Even the examples of duality in this report require much more elaborate research before drawing conclusions about safety and toxicity.

Another concern behind the hubbub may be the quick and false assumption that one type of low-dose hormetic benefit confers all others. Tiny doses of cadmium may cause water flea populations to rise, but do offspring carry genetic mutations? Minute amounts of dioxin may reduce rat tumors, but do they simultaneously affect the risk of diabetes or heart disease? Even if we determine a broadly beneficial dose for a given population, how do we accommodate for individual responses or cumulative exposure?

The answers are bound by a rusty chain of linear thinking that links public health policy to our general health perceptions. May the axe be quick and painless!