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In 1888, bacteriologists Emile Roux and Alexandre Yersin demonstrated that diphtheria occurs when bacteria release a toxin that damages tissues.
Then in 1890, Emil von Behring made the remarkable discovery that serum derived from the blood of horses injected with diphtheria toxin contains an 鈥渁ntitoxin鈥� that can be used to protect against as well as cure diphtheria. For this pioneering work, von Behring was awarded the first-ever Nobel Prize in Medicine and Physiology.
Paul Ehrlich, who would himself become a Nobel Laureate in 1908, proposed a theory for the formation of antitoxins. Certain white blood cells, he suggested, are equipped with 鈥渃hemical side chains鈥� that can link with particular toxins. When this happens, the cells grow more of the side chains that are then released into the bloodstream to seek out and destroy more of the toxins. These side chains were von Behring鈥檚 鈥渁ntitoxins,鈥� which Ehrlich now renamed 鈥渁ntibodies,鈥� colloquially referring to them as 鈥渕agic bullets.鈥� He predicted that chemists would soon be able to produce 鈥渂ullets鈥� in their laboratories to seek out and eliminate specific disease-causing agents. Now that time has arrived.
Georges Kohler, Cesar Milstein and Niels Kaj Jerne were awarded the 1975 Nobel Prize for developing a method that essentially converts Ehrlich鈥檚 vision into reality. It involves a complex series of steps that begins with injecting mice with a foreign substance, or 鈥渁ntigen,鈥� that then stimulates a variety of white blood cells, known as 鈥淏 cells,鈥� to produce a host of antibodies.
These B cells are isolated from the animals鈥� spleen and are fused with cultivated myeloma tumour cells to allow the newly formed 鈥渉ybrid鈥� cells to multiply quickly. Then the cells that produce the specific antibody that targets the antigen in question are isolated and are copied, or 鈥渃loned.鈥� It is from these cells that the sought-after antibody is finally isolated. Being cloned from one specific type of B cell, it is termed a 鈥渕onoclonal antibody.鈥�
Some monoclonal antibodies have been developed and are pharmaceutically categorized as 鈥渂iologicals鈥� since they are derived from living systems. They have had an impact as anti-inflammatory, anti-cancer and anti-viral medications. For example, 鈥渋nfliximab鈥� (Remicade) has had a huge impact on the treatment of Crohn鈥檚 disease, and trastuzumab (Herceptin) has proven to be effective in the treatment of breast and stomach cancer. Monoclonals can be recognized by the ending 鈥渕ab鈥� in their chemical name.
鈥淣ew 础濒锄丑别颈尘别谤鈥檚 Drug Slows Mental Decline by 27% in Clinical Trial,鈥� screamed a recent headline.
The clinical trial referred to, published in the New England Journal of Medicine, described the use of the monoclonal antibody lecanemab (Leqembi) in the treatment of early 础濒锄丑别颈尘别谤鈥檚 disease. One of the hallmarks of 础濒锄丑别颈尘别谤鈥檚 is a buildup of a naturally occurring protein called beta-amyloid that forms clumps in the brain and gums up the machinery. The monoclonal antibody, administered by intravenous infusion once every two weeks, was designed to target the amyloid deposits and mark them for destruction by immune cells called microglia.
As with any medication, there are side-effects including potentially serious ones such as swelling or bleeding in the brain. The incidence of these is not trivial, seen in about 13 per cent of patients treated with lecanemab. This risk, of course, has to be weighed against the drug鈥檚 benefits that are less than spectacular. The slowing of mental decline by 27 per cent actually translates to a 0.5-point difference measured on an 18-point scale that tests cognition. Nevertheless, this was the first time that a drug actually showed a slowing of the progression of the disease.
A second monoclonal antibody, donanemab, demonstrated similar results. Both of these drugs are very expensive, costing about $30,000 a year for a treatment that is burdensome for patients, leads to small reductions in cognitive decline, has significant side-effects and has unknown long-term consequences. The question is whether such expenditures can be justified in a crumbling health-care system.
Dr. Dean Ornish, who has long worked on reversing heart disease through a vegetarian diet, exercise, yoga and meditation with some success, believes that there is a cheaper way to achieve results similar to those seen with the monoclonals. In his study, 51 patients with early 础濒锄丑别颈尘别谤鈥檚 disease were randomized into experimental and control groups. The experimental group had vegan meals delivered to them, as well as supplements of omega-3 fatty acids, curcumin, coenzyme Q10, Lion鈥檚 mane mushroom and various minerals and vitamins, with some of the latter in higher doses than found in common daily multi-vitamin tablets.
The experimental group was also given a program of exercise and subjects were guided to learn relaxation techniques. After 20 weeks, all the patients underwent standard tests for cognition and the conclusion was that the patients in the control group continued to decline, while in the experimental group some actually showed an improvement. As with the drugs, the results were not overwhelming, but still significant.
For example, in the test that showed the best result, with a lower score indicating better cognition, the experimental group dropped from 21.5 to 20.5 while the control group increased 21.3 to 22.2. Another measurement involved a blood test for two types of amyloid proteins, termed beta-amyloid 40 and beta-amyloid 42. Both are found in the bloodstream, but the 42 version is the one found in senile plaques. An elevated level of 42 in the blood is indicative of more also occurring in senile plaques, so that a decreased ratio of beta amyloid 42/40 is a strong marker of 础濒锄丑别颈尘别谤鈥檚 disease and can be detected early in the disease progression, even before clinical dementia occurs. In this study there was a slight increase in the ratio, meaning that the amount of beta amyloid in the brain decreased. But again, the change was small.
There is yet another issue with Ornish鈥檚 study. Even if we assume that there is a benefit, there remains the question of which component of the program is responsible. Generally, in a randomized trial you want just one variable. In this case, there were many. Is the result due to the diet? The exercise? The meditation? One of the many supplements? We don鈥檛 know. The authors鈥� own conclusion is that 鈥渋n persons with mild cognitive impairment or early dementia due to 础濒锄丑别颈尘别谤鈥檚 disease, comprehensive lifestyle changes may improve cognition and function.鈥�
There is that troublesome word, 鈥渕ay.鈥� But at least the regimen will not cost $30,000 a year. Unfortunately, the magic bullet for 础濒锄丑别颈尘别谤鈥檚 disease remains elusive.
