New medical technologies and the evidence gap
New medical technologies are particularly appealing to those with incurable disease and those searching for the fountain of youth. However, there is often an evidence gap - the time between the discovery of a new technology and when it is finally tested and understood. Use of a medical technology in this gap without evidence can lead to disastrous results.
Radiation, for example, was shown to have anti-cancer properties when first discovered. As a result, many healthy people in the 1920’s died from drinking Radithor - a ‘healing elixir’ containing radium water. It wasn’t until the 1940’s and Hiroshima, two decades later, that we began to understand the dangerous effects of radiation. It turns out, radiation is more complex than we expected. It can cause AND treat cancer. It depends on many factors including the type of radiation, the dosage of radiation, and the location of radiation. The devil is in the details.
There are several more current examples of new medical technologies with an evidence gap: these include: the gut microbiome, intermittent fasting, sirtuins, epigenetics, whole genome sequencing, and stem cells.
Opportunism in the evidence gap
When a new medical technology like stem cells generates a lot of buzz and enthusiasm, it opens up a market. For-profit stem cell clinics are popping up all over the country. They are riding the positive publicity, and claiming to cure all kinds of disease with direct-to-consumer marketing. There are 570 clinics in the US and counting.
The reason these clinics are so successful is that they don’t have to convince other doctors (their peers) that stem cells work. All they have to do is convince the lay person - the sick, the vulnerable, and the gullible. Caveat emptor certainly applies in this situation. Let’s explore why other doctors are not convinced.
An introduction to stem cells
A stem cell has two properties. It can divide, acting as a source of new cells, and it can grow into different cell types. To understand stem cells let us go back to when we were first conceived. We all started out as a single fertilized egg - the zygote. (if you want to know how the egg gets fertilized please ask your parents). The zygote is the ultimate stem cell - it is totipotent - it can differentiate into any kind of cell in your body. It splits into two, and those two split into four, and those four into eight, and so on... until a fully grown human with 1 trillion cells emerges 9 months later. As the cells divide they become more functional, but restricted to one cell line. Some cells, for example, become skin cells and produce keratin to protect the body; others become nerve cells and release neurotransmitters to create neural networks. Once the cell has specialized, it can’t revert back to a stem cell nor can it divide anymore.
In the adult, some cell lines like blood and skin shed millions of cells a day. They must retain stem cells to serve as a source of new cells for that cell line; however, these ‘pluripotent’ stem cells are somewhat restricted and can’t produce other cell types. Your fat, for example, contains mesenchymal stem cells - they can differentiate into fat and other types of connective tissue such as bone and cartilage; however, they cannot differentiate into other tissues such as neurons or liver cells.
Pluripotent stem cells success stories
The most widely known and successful usage of pluripotent stem cells is the the bone marrow stem cell transplant. These procedures have saved hundreds of thousands of lives over the last 40 years of usage. Bone marrow is filled with stem cells because your red cells, white cells, and platelets are constantly being destroyed and renewed. A patient with a cancer of the bone marrow, such as leukemia, is treated with very high dose chemotherapy to wipe out the entire bone marrow. Next, a bone marrow stem cell from a healthy matched donor is placed in the bone marrow and, voila, a new bone marrow grows and starts to produce normal cells.
There have been some other impressive anecdotes of applying pluripotent stem cells. For instance, the case of a 7 year old child with a rare genetic condition causing his skin to lift off his body. Doctors removed a skin stem cell from his skin and inserted the normal gene. The repaired stem cell was cultured (induced to replicate), applied to his skin, and he was able to regrow 80% of the skin on his body. Two years later he is still doing well.
In both cases, the logic is simple and the results plausible - healthy stem cells of the same line as the diseased tissue are used. They are placed directly in the location of the diseased tissue and healthy tissue is grown in its place.
Stem cells and Parkinson’s Disease
Let me first explain Parkinson’s Disease. Parkinson’s Disease is caused by the progressive failure of neurons in a very small area of the brain, the Substantia Nigra. These neurons produce the neurotransmitter dopamine. Without dopamine in this part of the brain, patients develop difficulty with movement including: tremors, rigidity, posture, and problems with gait.
A plausible treatment for Parkinson’s with stem cells
In 2012, the Nobel prize in medicine was given to Shinya Yamanaka for his work leading to the development of Induced Pluripotent Stem cells (IPS). A few genes can be spliced into almost any cell in the body (a skin cell for example) converting it into a fully pluripotent cell - like a stem cell from a fetus. This cell can be differentiated into any cell type of your body. Unlike fetal stem cells, IPS cells are your own, and not prone to immune rejection. This makes them even better than fetal stem cells. Unfortunately, IPS cells are very expensive to make and take months to grow.
A recent study was published in Nature using this technology to treat Parkinson’s in a monkey model. IPS cells from the monkey were induced to become dopamine producing neurons. These cells were then surgically implanted into the substantia nigra of the same monkey. There was a significant clinical improvement in Parkinson’s symptoms, and the results were sustained for over two years. The monkeys were sacrificed and autopsied at the end of the experiment. The IPS cells were found to be functioning and there were no tumors.
Despite this initial success in an animal model, the authors of this paper do not suggest opening up clinics immediately to start treating everyone with Parkinson’s. Most scientists are aware of the evidence gap, and temper their recommendations accordingly. In this case, they call for the next gauntlet of experiments to test their hypothesis - clinical trials conducted in humans.
Once again, the logic is straightforward; a healthy stem cell of the diseased cell line (dopaminergic neurons) is directly implanted in the location of the diseased cells.
A magical treatment for Parkinson’s Disease with stem cells
There are a lot of stem cell clinics, (particularly overseas) already promoting the treatment of Parkinson’s Disease. What type of stem cells are they using, and how are the cells delivered inside the brain? It turns out, most clinics use mesenchymal stem cells harvested from the patient’s fat, which are given back in the bloodstream via an intravenous drip.
But hold on! I think I have some questions and comments:
The veins first take blood to the lungs. Wouldn’t fat stem cells get stuck in the small capillaries of the lungs causing clots?
If the stem cells made it past the lungs, what other organs would they end up in, and what effects would this have?
Supposing the stem cells all managed to travel to the brain, how would they cross the blood brain barrier?
If they did cross the blood brain barrier, why would they only go to the Substantia Nigra of the brain?
Isn't the engraftment rate very poor (stem cells do not survive in the location they are injected)?
Fat stem cells can’t differentiate into neurons. How do fat stem cells help the damaged dopamine secreting nerve cells?
Haven’t stem cells been shown to induce tumors?
No published human trials can be found.
Granted, there are studies in petri dishes showing stem cells doing some amazing things, and secreting powerful cytokines. However, the effects are not all beneficial, and they are dependent on the surroundings of the stem cells.
Putting this together, in order for an intravenous infusion of fat stem cells to help Parkinson’s Disease, there must be a series of unlikely events leading to an inexplicable distant effect. Sounds like magic. However, Arthur C. Clark did say,
“Any sufficiently advanced technology is indistinguishable from magic.”
But let's not be fooled her. This therapy is more like a classic magic trick, conducted by a magician that knows the art of misdirection and deception. Read a sample of the promotional websites presenting testimonials of dramatic cures, and neglecting to mention possible complications. You would think you were in Las Vegas.
Infusion of fat stem cells into the blood to treat Parkinson’s Disease not only lack plausibility, it could be dangerous. It should be held under extreme scrutiny until human clinical trials are completed. This should be contrasted with dopamine producing IPS cells implanted directly into the Substantia Nigra. They too, require human clinical trials to determine efficacy and safety; but, at least they are plausible.
Unlike some of my other more sobering emails, this one contains hope. I think stem cell technology may lead to a cure for Parkinson’s Disease (unless it is beaten to the punch by other innovative approaches). It is real science. It is extremely important to distinguish the plausible applications from the implausible ones, especially while we are in the midst of an evidence gap.
Every successful treatment is built on the rumble of many failures.