ALAN TYNDALL. Stem Cell Therapy; Hype or Hope?

What do you think of when you hear the phrase “stem cell therapy”? Miracle cures for wheel chair bound paraplegics? Building new organs to replace burned out old ones? Eternal beauty and youth? Immortality?

These were certainly some of the expectations of the public at large fed by social media and the lay press in general, following a massive number of scientific publications on the subject. Well over 180,000 papers in the peer reviewed medical data base called Pubmed are coded under “stem cell therapy”, and hundreds of centers worldwide offer everything from penis enlargement to centuries of longevity or cures for dreadful incurable progressive diseases. Many of these are either naively optimistic or cynically fraudulent, and some are outright dangerous. The FDA in the US recently published a statement on this and as a result Google no longer hosts such websites.

Let’s ask some clarification from science at this point with the definition of stem cell: a true stem cell, when dividing, gives rise to one daughter cell which remains “stem”, and the other which starts differentiating toward an end- stage functioning cell with a limited life span. The stem cell par excellence is the so called “embryonic stem cell”, obtained by destroying an early stage embryo called a blastocyst 3-5 days after an egg has been fertilized by a sperm in the laboratory. These are able to differentiate into any type of cell in the body, and are therefore called “pluripotent”.

However, the most commonly used stem cells are obtained from adult tissues. Nearly all our organs have these, the best example being the blood system which is able to produce billions of new cells every day for the whole of our life, thanks to the modest reserve of stem cells tucked away in the bone marrow.

As one could imagine, stem cell therapy with embryonic cells involves scientific, ethical, theological (and political) issues which will be discussed later on. On the other hand, there are few non-scientific issues complicating the field when the stem cells are obtained from individuals, mostly adults, and which have a limited ability to differentiate into other cell types (called multipotent stem cells). For example, blood stem cells.

When, at the beginning of this century the explosion on stem cell research occurred, only one therapeutic treatment with true stem cells existed, that with hematopoietic (blood) stem cells. In leukemia and other blood cancers, after chemotherapy +/- radiation has wiped all “bad” and “good” blood cells including their stem cells, giving back healthy blood stem cells from donors allows a new and healthy blood and immune system to develop. The Nobel Prize for Medicine was given to E Donnal Thomas in 1990 for this life saving development with over 1 million bone marrow (source of hematopoietic stem cells) transplants having been given worldwide saving hundreds of thousands of lives.
Well, sorry if I disappoint you, but at the moment there are only two approved indications for true stem cell therapy: the above mentioned bone marrow transplantation, and corneal transplant for damage to the front of the eye. Such a paucity of indications appears to contradict the public expectations and the abundance of claimed applications. Two major explanations could be the following.

Many so called “stem cell therapies” actually employ very early differentiated progenitor cells such as mesenchymal “stem” cells which are not truly “stem” and therefore do not survive indefinitely in the host. These cells are obtained in large numbers and with relatively inexpensive methodology from several tissues including fat, placental products and bone marrow. Based on their capacity to differentiate into fat, cartilage and bone in addition to showing some immunosuppressive activity in the laboratory, they have been used extensively in patients to treat inflammation and to regenerate damaged tissues. Their positive safety profile has encouraged hundreds of clinical trials, but so far resulting in only around 10 approved indications. But remember, these are not true” stem “cells, and should be correctly called mesenchymal “stromal” cells.

No therapy utilizing pluripotent stem cells has yet been approved.

The controversy on the use of embryonic stem cells relates to the ethical and theological issue of “ensoulment” i.e. the moment of the creation of the soul and therefore an individual human being. In the Christian faith this is at the moment when the sperm meets the egg (Papal Bull by Pius IX in 1869), in the Jewish and Muslim faiths, when the fetus “quickens” (the first maternal sense of fetal movements). Of course, this issue related and still relates also to abortion and its political and legal implications. These issues have led to the prohibition of such research in the US under the George W. Bush government, when such research moved off shore from the USA.

A good solution to this impasse in the use of embryonal stem cells came when it was found that a mature adult cell, say from the skin, could be genetically reprogrammed to return to a pluripotent state called induced pluripotent stem cells (iPSC), thus eliminating ethical issues and for which Shinya Yamanaka was awarded the Nobel prize for Medicine in 2012. One of the most useful application of such cells has been that for drug testing, sparing of the life of many laboratory animals.

Unfortunately, scientific progress has not progressed in this field as fast as human expectations and we can only feel compassion for desperate patients and their families seeking a glimpse of hope in the search for new therapies.

Media, both professional and social, should have the responsibility of delivering correct information, especially related to such sensitive issues as public health and not to use a suffering public for demagogic and political purposes. One such case was that related to the Stamina project, in Italy. Davide Vannoni, who was neither scientist nor medical doctor, led a team which began in 2007 treating patients, often children, with various terrible neurodegenerative conditions with mesenchymal stromal cells which he claimed had been reprogrammed to become functioning nerve cells. After a long process, including exposure of his wealthy lifestyle, he was finally convicted along with others in 2015 of conspiracy and fraud and sentenced to 5.5 years in prison. He died in December 2019 at the age of 59 from cancer.

This case is especially important since it involved extreme lobbying from desperate patients and families which, supported by some media groups, political parties and sympathetic (but not scientifically guided) judges, nearly resulted in pressuring the government to sponsor a clinical trial costing 3 million Euros against all scientific advice. There are still those who feel Vannoni and his methods were victims of a conspiracy from big pharma and other agencies.

This is not surprising. We humans most readily accept information that is consistent with our pre-existing deeply held beliefs; indeed, functional MRI studies of our brains suggest that information which challenges such beliefs activate the same brain regions which light up when challenged with real physical threat i.e. “fight or flight”. In addition, such information tends to deepen rather than alter the mindset of the subject, independent of its veracity. In psychology this is known as the” backfire effect” and applies to any area of belief be it political (as in the above study), religious, vaccination, climate change etc.

So much for the hype. What about the hope?

There is plenty! Correctly performed research and clinical trials are increasingly expanding the potential application of many cellular therapies, including stem cell therapy, in clinical practice and reducing the toxicity in bone marrow transplantation. As mentioned above, the life-saving potential of bone marrow transplantation comes at a high price from the chemotherapy and / or radiation needed to wipe out the malignant cells and prepare the patient to accept the transplanted healthy blood stem cells and reset the system.

Recent work has suggested ways of targeting just the blood cells by using a molecule to sneak in a toxin which then turns off the cell’s machinery leading to a quiet demise (killing me softly?). This is officially known as an antibody drug conjugate, popularly referred to as “ The Trojan Horse” approach.

With the absence of collateral damage to other tissues, this could result in a less toxic but equally effective treatment not just for traditional diseases such as leukemias, but also for others such as severe autoimmune disease like arthritis and multiple sclerosis.

It may also increase the use of blood stem cells taken from children with single gene defects e.g. sickle cell anemia, to be taken out of the child, genetically corrected in the laboratory, then given back after wiping out all the bad stem cells, and resulting in a normal blood system with their own cells life -long.

Work in progress!

Alan Tyndall was professor and head of the Department of Rheumatology at the University of Basel from 1991- 2013. His main interests are stem cell therapy of autoimmune diseases and systemic sclerosis (scleroderma). Alan has served on the boards of the European Society for Blood and Marrow Transplantation ( EBMT) and the European League Against Rheumatism (EULAR). He has published over 230 peer-reviewed papers, 100 of which relate to stem cell therapy, and 30 book chapters.
He received his undergraduate medical degree at the University of Sydney in 1972. His postgraduate qualifications are FRACP and FRCP(Ed), with postgraduate experience in Canberra, Sydney, and London.

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