For decades, stem cell therapy and stem cell research have generated much hope and controversy for the public and scientific community alike. While the controversy is still raging, the publication of ‘Flesh Made New’, a popular science book, is a timely contribution. In this book, hematologist and stem cell expert John Rasko teamed up with historian and writer Carl Power to chart the 100-year history of stem cell research, and the result is a mesmerising narrative of successes, failures, promises, even frauds.
Most of us are no stranger to stem cells. Over the past 10 years or so, stem cell therapy and stem cell research have inspired many headlines in popular media. Some scientists and doctors enthusiastically embrace on the research and treatment using stem cells. Funding agencies and philanthropy groups are keen to support stem cell research. Patients with incurable diseases desperately seek stem cell therapy as the last hope. We are promised that stem cells will one day be used for treating a multitude of ailments, ranging from dementia, autism, multiple sclerosis, spinal cord injury, Parkinson’s disease, heart failure to type 1 diabetes. However, virtually all promises have not been materialized, and patients are still hopeful. The media, scientists and patients have collectively generated much hope and hype. It is the hype of stem cell therapy that is the feature of this book.
Rasko and Power make an excellent point that “Hype tends to encourage amnesia. It fixes your attention on the future rather than the past, the latest rather than the long term, the breakthroughs rather than the deep continuities. Hype frames each discovery as a game-changer, a fresh start, a reason for looking forward, not back.”
With that statement as a rationale, the authors take us through the history tour of stem cell research, spanning from early 20th century to early 21st century. They draw on their well experience on stem cell research and medical history, and critical reading of hundreds of scientific papers to deconstruct the stem cell science. Readers will learn about heroic efforts of meticulous and good-intentioned scientists with their successes, their blunders, their fascinating personal lives and colorful personalities. Readers will also meet some charlatans, even downright fraudsters, who have generated much hype and compromised the stem cell science.
A shaky beginning
Readers will meet the brilliant French surgeon Alexis Carrel, who cultivated chicken heart tissue in test tube with what he called ‘embryonic juice’ (which was actually chicken plasma). He demonstrated that the tissue had survived long after the chicken’s death. Naturally, he thought that he had discovered the immortality of life. Actually, one of his papers (published in 1912) titled “On The Permanent Life of Tissues outside the Organism”. He became a celebrity in the world of medical science for that work.
However, it turned out that the good-intentioned doctor was completely wrong: human cells have limited life span such that they they die after about 50 times of division. His blunder, probably due to his bogus experiments or fraud, has delayed the field for the next 50 years.
Nevertheless, Carrel is still considered a genius who laid the first brick for stem cell science. In 1912, Alexis Carrel was awarded the Nobel Prize in Physiology or Medicine for his work in suture blood vessels and transplantation of organs. He was the first living person in the US to win the Nobel Prize in medicine, although he was a French citizen.
The creation of stem cell science
It is little known that the idea of stem cell therapy was originated from the atomic bombings of Hiroshima and Nagasaki in 1945. In a dispatch from Japan, the Australian journalist Wilfred Burchett described the health of the people living in areas affected by the bombings as follows: “suffered absolutely no injuries, but now are dying from the uncanny after effects. For no apparent reason, their health began to fail. They lost appetite. Their hair fell out. Bluish spots appeared on their bodies. And, the bleeding began from the ears, nose and mouth.” Doctors gave them vitamin A, but it did nothing to relieve the symptoms.
The symptoms are later known as “bone marrow syndrome”. Radiation kills off bone marrow, and the body of victims could not replace red blood cells, white blood cells and platelets, making their body starved of oxygen, and their immune system compromised.
Thus, in the aftermath of the bombings and during the Cold War period, doctors rushed to find a therapy for the new disease. Drugs were trialled, but none of them eventuated. In 1949, the breakthrough came when Leon Jacobson (University of Chicago) transplanted spleen from non-radiated mice into radiated mice. In subsequent year (1951), Egon Lorenz demonstrated that he could save a mouse that was given a lethal dose of radiation by injected bone marrow from a non-radiated mouse. Their work has opened a new era of bone marrow transplantation for leukemia.
The science of stem cell was actually created by two meticulous scientists: James Till and Earnest McCulloch of the Ontario Cancer Institute (Canada). In the early 1960s, Till and McCulloch studied the effect of radiation on bone marrow, and through a series of experiments, they identified a ‘new’ cells that they called ‘multipotent stem cells’. Their discovery was published in a rather low profile journal Radiation Research in 1961. Two years later they published further discoveries in Nature in which they categorically settled the long standing controversy: all blood cells are originated from a single cell called ‘stem cell’. (The original word was in German, ‘stemmzelle’, and was actually coined in 1905 by the German hematologist Artur Pappenheim).
The first bone marrow transplantation
One of my favorite scientists featured in the book is Donnall (‘Don’ for short) Thomas and his wife Dottie. Don Thomas is considered ‘the father of bone marrow transplantation’ and an unassuming giant in medicine. He graduated from the University of Texas at Austin with a BA (1941) and MA (1943), and with the help of his wife in essay writing, he got admitted to the Harvard Medical School in 1943.
After graduating from Harvard, he became chief resident then instructor at Harvard, where he helped Dr. Joseph Murray in providing care to patients with kidney transplantation. In 2003, Thomas and Murray shared the Nobel Prize for Physiology or Medicine for his work in bone marrow transplantation to cure leukemia and other hematologic malignancies.
Don Thomas was the pioneer who invented bone marrow transplantation, considered the first stem cell therapy. His ground-breaking work was actually conducted in a rather modest institution Mary Imogene Bassett Hospital in Coopertown (New York). He was recruited by Dr Joe Ferrebee to Coopertown in 1955, and started the bone marrow transplantation there. However, the success only came after all 6 patients died, and only 2 showed evidence of transient engraftment.
In a publication in 1957, Thomas warns that “the complexity of the problem of marrow transplantation, with its unknown quantities and potential hazards.” In 2005, after winning the Nobel prize, he still sounded the alarm: “We simply do not know whether these cells will ever be of use for patients with Alzheimer’s disease, Parkinson’s disease, or spinal cord injury.” This warning still rings true now ever.
Leroy Stevens was a developmental biologist, an unsung hero of stem cell science. He graduated from Cornell with a BS (1942) and University of Rochester with a PhD in embryology (1952). In 1958, while working on a strain of mice known as ‘129’ in the Jackson Lab in Bar Harbor (Maine), Stevens noticed a large testicular tumor (ie teratoma) on a mouse. Curiously, the tumor was composed of hair, skin, bone, and muscle tissues. In 1954, Stevens and Clarence Little (the founder of Jackson Lab) reported that 30 out of 3557 mice of strain 129 had teratoma. One of these tumors could be maintained through transplantation under the skin or into abdominal cavity of other mice over 16 generations.
In subsequent work, Stevens and colleagues traced the origin of teratoma to find out where and when it comes into being. Their question led them to look at the genital ridge in a 12-day prenatal mouse which has primordial germ cells. In 1970, Steven observed that the primordial germ cells looked like the cells of earlier embryos. Furthermore, by transplanting cells of early 129 strain embryos into testes of adult mice, he observed that some of the early embryo cells caused teratomas! Stevens called these cells ‘pluripotent embryonic stem cells’, the origin of the term ‘ES cell.’ That discovery heralded a new era of stem cell research.
Jamie Thomson is also prominently featured in the book. Trained as a biophysicist, Thomson received his doctorate in veterinary medicine in 1985. In the 1990s, while working on IVF projects in Wisconsin, Thomson and his team successfully created the first human ES cells. This important breakthrough was reported in a Science paper (1998), and was later considered “Scientific Breakthrough of the Year” article. The isolation of human ES cells has literally created a new science: regenerative medicine.
The discovery of ES cells has raised the hope of gene therapy. The idea is to transfer genetic material into patient tissues and organs to rescue their impaired functions. Stem cells, especially ES cells, can be considered vehicles for gene therapy. Moreover, human ES cells can, in theory, be genetically manipulated to introduce the therapeutic gene.
However, Thomson’s work on ES cells has also generated considerable controversy. The heart of the matter is that in order to create ES cells, human embryo must be destroyed, and that is considered a ‘murder’ by some. Understandably, the destruction of human embryo is not accepted by Pro-life people.
Gene therapy and shonky operators
In late 1990s, a gene therapy trial was initiated and the result was devastating. The first patient to received gene therapy was Jesse Gelsinger, 17 years old, who suffered a rare liver disease called ornithine transcarbamylase deficiency syndrome (OTCD). Jesse’s parent decided to participate in the gene therapy clinical trial head by James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania. On 17/9/1999, Jesse was unfortunately dead, and the treatment (gene therapy) had killed him. In retrospect, doctors thought that there was no need for him to be treated by gene therapy, because medication and diet could help control the disease.
The death of Jesse Gelsinger has sent a chilling message to the medical research world and inquiries were held. Rasko and Power write that “the final verdict: gene therapy had been over-hyped and pushed into clinical trials far too quickly”. Indeed, in competitive environment of medical research, scientists are incentivized to oversell any discovery that is mostly fragile and irreproducible.
Reproducibility is the cornerstone of science. However, in reality most (perhaps up to 90%) of medical research findings are either irreproducible or false. Rasko and Power referred to a study by Glenn Begley and Lee Ellis (Nature 28/3/2012) who validated 53 landmark studies published by some of the world’s top tier journals, and they could reproduce only 6 studies — a mere 11%. In other words, approximately 90% of the most important studies were not reproducible. Commenting on this paper, the eminent physicist Robert Weinberg of MIT said that “to my mind, that [paper] was a testimonial to the silliness of the people in industry — their naiveté and the lack of competence.”
Many high profile cases of irreproducibility and fraud, including the Paolo Macchiarini, Obakata and the Hwang Woo-Suk affairs, are mentioned in the book. One particular case involved Dr. Piero Anversa caught my attention is the ‘broken heart’ story. Conventional wisdom says that blood stem cells should only able to make new blood, not new heart or new muscle. However, in a paper in Nature, Anversa showed that stem cells from one tissue could be reprogrammed to have function in another tissue. He invented a new word: ‘transdifferentiation’. He further claimed that to repair a broken heart, one does not need to harvest blood stem cells, just give a hormone called G-CSF. His work in regenerative medicine was prominently featured in the New York Times with eye catching titles such as “Study finds heart regenerates cells” and “Stem cells yield promising results.” Anversa, a respected cardiologist, became a scientific celebrity.
However, Anversa’s findings could not be reproduced by other scientists. At Amgen, Begley who had the perfect skill and experience for the G-CSF study, could not reproduce the Anversa’s data. In subsequent years Begley found out that even Anversa’s lab could not reproduce their own findings. Other scientists also could not reproduce Anversa’s work, and they have published their ‘failure’ in Nature. Yet, by that time, there were 10 clinical trials with 200 patients who were put on the marrow-to-heart treatment!
Eventually, an internal investigation by Harvard University found that Anversa and his 2 colleagues had fabricated data, and their misdeeds stretched back a decade. Harvard University fired the 3 individuals, and Brigham Hospital (where Anversa conducted his work) was forced to repay the US government $10 million for grants that Anversa had obtained.
Rasko and Power remark that “bad science flourishes where hopes are highest, where the pressure to succeed and the promise of reward are greatest. Which suggests that the top science journals, the best research institutes, and the hottest fields of investigation attract more than their fair share of bad science.”
An interesting part of the book discusses the issue of ‘Medicinal Cannibalism’ which is also relevant to controversies surrounding stem cell therapy. Briefly, medicinal cannibalism is the practice of using the human body, dead or alive, to treat diseases. Apparently, during the Renaissance, Europeans regularly consumed human flesh and blood for hundred of years. Consumers included both the poor and the aristocracy in Germany, England, Italy and France. Yet, the authors write, “when European explorers ‘discovered’ the Americas, they were shocked to find cannibalism practised there. In their view, to eat a vanquished foe or a beloved relative was pure savagery.”
As savagery as it seems today, the drinking of human blood and the smearing of human fat are still practised by some people in the medical establishment nowadays. In 1954, Paul Niehans, a prominent Swiss doctor, used a method he called ‘cellular therapy’ to treat Pope Pius XII. His method was quite cannibalistic: he would kill a pregnant ewe to obtain its alive fetus, minced the required organs and mixed them with a salt solution, then injected into the Pope’s wasted buttocks. It is not clear whether the trick worked, because Niehans never provided any evidence of efficacy.
Fast forward to 2016, a young doctor from California named Jesse Karmazin opened a clinic in Monterey where he offered blood plasma from healthy young people to people with a health problem. He claimed that the plasma could fight against disease such as Parkinson’s disease, multiple sclerosis, diabetes, cancer. He also advertised that the plasma could rejuvenate and revitalize people’s heath. The plasma came with a rather hefty price tag: $8000 per litre! However, in 2019 FDA warned that such a ‘therapy’ has ‘no proven clinical benefits for the uses for which these clinics are advertising them and are potentially harmful.’ As we can see, the journey from an orthodoxical doctor to a quackery practitioner is not far.
In Flesh Made New, Rasko and Power make a point that most of existing stem cell treatments are essentially medicinal cannibalistic. They write: “skin grafts, organ transplants, blood transfusions and stem cell therapies can be considered forms of medicinal cannibalism. In each case, part of the body is turned into a remedy that, while not actually eaten, is consumed by, or incorporated into, the patient.”
So much for fantasy.
The French surgeon René Leriche once said that “Every surgeon carries within himself a small cemetery, where from time to time he goes to pray — a place of bitterness and regret, where he must look for an explanation for his failures”. If we replace the word ‘surgeon’ with the phrase ‘stem cell research’ we have a good summary of the past and current state of stem cell science. Indeed, the progress of stem cell science has been paved with unknown human lives for years and years before a modest success is known.
Most people tend to believe that the treatments they receive are safe and effective, that they have been rigorously tested and have passed stringent regulatory control. However, in stem cell science, the belief is flawed. Rasko and Power tell us that most advocated stem cell therapies are not evidence based; they have neither been rigorously tested nor passed regulatory control. The FDA has literally lost control over thousand of stem cell clinics that offer bogus treatments to unsuspected patients. And, the authors advise that ‘you need to be sceptical whenever you hear about an exciting new stem cell breakthrough, especially one that promises medical miracles. In all likelihood, it won’t live up to expectations.’
The public at large trusts that doctors and scientists produce a body of reliable knowledge for the benefit of humanity. However, this is increasingly not the case, because nowadays most of medical research findings are either false or unreliable. The marriage between fame, commercial interests, and scientific knowledge has produced a situation in which fame-seeking and profit motive cloud the ideal of dispassionate intellectual inquiry. Rasko and Power show that in the stem cell industry, the goal of relieving human suffering has sometimes become subservient to the pursuit of fame and money.
Are the authors trying to shame stem cell science? Absolutely not. They categorically state that ‘Our aim is not to discredit stem cell research […] We are marking on a map, so to speak, where the pitfalls and perils lie, the places where others have met with disaster and that should be avoided in future.’
I have enjoyed reading Flesh Made New very much. Using a narrative style, the authors deconstruct study by study, scientist by scientist, until we find ourselves immersed in the world of stem cell science. The good thing about this book is that it is not a US-centric narrative, because it documents scientists and work inside as well as outside USA (Yugoslavia, Ukraine, Canada, France, Japan, etc). There are lots of scientific information, but they are put in context of human interest, making it eminently readable by people of all backgrounds. Indeed, I think this book is a good primer for students beginning in the field of stem cell research, and a good reference sources for patients and the public alike.
As a non-native English speaker, I am hesitant to comment on the quality of language. However, I brave myself to say that the quality of writing is simply outstanding. There are lots of beautiful English expressions in the book that should be part of a teaching resource for science students. The language is non-technical and easy going. It is not an average popular science book, but readers don’t need a science degree to digest the information and data in the book.
A number of books on stem cells have been published, but Flesh Made New is the best treatment of this subject I have read so far. If you want to find out all about stem cells from the history of medical, ethical, and social perspectives, this is the must-read book for you. I highly recommend it to you.
Statement of CoI: I have no professional relationship with Dr Power and Professor Rasko. I have come to know Professor Rasko a few years ago when he gave a lecture at the Garvan Institute of Medical Research. I was impressed by his lecture. So, when this book was published only 4 weeks ago I was among the first to get hold of a copy to understand the current state of stem cell science.