IN 1697, John Dryden, translating the Roman poet Virgil, wrote that “From one root the rising stem bestows a wood of leaves, and vi’let-purple boughs.” More than 150 years later, the German naturalist Ernst Haeckel used the green stem of a plant that rises into unfolding complexity as an analogy for the diversification of life from single-celled ancestors, which he called Stammzellen: stem cells.
Haeckel believed that the development of a foetus followed a sequence corresponding to life’s historical evolution — from a single cell through a series of progressively more complex forms — often summarised in the phrase “ontogeny recapitulates phylogeny.” The single cell at the root of this sequence, and thus analogous to the single-celled organisms, was the fertilised egg. This Stammzell gave rise through repeated divisions to the approximately two hundred different cell types that make up a human body: from muscle cells to red blood cells, neurons to the liver. This definition of stem cell indicated that potential. Others later extended the definition again, to cover any cell capable of differentiating into different types.
A stem cell is a bundle of potential: scientists call it “pluripotent.” The genome inside all human cells is the same, or very close to it.
But the type of a cell is determined by patterns of expression of that genome. The cell’s nature is shaped by which proteins are made in what quantities within the cell. Once begun, the process of differentiation sets the cell down a path from which, usually, there is no return.
Differentiated cells are trapped in their specialisation. The direction of travel is only one way, and the process doesn’t start again until fertilisation through the fusion of gametes, the sperm and egg cells, leads to the production of stem cells. In plants a green shoot forcing its way through the earth may become a tree, but we know that a leaf that falls from the grown tree cannot.
As is so often the case in biology, this is not a fundamental law of reality. In the 1960s, the British biologist John Gurdon took a differentiated frog cell’s nucleus — the heart of the cell, containing its DNA — and injected it into an egg cell with its nucleus removed. The result was a tadpole. This remarkable finding showed that the genome of a differentiated cell still contained all the potential to make other cells. But this process still relied on having an “empty” stem cell on hand. It is the chemical makeup of the stem cell’s “body” that frees the potential gene expression of the inserted nucleus.
It took 40 years to work out how to turn a differentiated cell itself back into a stem cell. A team led by Shinya Yamanaka at Kyoto University in Japan managed the historic feat in the mid-2000s. Yamanaka and his colleagues carefully chose cellular factors that they thought were involved in maintaining the pluripotent state, then injected them into differentiated cells. Careful experimentation and trial and error found that, in mice, just four factors were enough to restart a cell’s history.
There was huge excitement about the promise of this technology: the possibilities for cellular medicine that grew what the body needed inside it were huge. But there was also fear.
When cells in the body change away from their programmed state “naturally,” we call it cancer. The risk to many researchers was that in messing with cellular differentiation, clinical trials might inadvertently introduce malignant cell types into patients. Some trials were stopped because of this fear.
In 2019, Japanese scientists got permission to inject pluripotent stem cells into four people with spinal injuries. The hope was that they would boost the growth of neurons to repair the spinal cord.
On March 21 this year, they announced the results at a press conference. The study has not yet been properly reviewed or published, but the claims are encouraging. Two out of the four men in the trial showed large improvements after the injections, and none experienced adverse effects. As Nature reporting on the conference summed it up: “A paralysed man can stand on his own… Another man can now move his arms and legs following the treatment.”
There is no way to tell from such a small trial whether the improvements should be attributed to stem cells. Patients with injuries to the spinal cord can sometimes recover without treatment; the body’s own remarkable capacity to heal and regenerate can be substantial. But this small study paves the way for larger trials that offer a glimmer of hope.
That hope could be dangerous. The promise of transformative therapies that are just around the corner is not new for patients with spinal injuries, and that faith can have the effect of diminishing the lives of real people now.
Providing services and support for people with life-changing disabilities is fundamental. Even if we dream of extrapolating the results of this small study, we should remember the two patients who saw no real benefit. It will take a lot more time and effort to test the therapy, including assessing the risk of longer term side-effects.
This is where the story will become messier. The scientists involved in the trial founded a startup in 2016 called K Pharma to commercialise stem cell therapies. It will have received a great boost from the positive PR surrounding this latest news.
Its therapies will be expensive, and they will not be available to everyone. The extent of future studies into the therapy will largely be defined by the money invested in this and other competitor startups, and publicly funded research.
The development of any imagined therapy starts as a bundle of unrealised potential, but every encounter with the real-world produces only one historical trajectory. But there is nothing inevitable about this process. As the ability to induce pluripotency back into differentiated cells shows, things that appear to be immutable — simple facts of nature — can sometimes prove much more flexible.