Rudolf Virchow in 1861, two years after he published Cellular Pathology. Image from Wikipedia Commons.
With their technology so severely limited (as compared with today’s world), I’m always amazed at how often the 19thcentury scientists got things right. Maybe it’s because we only hear about the scientists whose theories have survived the test of time: Charles Darwin, Louis Pasteur, Paul Ehrlich. Still, it is no small feat to develop such a theory, and it’s often amusing and informative to go back to its roots in history.
A few years ago I bought a 1940 edition of Rudolf Virchow’s Cellular Pathology, originally published in 1859. Virchow was a German physician with an aggressive personality and a tendency to be confrontational, but he also had a strong sense of empathy and was adept at forming collaborations with other scientists. Spending a good deal of time treating the lower class, Virchow was an early champion of social medicine, and he even tried to push the future German chancellor Otto van Bismarck to spend fewer resources on an army and more towards public health, to a point where Bismarck challenged him to a duel (Virchow declined). But Virchow is most famously known for his “cellular theory”. He challenged the popular idea at the time that cells were more or less passive bystanders during the disease process. In contrast, Virchow believed that diseases result from changes in cells, as opposed to just overall changes in tissues or organs. (In modern times, we’ve reduced this even further to identify changes in molecules).
But the most famous part of Virchow’s cellular theory is his argument against the then-accepted notion that cells could spontaneously arise from a thick organic fluid called the “cytoblastema”. The idea of spontaneous generation (the origin of living organisms from nonliving material) had been dying a long death at the hands of other scientists for the last two hundred years, and it was slowly becoming accepted that even microbes cannot spontaneously arise on their own (which had seemed to be the case in rotting meat). Virchow applied this idea to cells in the human body, saying that every cell must come from another living cell, as he clearly stated in Cellular Pathology:
Where a cell arises, there a cell must have previously existed (omnis cellula e cellula), just as an animal can spring only from an animal, a plant only from a plant… No developed tissues can be traced back either to any large or simple element, unless it be unto a cell.
“Omnis cellula e cellula” – all cells from cells. A fitting rallying call for such an important theory. Although it was such a game-changer, I have no doubt that had he not proposed it, someone else would have suggested it within a few years, especially since Louis Pasteur finally put the idea of spontaneous generation to rest the same year Cellular Pathology was published. (Actually, there is controversy as to whether Virchow stole the “all cells from cells” theory from the Polish scientist Robert Remak, who first proposed a similar idea some years before. No great idea is formulated in isolation – all ideas from ideas – but if Virchow did use Remak’s theory, we must fault him for not attributing the proper credit.)
The general principle that tissues, and therefore organs, and therefore organisms, ultimately originate from a single cell is the idea behind stem cell theory of modern times. We all start off as one cell, a zygote. The zygote divides, then divides again, and again, and again, and again… until the mass of cells eventually becomes a human being. Along the way, some cells start to change – “differentiate” – into more specialized forms – liver cells, nerve cells (neurons), muscle cells, and skin cells – until you have a fully-functioning human being. The amazing part of his process is that whenever a cell divides, it makes an exact replica of its DNA, so all of the different types of cells in our bodies have the same genes. So how can cells be so different, yet have the same set of blueprints?
The answer is that cells control which genes are going to be active, and they do this by turning genes on or off, or cranking them up or tuning them down. Therefore, a liver cell and a skin cell, even though they both have gene X, it may only be active in the liver cell and turned off in the skin cell. It’s as if each cell is an extremely complicated machine containing thousands of switches and knobs, and the degree and sequence of switch-flipping and knob-turning will determine what the machine does. What’s more, because all the cells in our body ultimately came from one cell, a sort of “family tree” can be drawn. The two most common cell types in the small intestine – enterocytes and goblet cells – are virtually “cousins” because their common ancestor is only two or three cells back on the family tree. However, an intestinal cell and a neuron are much more distantly related, even though they share the same DNA and are ultimately derived from the same cell.
Until recently, it was believed that you can only move in one direction on the cellular family tree: from zygote to differentiated cell. This is why embryonic stem cells are of great interest, because, according to stem cell theory, these cells can be persuaded to convert to any cell type, although this is no easy task. But lately there have been breakthroughs in reverting differentiated cells back to their ancestral cells (so-called “induced pluripotent cells”), which may be more useful (and less controversial) because these ancestral cells are much further along in the family tree than embryonic stem cells (think “grandparents” as opposed to “great-great-great-great-great-great-grandparents”). Scientists have applied this theory in attempts to develop cures for diseases where certain cells are missing or being destroyed, such as diabetes and neurodegenerative diseases. In the case of diabetes, type 1 diabetics suffer from a loss of the insulin-producing beta cells in the pancreas. One type of treatment, scientists are hoping, would be to remove some of these precious cells from the patient, coax them into multiplying in the lab to increase their numbers, and then put them back in the patient. The problem has been that the beta cells don’t seem to grow well, neither in the body nor in the lab, and the ones that do grow in the lab seem to undergo changes and don’t produce much insulin. So to get around this, researchers at The Hebrew University and Tel-Aviv University in Israel have applied stem cell theory. They isolated beta cells from the pancreas, and then they used a virus to induce the expression of certain genes which make the beta cells revert back to a state similar to their ancestral cells, which can divide in the lab. But the cells can still “remember” that they were once beta cells, so, once they have undergone sufficient divisions, they can be easily induced to undergo re-differentiation back into insulin-producing beta cells.
Of course, this is more of a proof-of-principal experiment and far from an actual therapy. Any treatment that involves a virus is going to undergo serious scrutiny, and a lot of work will need to be done to see what effects this manipulation has on the long-term safety and functionality of the beta cells. But it is an important step because theoretically it could be applied to many different cells in all types of tissues.
I think Rudolf Virchow would be proud. So much possibility from such an elegantly simple theory: all plants from plants, all animals from animals, all cells from cells.
Sources:
Virchow, Rudolf. Cellular Pathology. John Churchill London, 1859.
Simmons, John. Doctors and Discoveries: Lives that Created Today’s Medicine. Houghton Mifflin Harcourt, 2002.
Bar-Nur, O, et al. “Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells”. Cell Stem Cell, 2011.
