Cancer.
It only takes one cell gone rogue for it to spread like wildfire throughout the body,
multiplying and spreading throughout the organs until they can no longer function.
While genetic mutations are commonly associated with causing cancer, there is another key
player in cancer’s rapid development and proliferation: epigenetic changes.
Epigenetic changes are changes that regulate gene expression that don't involve changing
DNA base pairs themselves.
Some of these add different chemical groups to the DNA, such as DNA acetylation and methylation,
while other changes such as histone modification affect how tightly DNA binds to histones.
These epigenetic changes affect the accessibility of a gene to transcription factors, making
it more or less likely to be expressed.
In the human genome there are tumour suppressor genes which are responsible for preventing
cancerous cells from proliferating too fast by inhibiting their growth or triggering cell
death.
However, epigenetic changes in cancerous cells can prevent the expression of these genes,
while also increasing the expression of oncogenes – genes that promote abnormal cell growth.
It's like cutting the cell’s brakes and holding the accelerator down a one-way road
to cancer town.
You might be wondering: Wouldn’t removing these epigenetics changes allow us to turn
back time and revert the cancer cell back into a normal functioning cell?
Well to answer that, we have to go back in time ourselves.
In 1938, Nobel laureate Hans Spemann developed the concept of nuclear transplantation.
The process involved injecting a nucleus from an adult donor cell into an oocyte whose nucleus
had been removed, generating a cloned embryo.
This embryo could then be transferred to the uterus of another female where the embryo
could potentially grow.
This infant would be an exact clone of the donor animal.
In 1998, it was found that during this process, the oocyte could reprogram a terminally differentiated
cell back into an embryonic stem cell.
These stem cells were pluripotent, being able to differentiate and develop into any somatic
cell type in the body.
However, how this worked remained a mystery until Konrad Hochedlinger came along in 2002.
Hochedlinger and his group of researchers found that these oocytes had the ability to
reset the epigenetic modifications in terminally differentiated cells, leaving the genome unaltered
in the process.
In their 2004 paper, they hypothesised that nuclear transplantation of a cancer cell into
an oocyte could reprogram the epigenetic modifications contributing to the cancerous phenotype and
revert them back into non-cancerous pluripotent stem cells.
To test this, Hochedlinger and his group conducted nuclear transplantation of tumour cells into
embryos of mice.
The clones were allowed to develop into blastocysts, which were explanted in tissue culture to
derive embryonic stem cells.
They then inserted these embryonic stem cells into Rag2 deficient blastocysts.
Once these had matured, they analysed the grown chimera mice’s genotype and phenotype.
At the time they were only able to get living embryonic cells using melanoma, however, subsequent
studies have been able to generate embryonic stem cells from a larger variety of cancers
using similar methods.
Normally, Rag2 deficient mice have NO mature lymphocytes such as B and T cells.
However, using specific antibody B and T cells markers, Hochedlinger was able to detect the
presence of these lymphocytes in the Rag2 deficient chimera mice grown in his experiment.
They concluded that the B and T cells found in the mice were a result of the transplanted
embryonic stem cells becoming pluripotent and differentiating into these immune cells.
Furthermore, when comparing the genomes of the chimera mice with the original cancer
cells, they found that their genomic profiles were identical.
This confirmed that the embryonic stem cells were in fact the transformed melanoma cells
and not other non-transformed cells that had contaminated the experiment, something past
studies had failed to do.
Importantly, the grown mice had no evidence of the cancerous phenotype.
Thus, Hochedlinger concluded that the oocyte cytoplasm had successfully reprogrammed the
epigenetic changes in the tumour cell nucleus and reverted it back into a non-cancerous
stem cell.
So we cracked the code right?
We have the tools to reprogram all our cancer cells back into healthy stem cells.
Well, not quite.
In further tests Hochedlinger repeated the protocol using melanoma strains whose cancerous
phenotypes could be induced by high expression of the RAS gene.
He then gave the grown mice doxycycline in their drinking water to increase the RAS gene
expression.
He found that these mice developed a larger variety of cancers faster and more frequently
compared to the donor mouse model, suggesting that these cells were predisposed to getting
cancer, due to a failure to remove abnormal cancer-causing mutations in the genome itself.
The process also remains incredibly inefficient.
Less than 20% of the embryos injected with the cancer nucleus survived to even be examined
by Hochedlinger.
Also, even if we could find an oocyte large enough to stick a person inside, we wouldn’t
want to reset all their epigenetic modifications, because in functioning parts of the body,
they play an important role in regulating processes needed for survival.
So is epigenetic reprogramming the magic cure for cancer?
Unfortunately not at the moment.
But it provides a strong foundation for future research into epigenetics as a potential cancer
treatment.