In the magazine
Scientific America, I came across an article, Altered
Virus Calls Out Hidden Cancer Cells–and Might Help Fight Them, Too, which presents the novel findings that the infamous herpes virus
could actually be used to detect the early onset of cancer. With the
modification of the wild type Herpes virus it can not only be designed to
specifically attack cancerous cells, but it also acts as a vector for a blood
detectable biomarker. This finding could lead to a routine procedure for the
early detection of cancer without the patient being subjected to numerous
screening processes.
With early
detection being key for a good prognosis, Biomarkers (substances that can be
used as indicators for the presence of particular diseases) are valuable tools
that allow for both screening and detection of the early onset of cancer.
Unfortunately, there are currently only a select few types of cancers that have
known biomarkers. This leaves detections of cancerous cells or fully formed
tumors to be delayed until symptoms of the primary tumor or secondary tumor has
arisen and by then it can be too late. But don’t despair there is hope. Timothy
Cripe and his fellow researchers have discovered a way to target and mark
cancer cells that normally lack a known biomarker through virus modification. Cripe’s principle, as seen in the article Cancer screening by systemic administration of a gene delivery vector encoding tumor-selective secretable biomarker expression, was to single out
and target cancerous cells via a modified virus and force the affected tumor
cell to secrete the biomarker carried in the virus’s genome.
Virus and Biomarker Choice:
The virus Cripe
and his fellow researchers chose to use was the Herpes Simplex
Virus (HSV) type 1, for numerous reasons. First of all the herpes virus can
efficiently infect virtually all human cells types because it is able to interact with various cell surface receptors leading to numerous and different
possible methods for cell entry. The virus is capable of being produced in
sizable quantities, and previous studies have shown it to be safely controlled
with current antiviral drugs. To target the virus specifically to cancerous
cells, Cripe mutated the section of the HSV genome that encodes for the
ribonucleotide reductase (an enzyme that
catalyzes the formation of DNA building blocks
from RNA building blocks) large subunit
(ICP6/UL39) and the late
viral protein ICP34.5 (c134.5). “This mutation limits robust viral replication specifically to
tumors”(Cripe). HSV is also epigenomic
meaning that modifications of the cell’s DNA leave the sequence unaltered while
gene expression is effected, this allows for the biomarker to be inserted. In
this case the Bio Marker chosen was Gaussia luciferase (GLuc). This biomarker
is a reporter molecule that is in turn secreted from the cell. This Biomarker
is found to be significantly brighter than other luciferases, and can be
detected in both blood and urine samples.
Testing Method and Results:
To test the overall
strategy of exogenous biomarkers and tumor identification, Cripe and his fellow researchers injected mice with the modified and
bookmarked HSV and waited several days. Then they took blood
samples from both tumor absent and tumor-infected mice. They also harvested the
cancer effected organs to see not only if the GLuc levels but also that the
GLuc expression were coming from tumors and not normal cells. Note this
experiment was not only conducted not only in
vivo but in vitro as well and on
various types of tumors. This testing resulted in two Major findings. First,
there was a significant difference between GLuc levels in tumor present and
absence mice. Depending on the size of the tumor the GLuc levels ranged from 15
to 440- fold higher expression in tumor present mice compared to the
non-cancerous control mice. The results revealed 90% of all mice subjected with
cancer produced enough of the biomarker to be blood test detectable. Secondly, through
the “immunofluorescence for GFP expression and quantitative PCR” for the virus’s
genome the researchers were able to conclude that the virus copies were at
least 2100 fold greater in tumors than in healthy tissue.
Critique and Concerns:
Though I
found this article very interesting and with definite promise for becoming a
widely used method for cancer detection, I did come across some pitfalls and
further questioning. Up to now, this experiment has only been preformed on mice,
and though the researchers, in their scientific article, have calculated
theoretical mouse to human conversion, there is no published data supporting
that this will be reproducible in humans as predicted and with the same
significance levels. But, if their mice to human calculations are proven to be
accurate with further testing on humans, then if only 10% of the cells in the
tumor are infected with the tagged HSV a tumor as small a 1-4 mm in diameter
would be detectable, and if only 1% of the cells are infected a tumor the size
of 8.5 mm in diameter would be detected. Also, when Cripe wanted to identify whether
injecting larger doses of the virus would increase the in vivo GLuc secretion, he found that though there was a great
significance in the viral genome amplification (4000 fold when set to the
testing parameters) the Gluc levels in the blood only rose 10 fold. While this
increase is still significant, it definitely falls short of the viral genome increase.
The researchers have shown that the blood screening is doable and effective in
reveling the presence of mice tumors, even with small diameters, but is the blood
test as efficient as a test that could be developed for the screening luminescent
or viral count? A possibility to extend upon the provided research would be to
find a way to scan a patient
and their organs to detect the exact location of the tumor after the proposed
blood test detects that there is cancer present. I feel if this is possible it
would greatly improve the likely hood of early detection an survival rates
because not only would there be a was to detect the present of very small
tumors but at the same time have a way to locate the tumor resourced already
provided from the HSV injection.
Though this
technology could potentially save lives because of the benefits from early
cancer detection, I feel there will be public and ethical barriers to overcome. Both the primary and magazine article
hints at the possibility of human immune responsive. As with the advent of vaccines and immunizations, putting a virus into
someone intentionally does not come without backlash and fear of side effects.
Also, the mass production and supply of HSV could leave people with the fear of
alternative side mutations that could contain potentially harmful side effects.
Both articles hint at how previous
exposure to the virus will affect the levels of both viral genome integration
and in turn the GLuc levels. Though they present the fact that in previous
research pre immunized animals still experience therapeutic benefits form HSV
with sustained efficacy, I wonder how will
multiple injections of the virus effect the overall outcome in tracking
treatment. My main concern is that the tumor will become gradually resistant to
the HSV virus leading to a decrease in the GLuc levels for subsequent blood
tests showing a false sense of tumor shrinkage, but in actuality, the tumor did
not shrink and the virus was not being integrated as well. Another critique I
had with the article in the magazine is that it stated that it might help
reduce the size of the tumor, but I feel that the primary article did not
discuss that in enough detail to accurately make that assumption. The door of
targeting cancer cells is open reveling the possibilities for new and innovative
ways to detect the early onset of cancer.
Work
Cited:
Browne, Andrew W, et al. “Cancer Screening by Systemic Administration of a Gene Delivery Vector
Encoding Tumor-Selective Secretable Biomarker Expression.” PLoS One (11 May, 2011). Web. 15 May, 2012
Harmon, Katherine. “Altered Virus Calls Out Hidden Cancer Cells-and
Might Help Fight Them, Too.” Scientific
America, 11 May, 2011. Web. 15 May, 2012
