PERSONAL GENOMICS AS A DOUBLE-EDGED SWORD:

THE PROMISE FOR MEDICINE & THE PERILS OF DISCRIMINATION

Zach Jarou
Department of Physiology
Michigan State University

Spring 2008
 THE PERSONAL GENOMICS REVOLUTION

Paradigm Shift
Surrealist artist Rene Magritte, creator of the iconic “Son of Man”
which depicts a modern day businessman who’s face is concealed by an
apple of temptation, was once quoted as saying, “everything we see hides
another thing, we always want to see what is hidden by what we see.”
Although art & science employ drastically different methodologies, their
primary goals are the same: to explore & explain the world around us.
Magritte’s words are evocative a scientific perspective by which the
universe is nothing more than a large puzzle can be solved through logic,
reason & empirical observation. As we begin to piece more of the story
together, oftentimes we must rethink pervious assumptions in order to
satisfy new data
Within the last 50 years, the field of biology has undergone a massive
paradigm shift. As we delve deeper into the layers of matter that define us,
from a metaphysical standpoint we are nothing more than a walking,
talking chemical reaction. The discovery of the double helix structure of
DNA by Watson and Crick in 1953 forever revolutionized the field of
biology. Later, Crick’s “Central Dogma” of Molecular Biology would
elucidate the mechanisms by which cells store, transmit and use
information.

From Information to Machinery

Hierarchically, all organisms are comprised of many systems
containing various networks of organs specialized for a particular function
depending upon the types of tissue present. Tissues are collections of
interconnected cells performing similar functions according their
proteomes. As the molecular machines that are involved in many aspects of
cellular function, including enzymatic catalysis, signaling & structure. Each
protein within the cell performs a duty specified by the information
contained in its corresponding gene.
According to Crick’s “Central Dogma,” there is normally only a one-
way flow of information in the cell, where DNA is responsible for storing
the blueprints, which must be carried out of the nucleus in the form of
RNA to be translated into a protein at a ribosome. During protein
biosynthesis, the linear sequence of nucleotides comprising the DNA of
each gene is read in triplets, or codons, that specify particular amino acids
that are linked to form the primary structure of the protein. This primary
structure then folds locally into more energetically stable alpha helices or
beta sheets by forming hydrogen bonds. These secondary structures then
fold further to give rise to a tertiary, three-dimensional configuration;
quaternary structure refers to a supramolecular machine formed by the
aggregation of several individual peptides to perform a single function.
Changes in an organism’s DNA sequence can cause an alternate
amino acid to be selected for which causes the polypeptide to improperly
fold. Because a protein’s function is determined by its structure, it cannot
properly perform its role within the cell. This may have several negative
consequences for the organism, including genetic disorders.

Human Genome Project

At a cost of $3 billion, the Human Genome Project was one of the
largest scientific endeavors in all of history. Co-sponsored by the United
States National Institutes of Health and Department of Energy in 1990 and
lasting for a period of 13 years, the major goal was to sequence the 3 billion
base pairs responsible for coding proteins that make life possible for
mankind. Scientists also sought to identify the genes coded by these
sequences and digitize this information for computational analysis. Prior to
the investigation there was great speculation among scientists over the
number of genes present in the human genome. It is now commonly
believed that there are between 20 and 30,000, 50% of which still have
unknown functions. Interestingly, many scientists were shocked at how
few genes humans have in comparison to many plants and bacteria (HGPI
2007).

From an Economic Perspective

DNA sequencing technologies were also greatly improved as a result
of the HGP. For example, in the four-year period from 1996 to 2000, 4
billion quality bases were sequenced, beginning at a cost of $2 per base and
eventually declining to nearly zero. The second and third sets of 4 billion
bases took only two and one years, respectively.
Economically speaking, as the speed of sequencing increases, the
cost of production declines, resulting in an outward shift of the supply
curve. Ultimately, this results in a lower market equilibrium price for
genomic sequencing and a higher quantity of sequences provided. In 2008,
only 5 years following the completion of spending $3 billion to decode the
first genome, private companies such as Knome (know-me) are offering
whole genome sequencing (WGS) for as little as $350,000. While this price
does not make this technology available to the public at-large, it is available
for those fortunate enough to be able to afford it. And in perhaps what I
believe to be one of the most revolutionary scientific goals that will occur
within my lifetime, there is an industry-wide goal and belief that within the
next decade, continued technological advancement will make a $1,000
whole genome sequence possible. The implications of this are obviously
huge as at such a reduced rate, this technology has the capacity to
thoroughly diffuse the marketplace (Weinstock 2007).
 To avoid confusion, there are some companies currently offering
genetic analysis at the thousand dollar level, such as 23andMe and
deCODE, but rather than providing a comprehensive whole genome
sequence, they are limited in identifying only a limited number SNPs.
SNPs, single nucleotide polymorphisms, are simply one base-pair letter
variations in DNA that occur in greater than 1% of the population. To date,
approximately 3 million SNPs have been identified. SNPs can be used for a
variety of purposes, including stratifying the efficacy of drugs on different
individuals, paternity testing and forensic crime scene investigations.

ELSI & the Great Divide

Another unique aspect of the Human Genome Project was that in
addition to funding revolutionary scientific research, it also embodied the
creation of the world’s largest bioethics program. Approximately 3-5% of
the annual budget was devoted to addressing the ethical, legal, and social
issues surrounding the availability and use of genetic information.
Currently, there are two opposing schools of thought regarding how
mankind should interact with our carefully evolved blueprints. On one side
of the aisle, there are those who optimistically believe that genomics has
the potential to cure disease & enable us to solve many pressing world
issues, not only in the health care industry, but also through improved
agriculture, energy independence, carbon sequestration etc. On the other
hand, there are also some vehemently opposed to progressing down this
path. They believe that our genetic information is personal and permanent
and believe that under the guise of improved medical care they may be
paving the way for designer babies or discrimination by insurance
companies (HGPI 2007).
 THE PROMISE FOR MEDICINE

Preventive Care
From a medical standpoint, having access to a patient’s genome has
the potential to revolutionize the entire health industry. By identifying
genes that predispose an individual to a particular disease, precautionary
measures can be taken to avoid environmental conditions that may trigger
its onset. While the our current health care system is very useful for
trauma, focusing on the more fundamental causes of diseases will pave way
for a new type “Western-holistic-preventive” medicine, in contrast to the
largely reactionary system we have today. Overall, having access to this
information early in life will grant individuals more choices and more
control in deciding their overall health and future.

Gene Therapy
In cases where personal genomic sequencing revealed that an
individual contained “bad” or mutated genes, gene therapy could
potentially be used to cure these hereditary disorders. During this process,
new, correctly functioning copies of the defective genes are inserted into
the host genome so that they can be expressed as normal. There are several
components to this process, the most critical of which is a vector, or vehicle
for transmitting genetic material into a cell, commonly a virus. New genes
can then be inserted through the action of reverse transcriptase, which is
able to synthesize DNA from RNA, in a manner opposing that of the
“Central Dogma;” restriction enzymes can also be used to cut DNA at
particular sequences and insert new material.
While potential benefits of therapeutic gene therapy are numerous,
there are several difficulties that must be overcome before it becomes a
viable clinical option. First of all, disorders best treated by gene therapy are
those attributed to a disruption of just a single gene; unfortunately, most
disease states are associated with multiple interacting components.
Secondly, finding a good vector has proven to be more difficult than
originally anticipated. Retroviruses, the earliest used vectors are able to
effectively deliver new genes to host cells, when cells that divide in vitro are
transferred to the recipient, they stop division. To circumvent this
problem, researchers next began testing the efficacy of adenoviruses, which
are able to produce treated cells that divide in vivo. The downside of this
approach is that adenoviruses trigger a large immune response by the host;
through millions of years of evolution, our bodies have adapted
mechanisms to resist viral infection, regardless of whether the cargo is
good or bad. Finally, while gene therapy used to be talked about
prominently as one of the most promising areas of therapeutic science,
there have been a few cases in the past during which improperly handled
vectors caused patient death (Judson 2006).

Pharmacogenomics
In a drastically different approach to the “one-size-fits-all” style of
prescribing therapeutics, pharmacogenomics gives physicians the ability to
optimize effects for each patient based on their unique genetic makeup.
The majority of drug metabolism is mediated by the cytochrome P450
enzyme system in the liver. New technologies such as the Roche AmpliChip
allow easy analysis of CYP450 system component levels and variations. By
determining the efficiency of metabolism in each patient individually, side-
effects related to a build up of activated or precursor drugs can be avoided
and dosages can be tuned to be effective for a proper amount of time,
without wearing off.
While this technology is already available, it does have a couple of
hurdles to overcome before it becomes the norm. First, because of its
novelty, it is extremely costly to use for testing (often $1300+) and not
covered by insurance. The second obstacle is getting doctors trained on the
benefits of using the new technology. Most of them are reluctant to switch
and would rather continue using “trial & error” methods (Singer 2006).

Nutrigenomics
The saying used to be “you are what you eat,” but today most
nutritionists agree “you bring two things to the table, your appetite and
your phenotype” (Rodriguez). Nutrigenomics seeks to custom tailor our
diets to realize our fullest genetic potential. Nutrients in many of the foods
we eat have the ability to alter gene expression and because these nutrients
are acting each of our unique genomes, well all respond differently to the
foods we eat. We can make up for inherited genetic weaknesses by eating
differently or taking supplements when necessary. Another possibility is to
provide increased nutrient to entire populations via the genetic
modification of staple crops (Kummer, 2005).

Attention: Job Opportunity

Unfortunately, it doesn’t appear that the medical community is
prepared for the personal genomic revolution. In the United States, there
are only 509 clinical geneticists (for reference of how absurdly small this is,
there are 481 astronauts… in the WORLD).

THE PERILS OF DISCRIMINATION

Interpretation of Results
Having access to an individual’s genetic sequence is not necessarily
dangerous in itself; the danger more so is related to the manner in which
we choose to interpret the results. Each of use has mutations that place us
at risk for some disease, but that does not guarantee that we will develop it.
It is a modern day example of “nature vs. nurture,” but in fact there is no
black or white, only shades of gray; gene transcription is turned on and off
throughout life in response to variety of factors, both environmental and
genetic. Our genes are not like dominos, whereby the simple presence of a
gene creates a direct cause and effect pathway leading to contraction of the
disorder. Rather, our genetic profiles act as probabilistic guides that can
aid us in predicting our individual risk for certain conditions and empower
us to make positive lifestyle decisions to avert them.

Insurance Companies & Employers

Referencing the previous warning, there is no other group that would
like to adopt a fatalistic approach to genetic analyses as insurance
companies and employers. As profit-maximizing entities, their primarily
responsibility is to their shareholders; considering genetic abnormalities as
“pre-existing conditions” would save them large amount of money. This is
alarming, considering the fact that employer-sponsored health insurance
covers more than half of all Americans. In order to avert the danger of
being discriminated against, many individuals may choose to avoid genetic
testing altogether. Opting out based on fear will cause many to miss out on
advanced medical benefits in order to keep their current plans (GDFS
2007).

Worst-Case Scenario: Genetic Castes

Taking it to an extreme, some are worried that in the long run, this
technology will pave the way for a genetic caste system. Many people are
familiar with this idea as it was a theme that was explored in the 1997
drama, sci-fi, thriller Gattaca. In the film, children of the wealthy are
ensured to have only the best traits of their parents through the use of pre-
implantation screening while faith births result in genetically “inferior”
offspring.
The society in which the characters live is eugenically driven so that
only those with superior genotypes being able to secure professional jobs.
Despite being born with myopia and a congenital heart defect, the main
character Vincent is forced to assume the identity of a biologically
“superior” person in order to achieve his life-long dream of becoming an
astronaut.

THE FUTURE IS IN OUR HANDS

While the possibility for negative outcomes certainly does exist, one
would hope that our society is mature enough to not allow them to
manifest themselves. That idea that we should have to overlook the
numerous medical benefits as a result of our fear in the intentions of
society is extremely pessimistic. The technology IS coming; therefore it is
imperative that we are adequately prepared. First and foremost, it is
essential that there be increased scientific education of the public and
secondly, that we need to act politically to ensure that our rights are
protected.
Currently, HIPAA (the Health Insurance Portability and
Accountability Act of 1996) states insurance companies have the right to
collect genetic information from their members and use it to charge higher
rates. It does, however, acknowledge that genetics alone, without
diagnosis, does not constitute a pre-existing condition. During the Clinton
Administration, although he was unsuccessful in passing a version for the
private sector, Executive Order 13145 banned discrimination in Federal
employment based on an applicant’s genome. Currently in the legislative
process is GINA (the Genetic Information Nondiscrimination Act of 2007),
it has already been passed by the US House and is expected to reach the
Senate floor during the week of April 14, 2008 (HGPI 2007).
 REFERENCES
Baker, C. (1999). Your Genes, Your Choices. American Association for the
Advancement of Science.
“Genetic Discrimination Fact Sheet.” (2007, November). Retrieved April 1,
2008, from National Human Genome Research Institute, National
Institutes of Health. Web site: http://www.genome.gov/10002328
“Human Genome Project Information.” (2007, July). Retried April 1, 2008,
from U.S. Department of Energy Office Science. Web site:
www.genomics.energy.gov
Judson, H. (2006, November). Part I: The Glimmering Promise of Gene
Therapy. Technology Review. Retrieved April 1, 2008, from MIT.
Web site: www.technologyreview.com/
Kummer, C. (2005, August). Your Genomic Diet: Your genetic profile could
be the key to staying health and eating right. Technology Review.
Retrieved April 1, 2008, from MIT. Web site:
www.technologyreview.com/
Singer, E. (2006). Still Waiting for Personalized Medicine:
Pharmacogenomics promise to let doctors choose drugs and dosages
based on tests of your genetic profile. But just try taking a test.
Technology Review. Retrieved April 1, 2008, from MIT. Web site:
www.technologyreview.com/
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plummeting cost of DNA sequencing heralds the year of the personal
genome. Technology Review. Retrieved April 1, 2008, from MIT.
Web site: www.technologyreview.com/