Selected Student Papers
Janelle Pisarik
Paper #1
3 February 2005
Kuru, Prions, and Cannibalism:
An Interesting Link to Human
Genes’ Past
ABSTRACT: Prions are protein particles similar to viruses and they are
easily spread from human to human. Kuru is an acquired prion disease found in
the Fore tribe of Papua New Guinea. It is believed that Kuru was spread during
ritualistic cannibalistic activities. After DNA analysis of members of the Fore tribe
who participated in such activities, Dr. Simon Mead and his colleagues were able
to draw conclusions about the human prion protein gene. Heterozygosity for a
common polymorphism in this gene was shown to provide a resistance to prion
diseases, while homozygosity proved susceptible to these diseases. Different
forms of this polymorphism have been found all over the world, supporting the
assumption that these genes evolved over time in their respective ethnic groups.
While prion diseases can be transmitted through eating animals, the fact that
gene variations are cultural and that cannibalism is an easier way to spread the
disease and was practiced in many tribes, animal transmission is not considered
a high possibility. With the beginning of the kuru epidemic, homozygotic
individuals were selected against and thus a balancing occurred. With the lack of
cannibalism, many younger generations are more genetically diverse. The
author of the newspaper article did a very thorough job of explaining prions, kuru,
and scientific conclusions. There was no slant in the article and the author was
even able to include work from other, earlier studies to compare them with
current findings.
****
Anthropologists and scientists have long debated whether or not
cannibalism was practiced throughout history, or whether it was only practiced in
small, ritualistic communities and in times of starvation. New studies, however,
may confirm that cannibalism was, at one time, common throughout much of the
world. These studies deal with human DNA and the evolution of particular genes
associated with certain diseases that transfer readily through the act of
cannibalism.
The study originated in the early 1950s with Dr. D. Carleton Gajdusek’s
observations of members of the Fore, a tribe from the eastern highlands of
Papua New Guinea. Dr. Simon Mead and his colleagues continued research in
to this subject in the early 21st century. Attention was drawn to the Fore in the
mid-1950’s, when Australian authorities banned cannibalism, a ritual the Fore
had been practicing since the end of the 19th century. The Fore were found to be
suffering from a fatal neurodegenerative disease (a disease that slowly changes
and deteriorates the nervous system including our spinal chords and brains)
known as kuru. After the first noted case in 1920, the disease spread rapidly
among the Fore, who had no direct contact with the outside world. While the
disease spread rapidly, it seemed to mainly affect the tribe’s adult females and
children of both sexes. (It is well known that adult Fore males participate little in
the cannibalistic ritual.) Kuru killed 1% of the Fore population annually and it was
found that young adult women were non-existent in some villages.
Kuru is a form of what is known as a prion disease. Prions are protein
particles very similar to viruses and they are spread easily from one mammal to
another through the act of eating the meat of an infected animal or human. It is
believed that one human with a random mutation of a particular prion was
consumed by members of the Fore. Yet not all members of the Fore contracted
kuru. Why? Dr. Mead believes it has to do with human genes. In his experiment
he sampled the DNA of 30 Fore women over the age of 50. All of these
members had repeatedly participated in the mortuary feasts of the early 1900s,
yet they were still living without symptoms of the disease. Dr. Mead noted that
once an individual has consumed the prion, the prion proteins will begin to
deform the person’s normal neural proteins (hence the name
neurodegenerative), leading to the disease and eventually to death. While
examining the DNA samples, Mead discovered that there were polymorphisms
(variations of the same gene) at a specific spot on the human prion protein gene
(PRNP). This specific spot, labeled codon 129, exists as two polymorphisms in
Fore individuals. Twenty-three out of the thirty Fore women tested were found to
contain a copy of each of the polymorphisms; they are thus considered to be
heterozygotes for PRNP. However, other members of the tribe who contained
two copies of either of the polymorphisms (also known as homozygotic
individuals) died after partaking in the mortuary feasts. The combination of both
polymorphisms seemed to inhibit or greatly reduce the protein to protein
interaction that is needed to spread prion diseases, such as kuru in an individual.
Individuals that were homozygotic had an onset of kuru at the average age of
nineteen, while the heterozygotic individuals could harbor the prion for well over
thirty years without showing any signs of the disease.
The study of the Fore led to a worldwide study of prions and codon 129
and a shocking discovery was brought to light. Different ethnic groups contained
different polymorphisms of the human prion protein gene. Five polymorphisms
were found in total, all of which were ethnically dispersed, with a greater quantity
of different polymorphisms detected in African, South Asian, East Asian, Pacific,
European, and South American cultures. Yet heterozygosity of each culture’s
particular prion protein gene polymorphism at codon 129 was still shown to delay
the onset of prion diseases such as kuru, Creutzfeldt-Jakob disease, and madcow disease. The hypothesis on heterozygosity was further confirmed by the
fact that all of the people that contracted the human version of the prion mad-cow
disease were homozygotic at codon 129. About half of Europe’s population
today is heterozygotic for prion resistance, which would account for the low
frequency of mad-cow patients.
The question that remains, however, is why do we have these
polymorphisms to begin with? PRNP does not appear to scientists to be a
rapidly changing and evolving gene. Europeans, Africans, and members of the
Fore are all characterized by a very distinct version of the polymorphisms, thus
suggesting that changes in codon 129 are ancient. Also, natural balancing
selection of these polymorphisms has been seen. This means that while
homozygosity for either of the polymorphisms in a population is unwanted, both
polymorphisms are needed to insure heterozygosity. Those homozygotic
individuals die, while those with both copies live and breed, passing on both
polymorphisms. While researchers know that kuru began and was spread by
cannibalistic acts in the Fore tribe, strong inferences can be made about
cannibalism throughout the world. Prion diseases are only spread by eating
meat of an affected individual or animal. One might suggest that these
polymorphisms occurred due to the eating of affected animals, not humans. Yet
if this was the case, many animals with the same prion would have to be
consumed by most members of the population. The jump between animal and
human strains of prion diseases is so large, that it would be virtually impossible
for these diseases to be solely due to animal, and not human, ingestion. This
can be further proved by the fact that only 134 people have contracted mad-cow
disease out of the 50 million people that live in Europe. This minute number
would not be enough to evolutionally shape our genes and select for or against a
specific combination of polymorphisms in a population. While Dr. Mead could not
rule animal consumption as the spreading of prion diseases out completely, he
considers it highly unlikely, based on three things: how ethnically specific these
polymorphisms are; how quickly a prion disease could be spread throughout a
cannibalistic community, thus naturally selected for variations in the gene; and
how unlikely it is that every member of a community would have eaten the same
affected animals. Thus cannibalism seems a very likely solution to the origin of
the human prion protein gene.
These conclusions by Dr. Mead and his colleagues give rise the
authenticity of research reported by the popular press. One may ask how correct
the article in The New York Times entitled “Gene Finds Cannibal Pattern” really
is. In all actuality, the author did a very nice job presenting the process and
conclusions of the Gajdusek and Mead experiments and explaining the concept
of kuru and prions and how heterozygosity is beneficial. However, he
oversimplified the concept of polymorphisms. As opposed to explaining that
different ethnic groups contain different forms of the prion protein gene, he simply
said that certain individuals have a protective gene signature and others do not.
Overall, the article does not contain a slant, as the author simply presents the
information and assumptions made by Dr. Mead as opposed to analyzing the
information and producing his own conclusions.
In summary, prion diseases such as kuru are fatal neurodegenerative
diseases spread by eating infected meat. Humans have evolved to contain
polymorphisms of a prion protein gene at the codon 129. When someone with
two copies of the same polymorphism eats infected meat, they contract the prion
disease. However, if homozygotic individuals eat the same meat, they may not
show signs of the diseases for years afterwards, and possibly never even know
that they ate the prion. Different prions have evolved in different cultures, and
the main reason for this seems to be that cannibalism was practiced by different
cultures throughout the world. The article does a fine job of presenting a
scientifically accurate representation of the concept and nature of the
experiments preformed by Dr. Simon Mead.
Bibliography
Mead, Dr. Simon, et al. 2003. “Balancing Selection at the Prion Protein Gene
Consistent with Prehistoric Kurulike Epidemics.” Science 300: 640-643.
Wade, Nicholas. “Gene Finds Cannibal Pattern.” New York Times, 11 April 2003.
Chan Jing Quan, Alex
BIOS 11108 – 26th February 2005
Biology Essay 2 – Study Discovers Genetic Link to Atherosclerosis
Researchers have long suspected atherosclerosis to be a genetically
linked disease, since it has a higher tendency of affecting individuals who are
related to patients already diagnosed with the condition. Up till now, the specific
genes that may lead to a higher susceptibility to atherosclerosis in individuals
have not been positively identified by scientific research. However, in a recently
concluded study, a team of scientists might just have uncovered one such gene.
Atherosclerosis is a disease involving the inflammation and build-up of
plaque along the walls of major arteries, making them narrow and hard.
Diabetes, smoking, high blood pressure and high blood cholesterol levels may
promote damage to the arterial linings, setting up an inflammatory response that
results in plaque formation at these sites. It is this deposition of plaque (derived
from cholesterol in the blood) that causes the walls of the arteries to become
narrow and hard. This obstruction of blood-flow may eventually lead to potentially
fatal incidences of heart attacks (loss of blood to the heart) and strokes (loss of
blood to the brain). Thus atherosclerosis, if left untreated, is a life-threatening
condition.
A paper published in the 1st January 2004 issue of the New England
Journal of Medicine reports that a group of scientists from the University of
Southern California and the University of California, Los Angeles, have
uncovered a genetic link between a variation of the 5-lipoxygenase (ALOX5)
gene and the onset of atherosclerosis. Researchers have discovered a positive
correlation between the presence of this genetic variation in an individual’s
deoxyribonucleic acid (DNA) sequence and his/her susceptibility to acquiring the
disease.
DNA is a biological formation of specific sequences of nucleic acids that
serve as our body’s blueprints. Within this sequence is information that pertains
to how each part of our body is to be constructed and put together. Genes are
selected sequences of DNA that are construction codes for specific amino acid
sequences. These amino acids later combine to form proteins that make up the
cells, tissues and organs of our body. Hence genes are essentially sub-sections
of our body’s blueprint, each with a specific role to play in the proper functioning
of the body.
More specifically, the genetic sequence in question is the ALOX5 gene,
coding for the ALOX5 enzyme that plays a crucial role in the arterial lining’s
inflammatory response. An enzyme is a protein that facilitates biological
reactions within the body, and the ALOX5 enzyme aids in the formation of
leukotrienes that react with a product of fatty acids in the blood to induce arterial
inflammation.
Within the scope of this study, the objective was to determine the extent, if
any, to which possessing a variation of the ALOX5 gene increases the chances
that an individual develops atherosclerosis.
Headed by Professor James H. Dwyer, the team examined a randomly
selected cohort of 470 healthy men and women from the Los Angeles
Atherosclerosis Study between the ages of 40 and 60 who had not been
previously diagnosed with cardiovascular disease. In attempting to establish a
genetic link to the onset of atherosclerosis, the population of the test subjects
was limited to a controlled demographic profile so as to minimize the negative
effects that exogenous factors like location, culture and social circumstances
might have on the accuracy of the study. Even though the researchers
hypothesized that different individuals might be more or less genetically
predisposed to acquiring atherosclerosis, it was important that all test subjects
began the test healthy and “on a clean slate”, so that the onset of the condition
can be tracked more accurately in relation to their diets and lifestyles.
Atherosclerosis is considered a multi-variable disease, and the assessment of as
many factors as possible will aid in the credibility of any conclusions drawn.
Researchers took ultrasounds to measure the open diameter of the
subjects’ carotid artery (a major blood vessel in the neck), the thickness of which
is known to be a marker for atherosclerosis. The narrower the open diameter of
the carotid artery, the thicker and harder the arterial walls are thought to be,
indicating the inflammation and build-up of plaque along this lining. Ultrasound,
commonly used in pre-natal check-ups, is an ideal procedure in the examination
of this critically important blood vessel because it is a non-invasive procedure,
reducing the risk of any medical complications arising due to the study.
Furthermore, the team took DNA samples from subjects to determine their
genotypes with respect to the ALOX5 gene: ascertaining whether they were
heterozygous or homozygous for the common allele or variant allele. The alleles
of a gene are basically different versions of the genetic sequence that occupy the
same position, or locus, on a chromosome. The genetic material in human
somatic (body) cells is split into twenty-three pairs of corresponding
chromosomes and the ALOX5 gene is located on 10q11.2, which refers to a
band (11.2) on the long arm (q) of the tenth chromosome (10). Since a normal
individual has a pair of chromosome-ten’s, he/she can possess either a common
or variant allele on each of the two chromosomes. A person who has two copies
of the same allele has a homozygous genotype for that particular allele, while
he/she is considered to be of heterozygous genotype if he/she has one copy of
each allele.
In addition, since fatty acid consumption has been shown to affect the
onset of atherosclerosis, researchers also sampled six 24-hour records of the
subjects’ diet over a 1.5-year time span so that they could assess the subjects’
fatty acid consumption. A distinction was further made between the intake of
arachidonic acid (a fatty acid found in non-marine meat) and marine fatty acids,
since the former is thought to promote the build-up of plaque along the arterial
walls while the latter discourages this development.
The team then used data collected from the above methods to determine
how the different ALOX5 genotypes affected arterial width, and how these
different genotypic groups responded to the consumption of different types of
fatty acids.
Researchers found that 94% of subjects had at least one copy of the
common ALOX5 allele (homozygous for the common allele or heterozygous).
However, the team discovered that subjects who were homozygous for the
variant ALOX5 allele had significantly thicker arterial walls than their peers,
putting them at a greater risk of contracting atherosclerosis. The study further
proposed that this increase in risk is similar in magnitude to those faced by
diabetics but smaller than those experienced by smokers. Regarding the dietary
effect, and taking into consideration the genotypes of the individual subjects, it
was discovered that those who had at least one copy of the common ALOX5
allele showed little disparity in arterial diameter regardless of their diets.
However, subjects who were homozygous for the variant allele benefited, in
terms of having larger arterial diameters, from consuming more marine fatty
acids and less arachidonic acid. The results indicate that the common ALOX5
allele may aid in regulating the inflammation of arterial linings and that
consuming marine fatty acids, rather than arachidonic acids, may be a healthier
choice for subjects who are homozygous for the variant allele, since it appears to
inhibit the build-up of arterial plaque in the test group.
Though a commonplace diagnosis for the variant ALOX5 allele may not be
available in the near future, we can certainly benefit from the results of this study
by replacing our consumption of saturated fats (which form arachidonic acid in
our bodies) with omega-3 (marine) fatty acids found in fish oils. This will help
reduce the inflammation and plaque build-up in our arteries and hence lower our
susceptibility to developing life-threatening atherosclerosis later on in life. The
road to good health begins with simple lifestyle-changes; why not start making a
difference today?
Reference
“Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid,
and Atherosclerosis”
The New England Journal of Medicine, 1st January 2004, Volume 350, Pages 2937.
By James H. Dwyer, Ph.D., Hooman Allayee, Ph.D., Kathleen M. Dwyer, Ph.D.,
Jing Fan, M.S., Huiyun Wu, Ph.D., Rebecca Mar, B.S., Aldons J. Lusis, Ph.D.,
and Margarete Mehrabian, Ph.D.
Chan Jing Quan, Alex
BIOS 11108 – 24th January 2005
Biology Essay 1 – Gene is linked to susceptibility to depression.
Why is it that some people appear to be greatly affected by stressful
circumstances, while others seem to be able to sail through life relatively
unperturbed by its inevitable pressures? Why is it that some individuals appear to
be more susceptible to depression, while others seem to be able to bounce back
quickly from trying situations with greater optimism and enhanced vigor? These
are some of the questions a team of genetic biologists was trying to find answers
to when they embarked upon a study that followed the lifestyles of 847
Caucasian non-Maori New Zealanders over the course of twenty-six years. In
attempting to establish a genetic link to the occurrences of depression, the
population of the test subjects was limited to a particular demographic profile so
as to minimize the negative effects that exogenous factors like location, culture
and social circumstances might have on the accuracy of the study.
The object of the study, conducted by a team led by Avshalom Caspi at
the U.K. Medical Research Council's psychiatry research center at King's
College, London, was to investigate genes that might be activated by
circumstances that individuals encounter during the course of their lives. Genes
are selected sequences of deoxyribonucleic acid (DNA) that are genetic codes
for specific amino acid sequences that combine to form proteins that make up the
cells, tissues and organs of our body. Hence genes are essentially sections of
our body’s blueprints. Within the scope of this study, the initiating factor under
observation was the occurrences of adversely stressful situations.
More specifically, the genetic sequence in question was the ‘5-HTT’ (5-HT
transporter) gene, coding for a protein that finely controls the regulation of
serotonin (5-HT) in the body. A neurotransmitter is a chemical that transmits
signals within the central nervous system and serotonin is one such
neurotransmitter that is believed to play an integral part in the biochemistry of
depression and anxiety. The Swedish Medical Center rightly notes that
“serotonin, a chemical messenger in the brain, is known to have an effect on
depression and is the target of the serotonin reuptake inhibitors that are often
used in its treatment.” Here it is referring to the fact that serotonin is the target of
antidepressants like Prozac that affect its uptake. Therefore, it would follow
logically that a study that seeks to understand the genetic causes of depression
should focus its attention on the body’s own natural regulator of serotonin, the ‘5HTT’ gene.
Previous studies have shown that the ‘5-HTT’ gene is present in two
common alleles, which are basically different versions of a gene that occupy the
same position, or locus, on a chromosome which holds genetic material in the
form of DNA. The two common versions of the ‘5-HTT’ gene, denoted as the long
allele (l) and the short allele (s), are found on 17q11.2, which is the address of
the gene corresponding to its location on the long arm (denoted by ‘q’) of the 17 th
chromosome. Human beings have two sets of twenty-three chromosomes, and
each of the two 17th chromosomes has either an l or an s ‘5-HTT’ allele on it.
The study is based on animal studies conducted in recent history which
demonstrated that subjects which responded more favorably to stressful
situations were those that were homozygous for the l-allele, meaning that they
had two l-alleles in their DNA. Mice with either one or two copies of the s-allele
demonstrated more fearful reactions to stressful situations and loud noises, as
compared to their counterparts that were homozygous for the l-allele. This
seemed to indicate that the l-allele incorporates a genetic mechanism that offers
limited protection to the body against external stressors. Apparently the shorter
‘5-HTT’ allele is not as effective in regulating serotonin flow as compared to the
longer ‘5-HTT’ allele, resulting in the behavioral discrepancy observed.
The
scientists worked to calculate the number of stressful life events that took place
in their subjects’ lives between their respective 21 st and 26th birthdays. Romantic
disasters, bereavements, major illnesses, and job crises were among the
situations that the study paid particular attention to. At the age of 26, subjects
were assessed as to whether they experienced depression in the past year, with
researchers double-checking their results by comparing their assessments with
accounts of depression-related symptoms given by the subjects’ close friends.
At the end of the study, it was found that 17% of the subjects reported
having experienced a ‘major depressive episode’ in their 25th year, while 3%
reported suicidal tendencies during that same period of time, comprising 11% of
patients with at least one copy of the s-allele and 4% of patients homozygous for
the l-allele. Among the subjects who did not encounter major stressors in the 25 th
year, the probability of suffering from depression was found to be the same
regardless of the configuration of their ‘5-HTT’ alleles. However, among the
subjects who faced adversely stressful situations, 17% of the subjects who were
homozygous for the l-allele suffered from depression, compared to 33% of the
heterozygous subjects who had one of each allele, and 47% of the subjects who
were homozygous for the s-allele. This seems to indicate that the negative
effects of stressful situations portrayed themselves more strongly in subjects with
an s-allele and most strongly in subjects with two s-alleles, as compared to
subjects with two l-alleles who seemed best able to cope with adversely stressful
circumstances. Hence, the New York Times appropriately reports that “people
who have inherited the short allele from one parent and the long one from the
other are moderately vulnerable to depression.”
Furthermore, childhood abuse seemed to affect the subjects who were
homozygous for the s-allele more than it did the group that was homozygous for
the l-allele. Among the 11% of subjects who faced severe maltreatment as
children, 63% of the s-allele homozygous group suffered from a ‘major
depressive episode’ later on in life, as compared to just 30% of the l-allele
homozygous group, regardless of whether they have been abused as children.
This led the New York Times to report that the “long alleles also seemed to shield
those who experienced abuse during childhood - one subject in 10 from depression in adulthood.” Clearly, the propensity for depression is
significantly increased by the possession of the ‘5-HTT’ s-allele. In this respect,
the study’s results tally with research demonstrating that individuals with the sallele show more intense brain reactions to fearful stimuli than do those who
were homozygous for the l-allele (Hariri A. R. et al, Science, 19 July 2002, pp.
400).
On the other hand, researchers found no reason to conclude that the sallele would make one more likely to encounter stressful situations: the
occurrences of such recorded circumstances across both homozygous groups
and the heterozygous group did not vary enough to warrant such a claim.
Therefore the alleles merely affect an individual’s response to such scenarios
rather than the occurrences of such adverse situations.
Co-author Terrie Moffitt explains that one of the reasons why biologists
“have found the hunt for vulnerability genes so frustrating is that most studies
haven't taken environmental exposure into account.” According to her, that is
“like looking for genetic susceptibility to malaria in a sample that includes people
who live in mosquito-free places.” Apparently the environmental circumstances
surrounding this study played a critical role in allowing it to produce such
appreciable results.
Hence, the Swedish Medical Center justifiably reports that this “study is
part of a growing body of research that suggests that genes confer susceptibility
to depression. This supports the emerging view that the majority of mental
illnesses and other complex diseases cannot be explained by either genetic or
environmental factors alone. Rather, they arise from an interaction between
genetic and environmental factors.”
In this respect, the Columbia Broadcasting System (CBS) was not
particularly justified in making the claim that “Experts said the study… shows a
proven direct genetic link between emotionally distressing events and the onset
of clinical depression.” The reason being that biologists are still debating the
issue and that the general consensus is that both genetic conditions and
environmental circumstances play a critical role in the expression of genes and
the development of the above-mentioned psychological conditions. This truth is
very far from the CBS’ claim of a “direct genetic link”.
In closing, even though a genetic diagnostic test for the ‘5-HTT’ s-allele
may not be a definitive procedure with which to deduce an individual’s
susceptibility to episodes of depression, steps may be taken by the clinical
community to render preemptive therapy and counseling to such persons who
are diagnosed to be at a higher risk of developing depression in order to manage
the occurrences of such episodes in the future. Until further tests are undertaken
to provide more conclusive evidence, this is one of the ways in which genetic
studies may help to better the lives of members of the public.
References
“Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5HTT Gene”
Science, 18th July 2003, Volume 301, Issue 5631, Pages 386-389.
By Caspi Avshalom, Sugden Karen, Moffitt Terrie E., Taylor Alan, Craig Ian W.,
et al.
“Gene is Linked to Susceptibility to Depression”
New York Times, 18th July 2003.
By Mary Duenwald.
“A Genetic Link to Depression”
Columbia Broadcasting System, 17th July 2003.
By Paul Recer.
“New Research Finds a Genetic Link to Depression”
Swedish Medical Center, 18th July 2003.
By Elizabeth A. Peterson.
Genetic Regions Influential in Male Sexual Orientation Discovered
A recent study has shown that the genes a man inherits from his mother
or father may influence his sexual orientation.
Genetic scientists say that it is the first time that the entire human genome
has been scanned for the genetic determinants of male sexual orientation. These
genomic scans suggest that there are several regions of interest that may
influence homosexuality in males [1].
This news does not come as a surprise to lead author of the study Brian
Mustanski, PhD, a psychologist at the University of Illinois at Chicago who says
that “there is no one ‘gay’ gene” and that many regions of the human genome
together may have a genetic influence on sexual orientation. He also points out
that since human sexuality is a complex trait there will be other factors, such as
environmental factors, that determine its expression [2].
Previous Genetic Searches
The current study came about after a number of previous studies on twins
and their families found that male sexual orientation is moderately heritable [3].
The most conclusive study was conducted by Dr. Kenneth Kendler and his
colleagues in 2000. They found that there was a high degree of familial
resemblance for sexual orientation between siblings. In addition to that, they
found that the degree of resemblance was higher between identical twins than it
was between non-identical twins which suggest to the researchers that genetic
factors may have an influence on sexual orientation [4].
The results from twin and family studies led some scientists to conduct
studies on specific gene locations that they believed would have an effect on
sexual orientation. However, a great majority of these studies were inconclusive
because the gene locations that were chosen for the study often had little if any
statistically evident effect on sexual orientation [6]. This was mainly because
these scientists once believed that homosexual men inherited the genetic
influence of this behavior from their mothers; so they focused on the X
chromosome as the site for their specific genes [6]. The inconclusiveness of
these studies prompted Brain Mustanski and his colleagues to conduct a scan of
the entire human genome in search of an answer to the question of male sexual
orientation.
The Genomewide Scan Begins
Mustanski’s study is radically different from previous studies on this issue
for specifically one reason. While other studies focused solely on the X
chromosome -one of the two sex chromosomes- this study focuses on all of the
22 non-sex chromosomes and the X chromosome; which means that 23 of the
24 human chromosomes were scanned for possible regions of genetic influence.
The 24th chromosome is the Y sex chromosome - it determines the gender of an
individual – and it was not studied because it is believed to not contain any
genetic region of interest relevant to this study [1].
In the study researchers recruited 456 men from 146 unrelated families
with two or more gay siblings. Each participant’s sexual orientation was
determined through a structured interview and a standardized questionnaire. The
mean range of sexual orientation was 5.6 on a scale where 6 means that the
person is exclusively homosexual [1].
Genomewide Scan like Searching for Magician
The researchers gathered DNA from the blood samples of their
participants in order to obtain their genome and scan it for particular regions of
high similarity in the group of men [1]. Genetic scans can be compared to
scanning a town of 40,000 houses in search of magicians. So if you do not know
where magicians live in your town it would be faulty of you to assume that
houses that fit a certain criteria will yield magicians. Therefore, it would be easier
to find magicians in a town of that size if you able to systemize your search by
dividing the town into, say, 23 neighborhoods. Once that is done you can amass
a league of 403 people who you will spread evenly throughout the various
neighborhoods and their job is to knock on a specific door and inquire if the
occupants of that house has heard of any magicians living on their street. By
doing this you would be scanning the neighborhood for magicians in the most
efficient way.
Searching for magicians in this way is analogous to the method used
when scientists proceed with genomewide scans. But the 403 markers used in
this study are similar to the league of people that you amassed to canvas the
neighborhood. And the 40,000 houses you had canvassed are similar to the
rough approximation of genes that make up the human genome. Back to your
case, so the houses that will be most interesting to you are the houses for which
a lot of people in the neighborhood point out as the house that has a magician in
residence.
Results of Genomewide Scan
In a lot of ways the results of the genomewide scans were are like that
last analogy. The results of the researchers genomewide scan revealed that
chromosomes 7, 8, and 10 have a high number of clusters with the same genetic
patterns among the men in their study [1]. Plus, these genetic patterns were
shared by 60% of their study participants which is significant considering that
50% is the amount expected by chance alone [1].
Interestingly enough, the regions found on chromosomes 7 and 8 were
associated with male sexual orientation regardless of whether the man got them
from his mother or father. And the region on chromosome 10 was associated
with male sexual orientation only if they were inherited form the mother [1].
Future Research and Implications
Researchers say that the next step in this genetic search is for other
studies to verify that these same genetic regions are found in a different group of
men [1]. Once that occurs, researchers can start focusing on how the specific
genes within these regions of interest influence sexual orientation in males.
Though the findings reported by Mustanski and colleagues need to be
confirmed, the results of their study suggests that there is a genetic component
that does influence whether a man is homosexual or heterosexual. The
implications of this finding can be far-reaching. Scientifically, this could mean that
molecular analysis of genes involved in sexual orientation would lead to a better
understanding of one type of natural process that leads to a variation in sexual
orientation. This scientific knowledge would advance researchers understanding
of human variation, evolution, and brain development as it relates to sexual
orientation.
The political implication of such a discovery is also far-reaching for a
couple of reasons. Maybe the most obvious implication of such a discovery is
that past and present political documents regarding homosexuals would have to
ban the covert discrimination of homosexuals based on sexual orientation; the
reason being that homosexuality would then be considered a natural orientation
in that it is influenced by some genetic factors. The next reason piggybacks on
the first. It basically would deal with the rights accorded to heterosexuals being
extended to apply to homosexuals also. This may affect previously heterosexual
“rights” such as the institution of marriage and all the ramifications of that, and
the ability to adopt as readily as heterosexual couples. However, this discovery
could make it easier for people to discriminate against homosexuals because if
genetic regions are found to influence the sexual orientation then discriminators
could wrongly say that homosexuality to a genetic disease. Such a view would
increase the amount of aversive discrimination experienced by homosexuals
instead of decreasing it.
All of these scientific and political implications suggest that the perception
that people have of homosexuality as “natural” or “unnatural” will largely be
determined by many factors. High on this list of factors will be the discoveries
that are made through research studies such as the one that was conducted by
Mustanski and his colleagues.
Works Cited
Primary sources
[1] Mustanski Brian S.,. DuPree Michael G, Nievergelt Caroline M, Bocklandt
Sven, Schork Nicholas J., Hamer Dean H., A genomewide scan of male sexual
orientation, Human Genetics, Volume 116, Issue 4, Mar 2005, Pages 272 – 278.
[4] Kendler KS, Thornton LM, Gilman SE, Kessler RC., Sexual orientation in a
U.S. national sample of twin and nontwin sibling pairs. American Journal of
Psychiatry. 2000 Nov; Volume 157, Issue 11, pages 1843-1846.
[6] DuPree MG, Mustanski BS, Bocklandt S, Nievergelt C, Hamer DH., A
candidate gene study of CYP19 (aromatase) and male sexual orientation.,
Behavioral Genetics. 2004 May; Volume 34, Issue 3, pages 243-250.
Secondary sources
[2] Butler Sharon, “Genetic regions influencing male sexual orientation identified”
, EurekAlert 27. Jan. 2005. http://www.eurekalert.org/pub-releases/2005-01/uoiagri012705.php.
[3] Mustanski BS, Chivers ML, Bailey JM , A critical review of recent biological
research on human sexual orientation. Annual Review of Sex Research 2002,
Volume 12, pages 89–140.
Katie Dulmage
Bernard Strauss
March 9, 2005
Final Paper
Antimicrobial resistance is a growing problem that threatens our current
methods for combating bacterial infections. Infectious diseases are the third
leading cause of death in the US, and second worldwide [13]. A solution is
needed quickly – bacteria are rapidly producing progeny that is resistant to
common antibiotics used to treat them. One particular type of bacteria,
Pseudomonas aeruginosa, is extremely deadly to weak or recovering hospital
patients. It has become resistant to almost all of the antibiotics we have to treat
it. There have been several proposed solutions to this problem of fighting
bacteria like P. aeruginosa, such as developing new antibiotics. But this is not a
permanent solution. Dr. John Alverdy has conducted several studies on P.
aeruginosa and has put forth some new ideas on combating the problem of
antimicrobial resistance. Instead of developing new antibiotics – that the P.
aeruginosa will eventually become resistant to – he proposes that we block the
pathogen cell communication system so the bacteria cannot organize an attack
on the host. His ideas are unique and promising – and they may lead to cures
for other bacterial infections.
The popular use of antibiotics started very recently – around the 1940s
and 50s. Antibiotics such as penicillin were considered miracle drugs, curing
previously deadly diseases and infections. The use of antibiotics have saved
countless lives and weakened the threat of bacterial infection. However, its
effectiveness didn’t last for very long. Mutations in bacteria allow some of the
strains to become resistant to certain antibiotics. These strains will produce
progeny that are also resistant. And because of the rapid reproduction and
therefore rapid mutations, bacteria have been able to battle effectively against
antibiotics. Tuberculosis, gonorrhea, malaria, and childhood ear infections are
more difficult to treat than ever before because of mutations in the bacteria [13].
Dr. Abigail Salyers, a professor of microbiology at University of Illinois at
Champaign-Urbana urges, “What’s at stake is the possible loss of the effective
use of antibiotics. This would be the first time in history that a cure was actually
lost” [15]. Bacterial infections account for a large portion of hospital deaths. Two
million patients get an infection while hospitalized, and nearly 90,000 die as a
result [15].
In 1992, there were 13,300 hospital patients who died from infectious
diseases. Now, about 90,000 people die each year from infections contracted in
hospitals. This illustrates how rapidly bacteria can build up resistance to a drug.
Of the bacteria that cause infections in hospitals, 70% are resistant to at least
one common antibiotic used to treat them. The over-prescription of antibiotics
has attributed to the speed at which bacteria has evolved [13, 20]. Also, patients
may not finish the prescription they are given, resulting in the survival of the
strongest of the bacteria strains. These strains will produce progeny that are
resistant to the antibiotic.
All bacteria must reside within a host to survive. Some bacteria are
harmless, but other bacteria are potentially fatal if untreated. So far, antibiotics
are the only way to treat bacterial infections. Antibiotics interfere with the
bacteria’s functions in order to disable it, therefore leaving it unable to affect the
host. Though some antibiotics are found in nature, we have improved some of
them in labs and made more affective than its natural compliment. Antibiotics
have to be able to kill pathogens, but still be relatively non-toxic since they have
to go into our bodies [20].
Antibiotics are developed to target certain characteristics that are unique
to bacteria so the drugs don’t affect our own cells. There are several types of
antibiotics that target specific characteristics within the bacteria family: cell wall
inhibitors, cell membrane inhibitors, protein syntheses inhibitors, nucleic acid
effectors, and competitive inhibitors. A cell wall inhibitor is a type of antibiotic
that only works for prokaryotic cells since only they have cell walls. During the
synthesis of this type of bacteria, D-alanyl-D-alanine is needed to construct the
cell walls of the progeny correctly. The cell wall inhibitors act as D-alanyl-Dalanine, but instead prevent cell replication. If the bacteria recognize it as the
real thing and use it in its synthesis, the cell will eventually die without the chance
to replicate. Cell membrane inhibitors attack the bacterial membranes. There is
one problem with them, however: the drugs are not selective enough. The
membranes of the target bacteria are very similar to the host’s eukaryotic cell,
and therefore can be dangerous to the host. Protein synthesis inhibitors attack
the ribosome of the bacteria cell. It distorts it so it can no longer perform its
normal functions. Without functioning ribosomes, the bacteria die. Nucleic acid
effectors attack the DNA or RNA of the cell, preventing it from replicating.
Competitive inhibitors go into the enzymes bacteria normally interact with. If the
bacteria interact with these contaminated enzymes, they will be killed [20]. With
all these different ways of fighting pathogens, it seems we have won the battle.
But we have not won the war.
Because of the influx of antibiotics exposed to bacteria, they must evolve
in order to survive. Bacteria don’t have a built-in repair mechanism like we have,
which double-checks the transcription of genes. There is no way to check or
correct mistakes in replication. Without this ability to “proofread” it is very easy
for mutations to occur. These mutations will be passed on to other cells. Some
mutations will kill the cell, some will have no affect, but others will provide it with
ways to resist threats to its survival [20]. There are several ways bacteria have
evolved to resist antibiotics: the efflux pump, bacterial enzymes, and the
disguising capsule. Some strains of bacteria have developed a pump – called
and efflux pump – to release any antibiotics from inside the membrane. Others
have vesicles that can carry it out of the cell. Other strains of bacteria have
created an enzyme that they release to attack the antibiotics. They distort the
antibiotic chain, inactivating it [1, 20]. Some types of bacteria can create a
disguising capsule, changing its appearance to the antibiotic. The antibiotic fails
to recognize it as a target cell [1, 20].
P. aeruginosa is one of the most deadly bacteria because it is resistant to
our immune system, antibiotics, and chemical disinfectants; it can metabolize
quickly, and can live almost anywhere in the body [1, 3, 15]. There is little we
can do to treat it. 70% of people that contract it die. P. aeruginosa claims the
lives of 60 % of people in burn units, 50% of AIDS patients, and most of those
with cystic fibrosis. Many of the patients with burns, AIDS or cystic fibrosis don’t
die from those things – rather they contract a bacterial infection that kills their
already weak body. P. aeruginosa is usually found in the intestine; it attacks,
causing a lethal gut-induced sepsis in recovering hospital patients. Antibiotics
rarely help.
The average person comes in contact with P. aeruginosa almost every
day. It is found in several places: drinking fountains, faucets, streams, moist
soil, and raw vegetables [15]. In fact, normal, healthy volunteers swallowed live
cultures of P. aeruginosa and remained healthy [2]. In mice, when put under
stress and injected with P. aeruginosa, they die quickly; but if healthy mice are
injected with the same amount, they live. Why are only weakened patients killed
by these bacteria? There must be other variables.
Dr. John C. Alverdy, a gastroenterological surgeon and researcher at the
University of Chicago, has done several studies on the mysterious P. aeruginosa
with many of his colleagues. All that was known at the time was that P.
aeruginosa was linked to a probable death in critically ill patients. Critically ill
patients infected with P. aeruginosa are three times more likely to die than
uninfected patients [2].
Alverdy noticed that the post-surgery condition of patients (infected with P.
aeruginosa) altered their internal environment, resulting in an increase in PA-I
expression in strains of P. aeruginosa. PA-I lectin/adhesion allows P. aeruginosa
cells to adhere to the intestinal tissue – making it easier for it to attack indigenous
cells. Alverdy and his team used mice to learn more about this observation.
They injected mice with P. aeruginosa with the PA-I extracted. They survived [6,
16]. The discovery that PA-I affected the lethality of P. aeruginosa was very
important for creating ways to prevent the bacteria from killing their hosts.
Our current solution to bacterial diseases is to keep creating new
antibiotics, but this is a problem. Bacteria will always build up resistance, and
creating new antibiotics is only a temporary solution. Entering an escalating
evolutionary contest does not satisfy Alverdy as a solution to the problem of
resistance.
His solution begins with the understanding of cell signaling and
environment detection. Bacteria have the ability to detect changes in their
environment, allowing them to better prepare for the conditions. Bacteria can
sense their environment, population density, mobilize in groups, and activate
virulence genes all through bacterial communication systems [1].
One study has shown that when a single cell of N. gonnorrhoeae is moved
away from its micro-colony with laser tweezers, it moves toward the colony.
When restrained, the single cell twitches in effort to move closer to the rest of the
cells. This suggests that each cell can even sense its position and distance from
the group. It is evident that cells can also sense crowding – when cells are
abundant, they stop replicating so they don’t expire all their resources [10].
Bacteria have virulence genes, but they aren’t always expressed. That is
why P. aeruginosa is not harmful to a healthy human being. When it is living
happily within a host, those genes are not expressed. But, with the right stimuli,
such as radical changes in environment, they will express these genes [1, 4, 9].
Alverdy has seen that most killer bacteria are harmless until the host’s
tissue defense is weakened. When an individual becomes severely sick, he is
given drugs, given food directly into the veins, and is not allowed to have bowel
movements. The bacteria realize that their survival depends on that of the host,
so it seems odd that the bacteria would kill it. But, if the bacteria kill the host, it
has a chance to be passed on to another host – a bird could eat the dead
carcass and therefore be transferred into a new, healthy host1. Bacteria can also
sense when the host’s health is a problem, but won’t attack until the host
becomes severely sick and the treatments become extreme. The bacteria don’t
launch their attack until there is a dramatic change in environment. Based on
this evidence, Alverdy and Chang argue that the bacteria cells can communicate
with one another to release its lethal toxins when they sense that the patient is
very weak [1, 13].
Based on the assumption that bacteria can communicate with each other,
Alverdy and his partner, Dr. Eugene Chang have developed an alternative for
combating bacteria that interrupt this communication. This treatment forms a sort
of mucus, that covers the bacteria and blocks the signals they send to each other
– such as the signals that instruct the bacteria to release their lethal toxins.
1
Scheier, Lee. Page 30. 2004
During severe stress, the amount of mucus in the patient’s intestines
decreases. Alverdy studied mice and its reaction to P. aeruginosa and PEG 1520, a mucus made to imitate our natural mucus. These mice were induced with
catabolic stress and were under short-term starvation. This was done to mimic
the condition of post-surgery patients. They were then injected with P.
aeruginosa and PEG 15-20. The mice lived even though not a single bacterium
was killed. The PEG 15-20 has shown the ability to inactivate the lethal toxins
released by intestinal P. aeruginosa. PEG 15-20 is a great substitute for our
natural mucus that depletes under stressed environments. The PEG 15-20 did
not have an affect on the bacterial growth patterns like our natural mucus, but it
does affect the clumping pattern of P. aeruginosa. The artificial mucus distanced
the bacteria from the intestinal tissue because of an alteration of outer protein
charges. This indicates that the distance between the bacteria and the tissue is
an important factor in the attack of P. aeruginosa on the body. Even mutated
strains of P. aeruginosa were seriously impaired in the ability to attack the host
[17]. This method suggests that Alverdy and Chang’s predictions were right –
the bacteria attack only when they sense their host will no longer be able to
support them.
Alverdy had previously worked at the Michael Reese Hospital in Chicago,
and during that time, there were 5 patients who were dying of gut-derived sepsis,
caused by pseudomonas aeruginosa. There seemed to be no hope for them.
One patient was an 18 year old girl. Alverdy flushed 10 liters of polyethylene
glycol through her intestines. She recovered within 18 hours, as did the rest of
the patients. They all survived [13, 15].
Tricking the bacteria into thinking the host is healthy may be a more
promising method than developing more antibiotics. By blocking their
communication with each other and the external environment, they don’t sense a
change therefore don’t secrete their toxins. This is a very promising – and very
new – solution to the problem of antibiotic resistance. This method is non-toxic
and, in mice, there are no indications of side effects – no change in weight or
overall health. It seems to be very safe for clinical trial. Alverdy is currently
awaiting the approval of the FDA to conduct human trials [15].
The problem of antimicrobial resistance is no doubt something that we
should all be aware of. The relationship between the bacteria and the antibiotics
is very intricate, and we can see that developing different antibiotics will help in
the short run, but these solutions will not hold up for long. I find that many of the
resistance “solutions” to be very conservative, and ineffective. Alverdy and his
team seem to have the best solution so far. He argues that “antibiotic treatment
merely creates a never-ending, escalating arms race between medical
researchers and bacteria”[15]. Maybe this is a war that shouldn’t be fought. This
new approach is exactly what we need to combat this problem of antimicrobial
resistance.
References
1. Alverdy JC MD, Laughlin RS DDS, Wu L MD, PhD. “Influence of the Critically
Ill State on Host-pathogen Interactions Within the Intestine: Gut-derived
Sepsis Redefined”. Critical Care Medicine 31 (2). 2003.
2. Alverdy J, Holbrook C, Rocha F, Seiden L, Wu RL, Musch M, Chan E, Ohman
D, Suh S. “Gut-Derived Sepsis Occurs When the Right Pathogen With the
Right Virulence Genes Meets the Right Host”. Annals of Surgery: 232.
2000.
3. Blom AM. “Strategies developed by bacteria and virus for protection from the
human complement system”. Scand J Clin Lab Invest: 64(5). 2004.
4. Fuqua C, Winans SC, Greenberg PE. “Census and Consensus in Bacterial
Ecosystems: The LuxR-LuxI Family of Quorum-Sensing Transcriptional
Regulators”. Annual Rev. Microbiology: 50. 1996.
5. Gootz TD. “Discovery and Development of New Antimicrobial Agents”. Clin
Microbiol Rev: 3(1):13-31. 1990.
6. Kohler JE, Zaborina O, Wu L, Wang Y, Turner JR, Alverdy JC. “Components
of Intestinal Epithelial Hypoxia Activate the Virulence Circuitry of
Pseudomonas”. Gastrointest Liver Physiol. 2004.
7. Lazazzera BA. “Quorum Sensing and Starvation: Signals for Entry Into
Stationary Phase”. Curr Opin Mircobiol: 3. 2000.
8. McGowan, John E. Jr. ”Economic Impact of Antimicrobial Resistance”. Emory
University School of Medicine, Atlanta, Georgia, USA
http://www.cdc.gov/ncidod/eid/vol7no2/mcgowan.htm
9. Mekalanos JJ: Environmental signals controlling expression of virulence
determinants in bacteria. J Bacteriol: 174: 1–7. 1992.
10. Merz AJ, So M, Sheetz MP. “Pilus Retraction Powers Bacterial Twitching
Motility”. Nature 407: 98–102. 2000.
11. Moore MR, Hyde TB, Hennessy TW and others. “Impact of a Conjugate
Vaccine on Community-Wide Carriage of Non-susceptible Streptococcus
pneumoniae in Alaska”. J Infect Dis: 190(11):2031-2038. 2004.
12. Ochman, Howard, Moran, Nancy A. “Genes Lost and Genes Found:
Evolution of Bacterial Pathogenesis and Symbiosis”. Science 292: 2001.
An important issue in the 2004 presidential election, stem cells are hotly debated
and highly misunderstood. Religious groups equate using stem cells to harvesting babies
for their limbs, while scientists promise that stem cells will someday cure a countless
number of diseases and maintain they are vital for the future of medicine. In order to
understand stem cells, it is important to acknowledge that scientific research is still in the
developmental stages and doctors not ready to begin using stem cells to cure human
diseases. However, governmental bans on human stem cell research have hindered
scientific understanding of the medicinal benefits of stem cells on humans. A scientific
study conduced by Advanced Cell Technology shows significant progress in using stem
cells to repair damaged heart tissues in mice. A recent newspaper article published by
Reuters Health accurately explores the successes of this study. Both the study and the
newspaper article emphasize that, while important developments have been made with
animal experimentation, these developments must be perfected before such methods will
be ethically sound to use on humans.
The article published in Reuters Health refers directly to the study Dr. Robert
Lanza and his colleges conducted, even mentioning the study was published in the
journal Circulation Research. The author, Maggie Fox, quickly gets to the most
important point of the study—the superiority of embryonic stem cells as compared to
adult stem cells. As this is an online news sources for heath and medicine, the audience
targeted is one with a basic working knowledge of medical terms and an interest in the
details of a scientific study. However, aspects of Dr. Lanza’s study are skimmed over or
left out entirely.
Robert Lanza and his colleges at Advanced Cell Technology have designed an
important experiment that indicates the promise of embryonic stem cells for the future of
medicine. The mice used in this experiment had a disorder called infracted myocardium,
meaning an area of muscular tissue in the heart had been cut off from blood supply,
causing cells in the heart to die. Essentially, this is a heart attack. To replace the dead
muscle cells, fetal liver stem cells were injected into the mice. These stem cells were
derived from cloned mice embryos, which were cloned using a method called nuclear
transfer cloning.
Nuclear transfer cloning is a new process that could be important in the future as a
practical alternative to directly using embryonic stem cells. In this method, adult cells
from the mouse are extracted. These cells are fully differentiated, meaning they have
developed specific functions. The scientists are then able to change the nucleus of these
cells. Now, they have cloned a uniform group of cells that are undifferentiated and able to
affect more than one tissue or organ. The scientists develop embryos from these cells and
isolate certain cells from the liver of the cloned embryo. The liver is the place where the
stem cells are isolated because that is the site where differentiation occurs. These isolated
liver stem cells are injected into the mice in order to repair the damaged muscle tissue.
The cells were able to grow into the myocytes and coronary vessels, the types of heart
tissue destroyed by the heart attack.
Maggie Fox does not go into the details of nuclear transfer cloning. This phrase is
too scientific for her audience and unnecessary in her article. However, describing stem
cells as “the body’s master cells” seems to be an over simplification and misleading.
Calling stem cells “master cells” is confusing and could be interpreted as cells that
control the functions of all other cells in the body, a function that stem cells have nothing
to do with. She then goes on to use the word “differentiate,” without defining it as a cell
developing into a specific type of cell with specific functions. It is important to
emphasize that these cells have yet to develop into an individual kind of cell and thus are
versatile. Therefore, these stem cells can be used to repair damaged tissue anywhere in
the body. While Fox does mention the potential of the stem cells, she does not stress the
importance of this point.
Using nuclear transfer cloning has clear advantages over using normal embryonic
stem cells. With normal embryonic stem cells, the tissues developed can be rejected by
the immune system. The cells will be destroyed by the immune system’s white blood
cells. However, nuclear transfer cloning develops cells from the mice themselves and the
immune system of the mice recognizes the new cells and do not attack them. Fox does
not mention the difference between normal embryonic stem cells and cells developed by
nuclear transfer cloning.
Not only are there clear advantages to using nuclear transfer cloning, but
also stem cells from cloned embryos achieve significantly better results than
previous studies have achieved with adult bone marrow cells. This is a point that
Fox, correctly, feels necessary to emphasize. The process of using adult stem
cells involves, “many steps and much manipulation,” Fox writes. While adult cells
will regenerate the dead cells in the heart, more cells were necessary to achieve
the same results. To restore the dead tissue, approximately 200,000 adult bone
marrow cells had to be injected, as compared to 20,000 stem cells from cloned
embryos to regenerate the same amount of tissue. Using information obtained
during a phone interview with Dr. Robert Lanza, Fox adds that cutting down on
the time it takes to create the stem cells in lab is vital in treating a heart attack.
However promising the results, this method must be developed further
before it will be ready for humans. Nuclear transfer cloning may cause the
development of genes to be abnormal. Also, in order to connect the newly
restored blood vessels with the unaffected blood vessels, there is an excessive
growth of arteries called coronary vessels. This changes the way blood normally
flows. The extreme growth of coronary vessels and the possibility of abnormal
genes must be addressed before this method will be safe for humans.
In addition, the ethical implications of using embryos has been called into
question. Lanza and his colleagues at Advanced Cell Technology acknowledge
that ethics require embryos to not grow beyond the blastocyst stage. In a lab, an
embryo grows for about five days until it reaches the blastocyst stage. In the
blastocyst stage, some of the preembryo’s genes begin functioning, and the
resulting embryonic stem cells that have the potential to specialize into different
daughter cells depending on the genes that are expressed. If the embryo is
implanted in the lining of the uterus, it has the potential to grow into a child. Thus,
the stem cells could be considered a human. The method of nuclear transfer
cloning requires that the embryo develop further. The liver cells of this embryo
are the actual stem cells used to restore the dead tissue in the heart. Thus, the
embryo has developed specialized organs, making its resemblance to a human
even stronger. Fox acknowledges this important aspect of stem cell research.
Using nuclear transfer cloning on humans would require a serious examination of
ethics and would meet with great resistance from conservative Christian groups
and President Bush, who are concerned about protecting human life.
It is newspapers, not scientific journals, which shape the mind of the public.
Reuters Health’s audience is most likely better scientifically educated than the average
newspaper reader. Maggie Fox’s article reflects this notion. She is careful to represent Dr.
Lanza and his colleges’ study accurately. When information included in the study is left
out of her article, it is with good reason; the article must be concise to appeal to the busy
reader. She is able to accurately emphasize the most important point of the study:
embryonic stem cells show a far greater promise than adult stem cells. While much
research must be done before stem cells will be able to cure humans of diseases, Lanza’s
study gives hope to the future of stem cell research. If the current laws allow stem cell
research to continue unhindered, the promised medicinal benefits of stem cells will soon
become a reality.
Claire Elderkin
March 9, 2005
Biology 11108
Instructor: B. Strauss
Possible Reduction in Miscarriage
for Fetuses with Genetic Aberrations
Reducing levels of steroid 21-hydroxylase may reduce the chance of a
miscarriage in a fetus affected by sex chromosome aberrations, Vilma Mantovani and her
team of Italian scientists have announced. These scientists investigated the hormones of
48 Turner syndrome patients and 15 Klinefelter syndrome patients and reported an
association between reduced levels of steroid 21-hydroxyalase and the two syndromes.
While some with Turner syndrome and Klinefelter syndrome survive, these genetic
diseases are found primarily among miscarried fetuses. Vilma Mantovani, et al.,
questioned why some fetuses with sex chromosome aberrations survive, while other
fetuses are miscarried. The scientists from the Endocrinological Clinic of the Department
of Pediatrics at the University of Pavia hypothesize that reducing the level of steroid 21hydroxylase during pregnancy could prevent miscarriages due to Turner syndrome and
Klinefelter syndrome.
Steroid 21-hydroxylase is a protein need for multiple purposes, including
carbohydrate metabolism and the regulation of water balance. Steroid 21-hydroxylase
deficiency is caused by mutations in the CYP21 gene and it is the main cause of
congenital adrenal hyperplasia, a genetic disorder present at birth that causes an
overproduction of male sex hormones. In previous studies, heterozygote carriers of the
defects in the CYP21 gene have been found in Tuner syndrome patients and their
relatives. The aim of the study conduced by Mantovani, et al. was to determine if defects
in the CYP21 gene—which indicates a low level of steroid 21-hydroxylase—are
detectable in Turner syndrome and Klinefelter syndrome patients.
The test subjects underwent hormonal investigation. Blood samples were drawn
from all the patients initially and the level of 17-hydroxyprogesterone was measured.
Then, synthetic ACTH was introduced into the blood stream. ACTH is a hormone that
stimulates the adrenal cortex. After an hour, blood was drawn again. Mantovani, et al.
recorded the 17-hydroxyprogesterone response to adrenal stimulation. 17hydroxyprogesterone encourages the embryo to implant on the wall of the uterus. Thus, a
low level of 17-hydroxyprogesterone could lead to a miscarriage. The test for 17hydroxyprogesterone reveals if a patient has congenital adrenal hyperplasia.
Using blood samples, a molecular analysis of the CYP21 gene was performed.
Parts of the DNA sequence of the CYP21 gene were mapped using an automated
sequencer at Applied Biosystems in Forster City, CA. These parts included CYP21
exons, which is the part of DNA that is later used to copy RNA. Also mapped were exonintron junctions, which are the points where the exons and the introns meet. Introns are
non-coding sequences of DNA that are not used to code for RNA. The last part of the
gene that was mapped was the promoter region, which tells the RNA polymerase to
initiate transcription, the process that creates RNA from DNA. These three regions are
vital for the creation of RNA and, subsequently, of protein. Unlike a mutation in the
DNA of an intron, mutations in any of these sequences of DNA could lead to a mutation
in a protein that may lead to an alternation in phenotype, the displayed characteristics of a
person. In this study, gene mutations in the CYP21 gene and abnormal 17-
hydroxyprogesterone levels were found in many of the Klinefelter syndrome and Tuner
syndrome patients. This is the first time a relationship has been reported between patients
with Klinefelter syndrome and reduced levels of steroid 21-hydroxylase.
In order to correct possible errors, the scientists were careful to ensure that all the
patients originated from the same Northern Italian provenance. The 349 blood donors
used as controls were also from this provenance. The results for the controls create a
baseline reading to which the scientists can compare their test subjects’ results. The
controls also allow the scientists to ensure their results were not affected by an outside
influence, because the control and the experimental group are the same in every way
except for the presence of Turner syndrome and Klinefelter syndrome in the experimental
group. In this study, the scientists proved that their data was statistically significant. For
the ACTH test, 43.3% of the Tuner and Klinefelter syndrome patients showed abnormal
17-hydroxyprogesterone responses, compared to 16.2% of the control. Similarly, the
Tuner and Klinefelter syndrome patients who carried CYP21 gene mutations was 14.3%,
compared with 4.6% of the control. Using statistical tests commonly accepted in the
scientific community—Fisher’s exact test and Yates’ corrected Chi-square test—
Mantovani, et al., were able to prove their results were significant.
However, Mantovani, et al. are careful to point out that these statistically
significant results do not prove a causal relationship between the CYP21 mutation and
the non-disjunction defect that causes Tuner syndrome and Klinefelter syndrome. It is
possible that another gene could cause the non-disjunction. Non-disjunction occurs when
chromosomes or chromatids do not separate when the rest of a cell separates during
mitosis or meiosis. This results in one daughter cell having two chromosomes or
chromatids while the other cell has none. While non-disjunction may be caused by a
mutation other than CYP21, the scientists believe they have demonstrated a relationship
between the CYP21 mutation and the non-disjunction defect. Mantovani, et al.
hypothesize that reduced levels of steroid 21-hydroxylase could cause a survival
advantage among fetuses with chromosome aberrations.
The scientists described the reduction of the levels of steroid 21-hydroxylase as,
“causing relaxation of the maternal screening” (Mantovani, et al, 139). Women have a
natural screening mechanism that often causes babies with severe genetic defects to be
miscarried. This is an evolutionary feature. Until recent advances in science and
medicine, severely handicapped babies often did not live past infancy. Childbirth put
women in grave danger and delivering a baby that would die soon after birth put the
mother at risk unnecessarily. If nature has not determined these fetuses capable of
survival, is keeping these fetuses alive through science ethically sound? Children with
genetic diseases can be a financial burden to their families and society. However, not all
genetic diseases result in an early death and often those suffering from a genetic disease
go on to live happy, relatively healthy lives.
The two genetic diseases in this case are Turner syndrome and Klinefelter
syndrome. Turner syndrome affects females, causing them to have underdeveloped
breasts, sparse body hair, a webbed neck, short stature, heart defects and kidney
abnormalities. These women are infertile and do not menstruate. Instead of the normal
XX sex chromosomes, these women are XO, meaning one sex chromosome is missing.
Men with Klinefelter syndrome appear normal as children, but at puberty secondary sex
characteristics fail to develop or are underdeveloped. These men have small testes, a
feminine appearance, and are often sterile. Instead of being a typical XY male, these
individuals have an extra X chromosome and are thus XXY.
Turner syndrome and Klinefelter syndrome patients are capable of living
relatively normal lives. While they are often incapable of reproducing on their own, new
developments in science allow women with Turner syndrome to become pregnant using a
donor egg. Patients of both diseases have normal IQ levels and they can function
perfectly well in society independently. Vilma Mantovani, et al. may have discovered a
method for increasing the survival rate of Turner syndrome and Klinefelter syndrome
patients. Among conceptions, one in 1000 fetuses have Klinefelter syndrome, but among
newborns, only one in 2000 fetuses have Klinefelter syndrome. Thus, about 50% of
Klinefelter syndrome fetuses are spontaneously aborted. However, by reducing the level
of steroid 21-hydroxylase during pregnancy with the use of steroid hormones after
conception, fetuses with genetic deformities may have an increased survival advantage.
Nevertheless, Vilma Mantovani, et al. do not specify how these steroid hormones can be
obtained and there is no indication that their results are commonly used by gynecologists.
Source: Mantovani, Vilma, et al. Do reduced levels of steroid 21-hydroxylase
confer a survival advantage in fetuses affected by sex chromosome aberrations?
European Journal of Human Genetics. 10(2). February 2002. 137-140.
Aaron Webman
Human Heredity
28 February, 2005
First paper
Gene May Foil AIDS Virus
On January 7th, 2005 the New York Times published an article entitled
Gene May Foil AIDS Virus, Study Finds, written by Donald G. McNeil, Jr. This
article reports on a study, The Influence of CCL3L1 Gene-Containing Sequence
Duplications on HIV-1/AIDS Susceptibility, published the day before in Science
magazine. This gives a simplified explanation of the main points of the study
along with some background to the scientific mechanisms involved and other
additional information. In order to analyze the newspaper coverage of the study,
it will be necessary first to look at the information given in the original document
and then try to understand what McNeil is attempting to accomplish in his
secondary account.
The study entitled The Influence of CCL3L1 Gene-Containing Sequence
Duplications on HIV-1/AIDS Susceptibility was conducted by a group of
researchers led by Enrique Gonzalez, Hermant Kulkarmi, Hector Bolivar and
Andrea Mangano at the University of Texas and published on January 6th, 2005
in Science Magazine. The purpose of the study was to determine the effect of
duplications of the genetic segment containing the gene which codes for
CCL3L1, a chemokine that is known to suppress HIV, on the infection and
progression of HIV. In addition to several more nuanced discoveries, this study
determined that individuals with more duplications of this gene sequence tend to
be less susceptible to HIV.
In order to understand the implications of this study, it is necessary to
establish a basic conception of the mechanisms of HIV infection, the role of
protein receptors and chemokines in disease infection and the mechanisms of
protein and chemokine production as it relates to genetic sequencing.
The HIV virus infects host cells by interacting with protein receptors on the
cells’ surfaces. Two of these receptor proteins, CD4 and CCR5 (chemokine
receptor 5) are important to this study. Once this has happened, the virus can
enter the cell and use the host cells’ mechanisms of genetic reproduction for the
reproduction of the viral DNA (Lewis 340).
All proteins, including those that function as receptors on the surfaces of
cells, are designed according to specific DNA gene sequences. These
sequences, by means of intermediate forms of genetic materials, contain the
code for amino acids, which are synthesized to form the proteins. Gene dose,
which the study uses synonymously with copy number, refers to the number of
copies of a gene in a given person’s genome. Gene dose can determine how
much of a certain protein a individual will produce. This study concerns itself
specifically with the copy number of gene which codes for CCL3L1 (chemokine
ligand 3-like1) one of the receptor proteins found on the surfaces of cells. The
CCL3L1 gene has been located on the long arm of the 17th chromosome
(Gonzalez et al 1).
Another concept that comes up in the study and will require explanation is
the viral set point. When an individual is infected with HIV, the disease will often
spread very quickly at first but will subside after some time. The set point is the
point the infection reaches in the beginning and remains at indefinitely. Scientists
believe that the set point is a determinate for the amount of time it takes the
disease to progress (AIDSinfo).
The first major finding of the study was the positive confirmation of the
hypothesis that “it is not absolute copy number per se, but rather gene dose
relative to the average copy number in each population that confers HIV/AIDS
susceptibility.” The researchers determined this with the finding that people with
lower copy numbers of CCL3L1 were overrepresented statistically as HIVpositive (Gonzalez et al 2). The study received further evidence of the strength of
the association with the finding that in each population studied, for every increase
in copy number above the median for that population, there was a corresponding
decrease in HIV susceptibility. The decrease in susceptibility for every increase
in copy number varied between 4.5 – 10.5% depending on the population studied
(Gonzalez et al 2).
A second important discovery of this study was that in addition to reducing
susceptibility to HIV, an increase in CCL3L1 copy number also slowed the
progression of the disease among people infected (Gonzalez et al 2).
Interestingly, the one population which was not consistent with this trend was the
one study involving children (Gonzalez et al 3).
After demonstrating these statistical findings, the study turns to a
discussion of the mechanisms involved. The researchers looked at two
conditions known to help predict the outcome of the disease: the viral set point
and the rate of change in CD4+ T Cell counts. The study determined that “low
CCL3L1 doses were associated with a higher viral set point and greater
subsequent T cell loss.” In other words, in individuals with low copy numbers, the
disease progressed more rapidly than in individuals with higher copy numbers.
These findings, the study says, “might help explain the association between
CCL3L1 gene dose and risk of acquiring HIV and disease progression. This is
because chemokines, like CCL3L1, are thought to block the interaction between
gp120 (glycoprotein120 – a receptor on the surface of the virus) and CCR5
(explained above) therefore preventing gp120 from using CCR5 to enter the
potential host cell (Gonzalez 3).
Before moving on to looking at the newspaper article it will be helpful to
recap the major points covered in the research study so they can be compared to
the information McNeil provides. First, among HIV-positive individuals there is a
disproportionate representation of individuals with low CCL3L1 copy numbers.
Second, higher copy numbers of CCL3L1 correlated with slower disease
progression. Third, those with lower CCL3L1 copy numbers had higher viral set
points and lower T-cell counts.
Of these three major conclusions discussed in the study, only the first
conclusion is referred to specifically in the New York Times article. There are
many possible justifications for the journalist’s decision. The most obvious reason
is that the first conclusion appears to be the most important. For many people
HIV/AIDS is a source of fear and grief, so any scientific discovery that shows any
indication of a mechanism to prevent or weaken the virus is a great source of
hope. This article is not written for an audience that is specifically interested in
science. The first conclusion with its human interest value is more appropriate for
this publication than conclusions about viral set points and T-cell counts, which
are more esoteric and technical. The second conclusion is not given specifically
in the Times article but could be included under the general statement “that
people with extra stretches of genetic material coding for a chemokine known as
CCL3L1 are better protected against the AIDS virus than people with fewer of
them” (McNeil).
After telling his readers about the main discovery of the study, McNeil
provides a bit of the scientific background to the role of CCL3L1 in HIV infection.
McNeil attempts to make this technical information more accessible by putting it
in human terms. He refers to the chemokine as a “distress call,” CCR5 receptors
as “alarm bells,” the HIV virus as the “invader” and the function of a host cell
infected by a retrovirus as a “virus factory.” McNeil’s decision to include this
information and in these terms reflects the same motivations given for including
similar information in the first part of this paper - for the lay person to understand
the importance of this study it is necessary to grasp the basic mechanisms
involved.
Another interesting thing McNeil does in his treatment of this study is his
reference to Dr. John P Moore, an AIDS researcher at Cornell University. Dr.
Moore was not involved in this study but the inclusion of his comments in the
newspaper article serves several purposes. First, the reference to a source with
an important position at a reputable and recognizable institution lends credibility
to the report. Second, his comments help the reader but the findings of the study
in an appropriate context, as he says, the discovery “adds to the understanding
of how genes affect the progress of AIDS.” Perhaps the most important function
of Dr. Moore’s comments is to put the study in perspective. Although he allows
that the study is important, Dr. Moore tells the Times’ readers that this discovery
“doesn’t change the world on its axis,” warning them against overestimating its
implications.
Although Dr. Moore warns the readers of The New York Times not to
overestimate the importance of the research, it appears that to many people this
was an important discovery. A simple “google” search for CCL3L1 will reveal
dozens of news articles in dozens of languages referring to this study. In addition
to traditional news agencies a number of special interest sites, especially those
dealing with AIDS and GLBT issues, reported on these new findings. As was
mentioned earlier, due to the catastrophic scope of the HIV/AIDS epidemic, any
positive research discoveries are immeasurably important to a countless number
of people and for this reason it is important.
Bibliography
AIDSinfo: HIV/AIDS glossary. http://aidsinfo.nih.gov/ed_resources/glossary.
Gonzalez, Enrique et al. “The Influence of CCL3L1 Gene-Containing Sequence
Duplications on HIV-1/AIDS Susceptibility.” Science.
10.11.26/science.1101160 (6
January 2005) http://www.sciencemag.org/cgi/rapidpdf/1101160v1.pdf
Lewis, Ricki. Human Genetics: Concepts and Applications. Boston. McGraw Hill,
2005.
McNeil, Donald G. Gene May Foil AIDS Virus, Study Finds. 7 Jan. 2005.
http://query.nytimes.com/search/restricted/article?res=F60617FA3A5D0C
748C
DDA80894DD404482 (Accessed 1 Feb. 2005)
Te (Victoria) You
Human Heredity
Professor Strauss
January 25, 2005
NY Times: “Gene Study Identifies 5 Main Human Populations”
Nicholas Wade of the New York Times writes in his article, “Gene Study
Identifies 5 Main Human Populations,” that scientists studying neutral DNA
markers of 52 “human groups”2 worldwide have identified 5 main populations
corresponding to major geographical regions: “Africa, Europe, Asia, Melanesia
and the Americas”3. Wade alludes to a paper4 co-authored by Dr. Kenneth Kidd
of Yale and a study led by Dr. Marcus Feldman of Stanford, the purpose of which
was to help correlate disease patterns to genetics, and “to establish an
evolutionary framework based on the random consequences of the historical
demographics of modern human populations”5. According to the article,
Feldman’s study found that “self-reported population ancestry” is an acceptable
alternative to genetic ancestry, and also “less expensive and less intrusive” 6.
By studying neutral genetic markers7, scientists are able to identify small
differences in the polymorphisms8 of the five major populations (while 95% of the
Wade, Nicholas, “Gene Study Identifies 5 Main Human Populations”, The New York Times [nytimes.com
Dec 20, 2002].
3
Ibid.
4
Kidd, K.K., Pakstis, A.J., Speed, W.C., and Kidd, J.R, 2004. Understanding Human DNA Sequence
Variation. Journal of Heredity: 95(5): 406-420.
5
Ibid.
6
Wade, Nicholas, “Gene Study Identifies 5 Main Human Populations”, The New York Times [nytimes.com
Dec 20, 2002].
7
DNA segments with no apparent function in the body
2
human polymorphism is found in people all over the world9). However, Wade’s
article illustrates how, despite the scientists’ assertions on the geographical
nature of their distinction among the five abovementioned population groups,
their studies raise the inevitable issue/controversy of race in science and spur
more debate over the social v. biological conception/perception of race.
As geneticists work towards one of the “grand challenges” put forth by the
National Human Genome Research Institute—that of developing “a detailed
understanding of the heritable variation in the human genome”10, they encounter
genetic variations among ethnic groups and the subsequent challenge of
addressing such variations with professionalism and accountability. It has never
been easy for one to tread the controversial border between society/humanity’s
and science’s respective perceptions of division among human populations.
Many scholars/researchers are thus careful to limit their scope to their own
disciplines. In their studies of gene variations in different ethnic groups, Kidd et
al. distinguished between the social and moral concept of equality among
individuals and the biological perspective that “all human beings independently
conceived are genetically unique”11.
Analyzing a set of polymorphisms (more than 100 polymorphisms per
study) and using 38 populations with slightly more than 50 individuals per
population12, Kidd et al. measured gene frequency variation in such studies as
8
A DNA base/sequence at a certain locus that varies in at least 1 % of the population
Wade, Nicholas, “Gene Study Identifies 5 Main Human Populations”, The New York Times [nytimes.com
Dec 20, 2002].
10
Kidd, K.K., Pakstis, A.J., Speed, W.C., and Kidd, J.R, 2004. Understanding Human DNA Sequence
Variation. Journal of Heredity: 95(5): 406-420.
11
Ibid. 407
12
Ibid. 408
9
allele frequencies, average heterozygosity, distribution of ancestral alleles,
haplotype frequencies, nonrandomness along the DNA, principal component
analyses, and tree analyses13.
From their studies, Kidd et al. concluded that several of the studies that
they did for this paper supports the “Out of Africa”14 theory which states that
human beings originated from Africa and migrated to Europe, Melanesia, the
Americas, and Asia over time. The only data that does not support this theory is
that of the average heterozygosity of populations, where the high heterozygosity
shown by Europeans could imply origination of humans from Europe. However,
Kidd et al. asserts that such unusually high heterozygosity among Europeans is
“almost certainly the result of ascertainment bias”15, for many of the
polymorphisms selected for this study were identified and chosen because they
showed high heterozygosity in Europeans. Otherwise, the high frequency of the
presence of ancestral alleles in African populations, the greater haplotype
diversity in African populations, and the greater LD16 in non-African populations
are all indicative of the “Out of Africa” theory. Kidd et al. stated that random
genetic drift (of human populations out of Africa) could account for much of the
abovementioned genetic variation17. The supporting data culminate in a genetic
tree, in which Africans (the “founders”) are placed at one end, branches off
Native Americans and Asians with a common ancestor, and Europeans and
13
Ibid. 406-420
First supported molecularly by studies of mitochondrial DNA (Cann et al. 1987)
15
Ibid. 410
16
Linkage Disequilibrium: describes nonrandom combinations of alleles at multiple sites on chromosomes
in the population
17
Ibid. 408
14
Middle Easterners with another common ancestor, while some “misfit”
populations such as the Khanty and the Micronesians are scattered in between.18
This is one important characteristic in the distinction among human populations
that Wade failed to mention in his NY Times article.
Since Kidd’s study is not the only one that Wade cited in his article, the
article proceeded in an understandably different direction than it would have had
Kidd’s paper been its only primary source of information. The parts of Wade’s
article that alluded to Kidd’s original paper were faithful to the corresponding
parts in Kidd’s paper. However, in addition to making reference to Kidd’s study
on genetic variation among populations, the article also alludes to a study on the
relationship between gene pool variations and disease patterns19. Nowhere in
Kidd’s paper did it mention relevance to disease patterns.
Furthermore, Wade’s article put a great deal of emphasis on race,
whereas Kidd’s original paper avoided discussions of “race” and chose to deal
mainly with issues of DNA variation across populations defined by their
geographical location. Again we return to the debate over race in the
sociological and biological contexts, to where biologists are careful not to offend,
and where sociologists have not the competence to go20. On one hand, the
article cited the American Sociological Association, which warned against
“contributing to the popular conception of race as biological”21. On the other
hand, the article quoted a leading sociologist dismissing the earlier comment and
18
Ibid. 417
Dr. Marcus Feldman, Stanford
20
Dr. Troy Duster as quoted in Wade, Nicholas, “Gene Study Identifies 5 Main Human Populations”, The
New York Times [nytimes.com Dec 20, 2002].
21
ASA, Ibid.
19
emphasizing drawing the line between sociological and genetic concepts of race
as two distinct frameworks.
Nicholas Wade’s NY Times article accurately cited and interpreted the
symposium paper compiled by Dr. Kenneth Kidd et al. on “Understanding Human
DNA Sequence Variation”, though the article was written with a wider scope
(encompassing some sociological viewpoints on race) than the original paper.
Kidd’s study on polymorphisms in DNA markers among different populations
sought to determine the relationships that existed between genetic variation and
population genetics. As Wade’s article pointed out, Kidd’s paper concluded in
support of the preexisting theory of human populations originating in Africa and
later developing variation mainly via random genetic drift. Based on genetic
similarities among populations, Kidd et al. were able to group today’s human
population into five major groups, four of which can be distinguished by similar
genetic distances. While this study was only done in a limited scope, it presents
a more complete picture of modern population genetics and raises once again
the issue and definition of race across disciplines.
Works Cited Page
Kidd, K.K., Pakstis, A.J., Speed, W.C., and Kidd, J.R. 2004. Understanding
Human DNA Sequence Variation. Journal of Heredity: 95(5): 406-420.
Wade, Nicholas. “Gene Study Identifies 5 Main Human Populations.” The New
York Times 1 Dec. 2004.