As part of the Darwin Bicentennial Lecture Series at Appalachian State University, Dr. Paul Ewald, author of Plague Time: The New Germ Theory of Disease, recently gave a presentation on the genetic basis of cancer. During the lecture, Dr Ewald spent a considerable amount of time discussing the role of infectious agents, specifically viruses, as the causative agents of cancer. Specifically, Dr Ewald talked about the human papillomavirus (HPV), and how screening of seemingly unrelated cancers, such as breast cancer and cancers of the head and neck, are linking this virus as a potentially more important agent in cancer formation than previously thought.
If infectious agents are responsible for priming cells to enter into a tumor-forming stage, as Dr Ewald's work strongly suggests, then the use of vaccines against these agents could be a major advance in the evolution of preventative strategies against cancer. HPV vaccines are already recommended for young women to prevent against cervical cancer later in life. Now it appears that these vaccines may have potential benefits in other areas as well.
Interestingly, a recent article in Science Daily (Genetic Markers for Aggressive Head and Neck Cancers) presents data from a study at the Albert Einstein College of Medicine that a specific type of genetic markers, called microRNAs, may be used to identify individuals who are highly susceptible to forms of head and neck cancer. The researchers in this study propose that genetic screening may be useful in the development of new treatments for these cancers.
Is is possible that the microRNA markers identified by the team at the Albert Einstein College of Medicine are actually indicating susceptibility to the HPV virus? We know that everyone who carries HPV does not necessarily develop cancer, but the reason why is not yet clear. It could be that a genetic susceptibility is the key. Certain genetic combinations could promote HPV influence, and result in the formation of the cancer phenotype. If this is the case, then trials of using the HPV vaccine on individuals who have these specific microRNA markers are definitely in order. This could provide some very useful insights on new treatments of specific types of cancers, specifically those that have been identified to be associated with an infectious agent.
Showing posts with label genome analysis. Show all posts
Showing posts with label genome analysis. Show all posts
Friday, March 20, 2009
Wednesday, February 11, 2009
Walmart Offers Genome Sequencing? Not Yet...But Maybe Soon
A company called Complete Genomics has recently announced that they intend to market the $5000 complete genome sequencing package. $5000 is not cheap, but it is definitely cheaper than some of the earlier efforts at genome sequencing.
The Human Genome Project cost 2.7 billion dollars, or roughly $1 per nucleotide in our genome. If the claims by Complete Genomics are correct, then the cost of having your 3 billion (+) nucleotides in your genome sequenced is be reduced to around $0.000016 each. And that opens the door for some pretty interesting developments....
First of all is the fact that the $5000 genome will ignite a form of biotech price war. When the first wide-screen plasma TVs hit the market, their average price was well over $5000. Many people wondered who would pay that much for a TV? But, very quickly, the price came down to the point where now you can get a wide-screen plasma for around $500. The same thing should happen with genome sequencing. Competition and technological advances will drive down the price, maybe even to less than $500. There is already financial incentive, the Archon X Prize in Genomics is offering $10 million to the first company to sequence 100 human genomes in less than 10 days. This is still a formidable task, but so was getting around the world in less than 80 days to Jules Verne.
The availability of inexpensive and rapid sequencing of individual genomes will be a huge asset to companies who need large databases for genomics work. Once these large databases become available, extensive association studies of the human genome become possible. These studies have the potential to reveal rare gene combinations that may be associated with some forms of diseases. This, in turn, has the potential to facilitate the development of new treatment options. As in any scientific experiment, the larger the database, the greater the chance of finding something rare and interesting. Right now, we are limited the availability of these large databases by cost...but it looks as if that may be changing.
Of course, there are real ethical questions that need to be addressed, mainly to do with the confidentiality of the genetics information and who ultimately owns the rights to your DNA. After all, the insurance companies would love to know about that rare allele you are hiding that will not only shorten your life (and time paying premiums) and cost them thousands in medical costs. We should be cautious of who has access to this information, but not so overly cautious as to delay development time of new technologies. In the long run, the availability of inexpensive genomic sequencing will advance medicine in ways that are currently only science fiction.
For more information on the work being done by Complete Genomics, see the article by Peter Aldhous "Genome Sequencing Falls to $5000"
Saturday, October 25, 2008
Fruit Flies Enter the Political Battle
The political fray has entered into the world of genetics, and as usual, our politicians have no real idea what they are talking about. In an October 24th speech about children with special needs, Sarah Palin, the Republican nominee for Vice-President, made the following statement about funding for IDEA, or the Individuals with Disabilities Education Act.
“This is a matter of how we prioritize the money that we spend. We've got a three trillion dollar budget, and Congress spends some 18 billion dollars a year on earmarks for political pet projects. That's more than the shortfall to fully fund the IDEA. And where does a lot of that earmark money end up? It goes to projects having little or nothing to do with the public good -- things like fruit fly research in
There is no doubt that more money needs to be spent on research and education of people with disabilities. However, the assumption here is that fruit fly research is a waste of time and money. Nothing could be further from the truth. The simple fact that we have an understanding of genetics can be traced back to Thomas Hunt Morgan and the first use of fruit flies.Since then, four Nobel Prizes, including one to Thomas Hunt Morgan (1933), have gone to "fruit-fly" researchers. Obviously the scientific community values the contributions of the fruit fly to the study of genetics.
Research into Drosophila genomics paved the way for the Human Genome Project. In other words, research using fruit flies, and other model organisms such as the mouse, nematode (C. elegans), and weed (Arabidopsis thaliana) are critical towards our understanding of the molecular world of inheritance and disease.
Time to get some Straight Talk. We owe thanks to geneticists who use this model organism, not ridicule.
Additional links:
A Brief History of Drosophila’s Contributions to Genome Research
A Systematic Analysis of Human Disease-Associated Gene Sequences In Drosophila melanogaster
Sunday, September 14, 2008
The Reality of Race
What really makes us different? As the father of two young children, I am constantly amazed at how my children begin to distinguish themselves from others in their class. At a very young age, they barely recognized that not all people were the same, and what differences they did note were more of a curiosity to them than a type of distinction.
Now, however, as they exit middle school, they are well aware that some people are "different" from them. Sure, some of it is their social environment — we all know that middle schools are not the model of social integration. But as a scientist, I always have been intrigued by the apparent need to define ourselves as unique, even when it is clear from a scientific perspective that the majority of these differences are due to very minor variations in our genetic makeup.
Despite the ongoing "nature versus nurture" argument between the social scientists and geneticists, as scientists we always have suspected that our underlying differences would have to be controlled by genetics and the biochemical pathways that those genes regulate. While we now recognize that the environment does play a role in gene expression, and few of us believe that we are genetic automatons, barely a week goes by when we are not made aware of a new discovery on the genetic basis of a behavior or a disease. Genes control phenotypes. If race is such an important aspect of our society, as is clearly demonstrated by the latest political cycle, why has it taken us so long to really take a good look at the "phenotype" of race, and determine whether race is genetic?
Over the past several years there have been a number of articles that address the concept of race. One of my favorites is "Does Race Exist?" by Michael Bamshad and Steve Olson, from the Nov. 10, 2003, issue of Scientific American. I make this a required reading article for all of my science classes, from non-scientists to future geneticists.
The basic premise of this article is that the pigmentation level of an individual's skin is a poor criteria to use to identify them as belonging to a specific race, and that the use of these phenotypic races in medicine is bound to create problems.
The authors give an example of African Americans, who are typically identified as being of African descent. However, Africa is not home to a group of genetically identical individuals. Sub-Saharan Africans are genetically different from those from South Africa and the Mediterranean regions.
What is really important is how these populations of humans have historically adapted to selective forces including disease and the environment. Groups that have responded to similar selective forces are more correctly classified as a "race" than those with similar skin colors.
A recent NewScientist article, "Watson vs Venter: the loser is race-based medicine," brings two of biotech's big names to center stage on the discussion of race. James Watson and Craig Venter have made their genomes available publically. (For details see Venter and Watson.)
As Ewen Callaway reports in the article, an analysis of Watson's genome indicates that Watson, a phenotypic Caucasian, possesses a number of mutations that are found most commonly in populations from East Asia.
What this means is that Watson's doctor may prescribe him codeine or antidepressant drugs based upon his Caucasian phenotype, without realizing that at the metabolic level, Watson's cells are operating as if he is Asian.
The same thing is probably happening in each of us. Now that the two big boys, and their associated financial clout, are involved in the discussion, maybe we can really start to talk about what race means.
I, for one, am encouraged that these discussions are starting to gain momentum. At a time when humanity appears to be obsessed in establishing differences based upon race, sexual orientation, ethnicity and religious preference, it is promising to see that the scientific community is working to dispel these notions.
Research into the genetic basis of race needs to continue, not only for the development of new drugs, but to break down society's stereotypes of race. We need to recognize that while the person next to us may look different than we do, he or she may have more in common with us as an individual than a person of our perceived "race." I have a hard time seeing how anything negative can come from this realization.
This entry was originally published as "The Differences Within Us: The Latest Scientific Discussions on Race and Medicine" in the Sept 11, 2008 volume of Bioworld Perspectives. It is reprinted here by permission of AHC Media.
Now, however, as they exit middle school, they are well aware that some people are "different" from them. Sure, some of it is their social environment — we all know that middle schools are not the model of social integration. But as a scientist, I always have been intrigued by the apparent need to define ourselves as unique, even when it is clear from a scientific perspective that the majority of these differences are due to very minor variations in our genetic makeup.
Despite the ongoing "nature versus nurture" argument between the social scientists and geneticists, as scientists we always have suspected that our underlying differences would have to be controlled by genetics and the biochemical pathways that those genes regulate. While we now recognize that the environment does play a role in gene expression, and few of us believe that we are genetic automatons, barely a week goes by when we are not made aware of a new discovery on the genetic basis of a behavior or a disease. Genes control phenotypes. If race is such an important aspect of our society, as is clearly demonstrated by the latest political cycle, why has it taken us so long to really take a good look at the "phenotype" of race, and determine whether race is genetic?
Over the past several years there have been a number of articles that address the concept of race. One of my favorites is "Does Race Exist?" by Michael Bamshad and Steve Olson, from the Nov. 10, 2003, issue of Scientific American. I make this a required reading article for all of my science classes, from non-scientists to future geneticists.
The basic premise of this article is that the pigmentation level of an individual's skin is a poor criteria to use to identify them as belonging to a specific race, and that the use of these phenotypic races in medicine is bound to create problems.
The authors give an example of African Americans, who are typically identified as being of African descent. However, Africa is not home to a group of genetically identical individuals. Sub-Saharan Africans are genetically different from those from South Africa and the Mediterranean regions.
What is really important is how these populations of humans have historically adapted to selective forces including disease and the environment. Groups that have responded to similar selective forces are more correctly classified as a "race" than those with similar skin colors.
A recent NewScientist article, "Watson vs Venter: the loser is race-based medicine," brings two of biotech's big names to center stage on the discussion of race. James Watson and Craig Venter have made their genomes available publically. (For details see Venter and Watson.)
As Ewen Callaway reports in the article, an analysis of Watson's genome indicates that Watson, a phenotypic Caucasian, possesses a number of mutations that are found most commonly in populations from East Asia.
What this means is that Watson's doctor may prescribe him codeine or antidepressant drugs based upon his Caucasian phenotype, without realizing that at the metabolic level, Watson's cells are operating as if he is Asian.
The same thing is probably happening in each of us. Now that the two big boys, and their associated financial clout, are involved in the discussion, maybe we can really start to talk about what race means.
I, for one, am encouraged that these discussions are starting to gain momentum. At a time when humanity appears to be obsessed in establishing differences based upon race, sexual orientation, ethnicity and religious preference, it is promising to see that the scientific community is working to dispel these notions.
Research into the genetic basis of race needs to continue, not only for the development of new drugs, but to break down society's stereotypes of race. We need to recognize that while the person next to us may look different than we do, he or she may have more in common with us as an individual than a person of our perceived "race." I have a hard time seeing how anything negative can come from this realization.
This entry was originally published as "The Differences Within Us: The Latest Scientific Discussions on Race and Medicine" in the Sept 11, 2008 volume of Bioworld Perspectives. It is reprinted here by permission of AHC Media.
Friday, June 6, 2008
The Latest Evolution of the -Omes: The Diseasome Comes to Life
In 1988 if you had told most scientists that the human genome would be sequenced within 20 years, and that the resulting genome would turn out to be the least complicated of the –omes, most of them (including this one) would have said that you had been reading too much science fiction.
I distinctly remember discussions in graduate school about how the human genome probably contained around 150,000 genes. As the years progressed, techniques improved and research continued ... and the size of the human genome began to collapse quickly. At one point I remember hearing a colleague comment on how humans appeared to be "de-evolving" at a record pace! By the year 2000 the human genome had shrunk to around 50,000 genes, and over the next eight years it continued to contract. Recent estimates place the number of genes at around 24,000–30,000.
What had happened was not some major evolutionary genomic constriction event; rather, it was a greater understanding of how genes interacted and were processed by the metabolic machinery of the cell. Scientists began to think that it was not the genes themselves that were important; it might be the gene products that truly mattered.
For many molecular biologists, and probably most of the biotechnology community, the genome turned out to be somewhat of a bust. A disease is a phenotype, an outward portrayal of a trait, which in the case of most diseases has an underlying cause in the genome, but not in all cases. Creutzfeldt-Jakob disease is a nice example of a condition that is caused not by a defect in a gene (although there is some suggestion of genetic susceptibility), but rather by a malfunctioning protein called a prion. In fact, most diseases are caused by protein-related problems. Thus, in order to understand human disease it was necessary to take a good look at the proteome, or the sum of the proteins within a cell.
The size of the proteome appears to be even more elusive than the size of the genome. Estimates range from between 90,000 to more than 400,000 proteins in the human proteome. Of course this number is dependent on a number of items, including cell type, influence of external stimuli, cell age, nutritional state, etc. The proteome is the cell's response to its environment, and therefore it is expected that it will fluctuate depending on the needs of the cell.
So while some still work to identify the entire proteome, attention has shifted to what the proteome can tell us about the health of a cell. To do that, it was necessary to understand interactions within the proteome. This is called the interactome and it encompasses the study of all interactions at the molecular level within cells. The interactome is based primarily on protein-protein interactions. This led to amazing breakthroughs in systems biology, which integrated biochemistry, molecular genetics and cell biology to more fully understand how cells work.
Something very interesting occurred at this point. When studying protein interactions it is often useful to go back and identify the genes that code for each protein. Advances in biotech have made this a relatively easy process, and it was only a matter of time before scientists began to uncover some intriguing connections. In a New York Times article by Andrew Pollack, the author interviews scientists who have used studies of the proteome and interactome to reveal genes common to both heart attacks and muscular dystrophy — two seemingly unrelated conditions.
In other words, molecular science has come full circle. An understanding of the genome is once again important, but so is an understanding of the interactome and proteome. Together, these items are sometimes called the diseasome. The diseasome represents the latest evolution of the -ome; it fully integrates all information to understand factors that may cause a disease.
If you are having a hard time visualizing the diseasome, then a quick visit to an interactive graphic on a portion of the diseasome prepared by The New York Times will help immensely. If you notice, there are connections in this diagram that seem to be impossible if you think only about the disease, such as genes linking myocardial infarctions and Alzheimer's disease. But if you step back from the disease for a second, and integrate the information, it starts to make sense. At the cellular level, metabolic activities are directed by genes and proteins interacting in complex manners. Since there are a limited number of genes and proteins, but a seemingly unlimited number of diseases, then there must be common factors that we have previously missed.
So what does all of this mean? The ability to visualize these interactions may allow medical researchers to develop innovative methods of detecting and treating disease states. Some, such as Dr. Albert-László Barabási at The New England Journal of Medicine and Northeastern University, have called this network medicine.
In the very near future, as more of these interactions are mapped out, doctors may begin to prescribe unique combinations of drugs that would have not even been considered 10, or even five, years ago.
Diseases that previously were thought to be too complex to cure, such as muscular dystrophy and diabetes, may very soon be things of the past.
Note: this article first appeared in the June 5, 2008 issue of BioWorld Perspectives, and is reproduced here by permission of AHC Media, LLC
Monday, March 3, 2008
New Hope for Short People???
"Tall people have tall children, and short people have short children." For many this statement summarizes all that needs to be known regarding the relationship between a person’s height and heredity. For geneticists, however, these types of general observations represent an open intellectual challenge, since a more careful observation of the human population reveals that there is considerable variation with regards to height, and that it is possible for tall people to have short children, and vice versa.
A Quantitative And Multifactorial Trait
For years scientists have known that height is a quantitative trait, meaning that the population does not fall into distinct phenotypic classes. Anyone who purchases clothes knows that people are not "tall," "short" or "medium." Instead, height in humans is distributed around a mean value. This form of distribution, or bell-shaped curve, is characteristic of a trait that is under the influence of multiple genes, each one having an additive effect on the phenotype. The more of the
alleles that a person has, the further along the distribution the phenotype is located.
Geneticists also recognize that height is a multifactorial trait. Multifactorial does not mean simply that multiple genes are involved. The term multifactorial indicates that there are both genetic and environmental factors that are contributing to the observed phenotype.
A wonderful illustration of the multifactorial basis of human height is provided by Ricki Lewis in her textbook, Human Genetics, Seventh Edition. Lewis presents two photos of the graduating class of Connecticut Agricultural College, one taken circa 1920, the other in 1997. In both photos, the students were placed into phenotypic classes by height (to the nearest inch). The distribution of both classes follows a distinctive bell-shaped curve characteristic of a quantitative trait. The difference is that the mean height of the 1997 class was much greater than that of the 1920 class. Whereas the tallest individual in 1920 was 5’9", the tallest individual in 1997 was 6’5".
Since it is unlikely that a "tall" mutation has infiltrated the entire graduating class, and therefore the genetic basis of the two populations should be roughly the same, then there must be some other factor involved. Human geneticists and medical professionals say that the overall change in height over the past several decades is primarily due to improvements in human nutrition – an environmental factor. Building on this, geneticists have suggested that human height may be the
result of the interaction of environmental factors with several major genetic mechanisms and a host of minor genes.
Use Of Genome-Wide Association Studies
As a geneticist who has studied quantitative traits in Drosophila, I can testify that one of the hardest problems facing quantitative geneticists is the ability to tease out the influence of major and minor genes on a phenotype. Many methods exist to investigate the contributions of a single gene to a phenotype, but searching for all of the minor contributing genes has remained a relatively difficult task. Recently, a research group led by Timothy Frayling at Peninsula Medical School in Exeter, UK, reported the use of the genome-wide association studies (GWAs)
to identify genes responsible for variations in the height of humans (Nature Genetics, October 2007). The use of association studies in human genetic analysis is nothing new as they have been used with a variety of genetic markers for several decades. However, the use of GWAs in this manner is something significant as it allowed the researchers to look at contributing alleles across the genome, and not simply in the vicinity of candidate genes. This technique should give researchers the ability to identity a greater number of minor genes, or those that make smaller contributions to the phenotype in question. This could prove to be very useful for complex diseases and traits that are under the control of multiple genes.
Breakthroughs In HMGA2
The gene that Frayling’s group identified, HMGA2, is not a new discovery. As the researchers report, it has been known for some time that severe disruptions of this gene can cause drastic changes in the height phenotype (dwarfism and gigantism) of mice. What Frayling was able to show is that certain alleles of this gene are associated with height at specific times during development. Interestingly, the associations indicated that certain alleles are associated with an
increase in height between the ages of 7 and 11 years and persisting into adulthood. This identification of this temporal importance suggests that other genes remain to be identified that play a role earlier in life. But there is also a catch – the gene that is responsible for the added height is also associated with an increased risk of certain types of cancer. The gene product of HMGA2 belongs to a family of proteins that act as DNA-binding proteins, meaning that HMGA2 most likely has a role in the regulation of gene expression. Although HMGA2 is not an oncogene, it has been observed to be overexpressed in certain types of tumors, meaning that while a gene might be a minor gene in one quantitative trait, it may be a major gene for another trait.
With the developing promise of gene therapy might it be someday possible to prevent individuals from being vertically challenged? In today’s world there is always someone who will want to capitalize on a discovery such as this by promising increased height to short people. Though some might see it as an opportunity to change or select the phenotype of an individual, in reality this paper has a far greater significance. The identification of HMGA2’s role in height
is an important breakthrough in the study of complex quantitative traits, and it demonstrates the power of new genome analysis techniques that are coming online. As Frayling and his colleagues suggest, the true power of this technique will be when it is applied to the study of complex diseases.
A Quantitative And Multifactorial Trait
For years scientists have known that height is a quantitative trait, meaning that the population does not fall into distinct phenotypic classes. Anyone who purchases clothes knows that people are not "tall," "short" or "medium." Instead, height in humans is distributed around a mean value. This form of distribution, or bell-shaped curve, is characteristic of a trait that is under the influence of multiple genes, each one having an additive effect on the phenotype. The more of the
alleles that a person has, the further along the distribution the phenotype is located.
Geneticists also recognize that height is a multifactorial trait. Multifactorial does not mean simply that multiple genes are involved. The term multifactorial indicates that there are both genetic and environmental factors that are contributing to the observed phenotype.
A wonderful illustration of the multifactorial basis of human height is provided by Ricki Lewis in her textbook, Human Genetics, Seventh Edition. Lewis presents two photos of the graduating class of Connecticut Agricultural College, one taken circa 1920, the other in 1997. In both photos, the students were placed into phenotypic classes by height (to the nearest inch). The distribution of both classes follows a distinctive bell-shaped curve characteristic of a quantitative trait. The difference is that the mean height of the 1997 class was much greater than that of the 1920 class. Whereas the tallest individual in 1920 was 5’9", the tallest individual in 1997 was 6’5".
Since it is unlikely that a "tall" mutation has infiltrated the entire graduating class, and therefore the genetic basis of the two populations should be roughly the same, then there must be some other factor involved. Human geneticists and medical professionals say that the overall change in height over the past several decades is primarily due to improvements in human nutrition – an environmental factor. Building on this, geneticists have suggested that human height may be the
result of the interaction of environmental factors with several major genetic mechanisms and a host of minor genes.
Use Of Genome-Wide Association Studies
As a geneticist who has studied quantitative traits in Drosophila, I can testify that one of the hardest problems facing quantitative geneticists is the ability to tease out the influence of major and minor genes on a phenotype. Many methods exist to investigate the contributions of a single gene to a phenotype, but searching for all of the minor contributing genes has remained a relatively difficult task. Recently, a research group led by Timothy Frayling at Peninsula Medical School in Exeter, UK, reported the use of the genome-wide association studies (GWAs)
to identify genes responsible for variations in the height of humans (Nature Genetics, October 2007). The use of association studies in human genetic analysis is nothing new as they have been used with a variety of genetic markers for several decades. However, the use of GWAs in this manner is something significant as it allowed the researchers to look at contributing alleles across the genome, and not simply in the vicinity of candidate genes. This technique should give researchers the ability to identity a greater number of minor genes, or those that make smaller contributions to the phenotype in question. This could prove to be very useful for complex diseases and traits that are under the control of multiple genes.
Breakthroughs In HMGA2
The gene that Frayling’s group identified, HMGA2, is not a new discovery. As the researchers report, it has been known for some time that severe disruptions of this gene can cause drastic changes in the height phenotype (dwarfism and gigantism) of mice. What Frayling was able to show is that certain alleles of this gene are associated with height at specific times during development. Interestingly, the associations indicated that certain alleles are associated with an
increase in height between the ages of 7 and 11 years and persisting into adulthood. This identification of this temporal importance suggests that other genes remain to be identified that play a role earlier in life. But there is also a catch – the gene that is responsible for the added height is also associated with an increased risk of certain types of cancer. The gene product of HMGA2 belongs to a family of proteins that act as DNA-binding proteins, meaning that HMGA2 most likely has a role in the regulation of gene expression. Although HMGA2 is not an oncogene, it has been observed to be overexpressed in certain types of tumors, meaning that while a gene might be a minor gene in one quantitative trait, it may be a major gene for another trait.
With the developing promise of gene therapy might it be someday possible to prevent individuals from being vertically challenged? In today’s world there is always someone who will want to capitalize on a discovery such as this by promising increased height to short people. Though some might see it as an opportunity to change or select the phenotype of an individual, in reality this paper has a far greater significance. The identification of HMGA2’s role in height
is an important breakthrough in the study of complex quantitative traits, and it demonstrates the power of new genome analysis techniques that are coming online. As Frayling and his colleagues suggest, the true power of this technique will be when it is applied to the study of complex diseases.
This article was originally published in BioWorld Perspectives (vol 1 # 46) in November 2007 and is reprinted here by permission from AHC Media LLC.
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