Wednesday, August 26, 2009
Does our DNA make decisions for us?
In this week’s Proceedings from the National Academy of Science, Christina S. Barr and colleagues report that a mutation in the CRH gene is associated with increased stress-induced alcohol consumption in primates. What are the implications of this study and those like it? What does it mean if a DNA mutation can shape behaviors that affect our society?
First, let’s catch up on the basics. The CRH gene is the piece of DNA that encodes instructions to make corticotropin-releasing factor (CRF), a piece of cellular machinery required by our bodies for stress adaptation. Too much CRF activity can lead to increased anxiety or depression-like symptoms.
Barr’s research involves a mutation in a region of the DNA directly before the CRH gene, called the CRH promoter. In a sense, a gene’s promoter is like password protection for the gene. If the cell doesn’t use the proper combination of factors to satisfy the password, the instructions in the gene cannot be accessed. Other times, a faulty promoter will allow access to the gene too often. In the current study, the mutation in the promoter for CRH causes the cell to make too much CRF.
To determine if the CRH mutation affected stress-related behavior, Barr exposed young macaques to peer rearing (as opposed to mother rearing), an environment that is known to induce stress in these young animals. Next, Barr’s team measured the differences in alcohol consumption between normal macaques and those carrying the CRH mutation. After early stress exposure, the macaques with the CRH mutation consumed significantly more alcohol than the controls with a normal CRH gene.
Stop and think about this result for a moment. What does it mean if a gene mutation significantly affects a quantifiable behavior? To what extent does our genetic make-up contribute to the thousands of decisions every individual makes each day. The outcome of most decisions is benign; what one eats for breakfast or wears to work most likely won’t evoke a second thought. Other decisions, however, can have large impacts on society. The choice to consume excessive amounts of alcohol, engage in violent behavior, or disregard accepted social contracts can land a person in jail, if not worse.
Science progresses at an exponential pace. It is not unlikely that ten to twenty years from now, many more genes will be associated with specific behaviors. There will be a time when a jury will need to decide if a crime was committed with criminal intent or if the accused was at his DNA’s will. To properly handle these future scenarios, we as a society need to develop a basic understanding of cellular biology and learn how to assess the possible implications when something has gone amiss at the genetic level.
One hundred years ago, demons and devils were blamed for unacceptable behavior. One hundred years from now, who will be on trial: the perpetrator or his DNA? These are not questions for a science fiction novel or the next blockbuster film. These are relevant issues that warrant discussion based on educated reason.
Reference: Christina S. Barr et al. “Functional CRH variation increases stress-induced alcohol consumption in primates.” PNAS August 25, 2009. DOI: 10.1073/pnas.0902863106
Friday, August 21, 2009
Early to bed, early to rise, makes a man healthy, wealthy, and A MUTANT?!
Your eyes meet. A foggy haze hangs in the air as you lean in for the kiss. Your lips are just about to touch, and the alarm goes off! We all know the feeling. Just ten more minutes!
For some, those ten minutes come after a comfortable seven to eight hours of sleep. For others, only six hours separates the night and the morning. While shorter sleep cycles lead to chronic sleep deprivation in a large percentage of the population, there are certainly individuals who find six hours of sleep sufficient. Why is it that a lucky few require only a fraction of the recommended seven to eight hours of sleep per night?
It looks as though the answer may reside once again in our DNA. In last week’s issue of Science Magazine, Ying He from the University of California at San Francisco reported that a small mutation in the DEC2 gene significantly decreases the length of a night’s sleep. He’s team identified the DEC2 mutation in two related individuals who indicated very early wake up times in a survey, reportedly sleeping nearly two hours less than other family members.
To study the significance of the DEC2 mutation on sleep cycles, He and colleagues generated transgenic mice that expressed the mutated human form of DEC2, called DEC2-P385R. He’s team found that mice expressing DEC2-P385R indeed had longer activity periods paired with shorter sleep phases. While many groups would be happily satisfied with this finding, He’s group took the experiment one step further. They next expressed the mutated mouse form of DEC2, called mDec2P38R, in fruit flies and recorded daily fruit fly activity. Remarkably, He found that mDec2P385R-expressing flies exhibited significantly less sleep-like behavior as measured by the duration of rest periods in light and dark conditions.
Not only did He’s study identify a sleep-specific behavioral function for the DEC2 gene, He's study also showed the remarkable conservation of DEC2 activity between vastly different species. While many genes are in fact shared between humans, mice, and flies, the amount of function that is retained for many genes is unclear. He and colleagues have now shown that DEC2 retains the ability to control sleep behavior in both the fly on your banana as well as in your neighbor next door.
Although this finding is fascinating, it is not yet a cause for jealousy over our peppy mutant friends. Many genes in our DNA carry out more than one function. Therefore, unknown consequences of the DEC2 mutation may yet remain hidden. Until we fully understand the spectrum of DEC2 actions, I wouldn’t be rushing to take a pill of DEC2-P385R.
The Bottom Line: The next time you’re late for work because you slept in, you can blame it on your DNA!
Reference: He et al. “The transcriptional Repressor DEC2 Regulates Sleep Length in Mammals. Science 14 August 2009: Vol. 325. no. 5942, pp. 866 – 870. DOI: 10.1126/science.1174443
For some, those ten minutes come after a comfortable seven to eight hours of sleep. For others, only six hours separates the night and the morning. While shorter sleep cycles lead to chronic sleep deprivation in a large percentage of the population, there are certainly individuals who find six hours of sleep sufficient. Why is it that a lucky few require only a fraction of the recommended seven to eight hours of sleep per night?
It looks as though the answer may reside once again in our DNA. In last week’s issue of Science Magazine, Ying He from the University of California at San Francisco reported that a small mutation in the DEC2 gene significantly decreases the length of a night’s sleep. He’s team identified the DEC2 mutation in two related individuals who indicated very early wake up times in a survey, reportedly sleeping nearly two hours less than other family members.
To study the significance of the DEC2 mutation on sleep cycles, He and colleagues generated transgenic mice that expressed the mutated human form of DEC2, called DEC2-P385R. He’s team found that mice expressing DEC2-P385R indeed had longer activity periods paired with shorter sleep phases. While many groups would be happily satisfied with this finding, He’s group took the experiment one step further. They next expressed the mutated mouse form of DEC2, called mDec2P38R, in fruit flies and recorded daily fruit fly activity. Remarkably, He found that mDec2P385R-expressing flies exhibited significantly less sleep-like behavior as measured by the duration of rest periods in light and dark conditions.
Not only did He’s study identify a sleep-specific behavioral function for the DEC2 gene, He's study also showed the remarkable conservation of DEC2 activity between vastly different species. While many genes are in fact shared between humans, mice, and flies, the amount of function that is retained for many genes is unclear. He and colleagues have now shown that DEC2 retains the ability to control sleep behavior in both the fly on your banana as well as in your neighbor next door.
Although this finding is fascinating, it is not yet a cause for jealousy over our peppy mutant friends. Many genes in our DNA carry out more than one function. Therefore, unknown consequences of the DEC2 mutation may yet remain hidden. Until we fully understand the spectrum of DEC2 actions, I wouldn’t be rushing to take a pill of DEC2-P385R.
The Bottom Line: The next time you’re late for work because you slept in, you can blame it on your DNA!
Reference: He et al. “The transcriptional Repressor DEC2 Regulates Sleep Length in Mammals. Science 14 August 2009: Vol. 325. no. 5942, pp. 866 – 870. DOI: 10.1126/science.1174443
Sunday, August 16, 2009
Obesity-Blocking Neurons Found in Fruit Fly Brains
Obesity is a growing problem around the world, no pun intended. Lean models grace the covers of health and fitness magazines, but they certainly do not represent the average reader. Heaviness once was a symbol of wealth and prosperity. Today, extra weight is associated with laziness, a lack of concern for one’s self, and in some cases poverty. We now seem to be in an eternal struggle to permanently eliminate excess fat.
Weight gain is commonly a symptom of overeating combined with a lack of exercise. In some unfortunate cases, failure in an area of the brain known as the hypothalamus can lead to excess body fat. The hypothalamus responds to hormone signals from the body to regulate both hunger and metabolism. If the hypothalamus is compromised, abnormal eating behaviors as well as inadequate metabolic processing can occur. Due to the current obesity “epidemic,” there is an increased interest in understanding neural control over the factors that affect weight gain.
The ability to test predictions about brain activity and obesity in humans is limited due to the ethical problems generated by inhibiting human neural function. Clearly, another model is needed to study the association of brain performance and fat processing.
Both humans and fruit flies share many aspects of fat storage and metabolism. Each organism absorbs fat in the intestine, contains dedicated tissue for fat storage, and synthesizes new fat in specialized cells. In fact, many of the molecular factors required for each of these biological events is conserved between humans and flies.
Last week, a group of scientists lead by Dr. Bader Al-Anzi of the California Institute of Technology reported one more similarity: as in humans, there are neurons in the fruit fly brain that control eating behavior and fat metabolism.
Al-Anzi’s team adapted a chemical test, called rapid thin layer chromatography, to measure the total fat levels in the adult fruit fly body. The group screened the fat levels in hundreds of flies, each fly containing a brain with different combinations of neurons inhibited. His team successfully identified two populations of neurons, called c673a and fruitless, that when inhibited generated fat flies. Interestingly, when these same neurons were hyper-activated, the flies were significantly leaner!
Upon closer examination, Al-Anzi and colleagues determined that the inhibition of c673a neurons provoked increased food intake and decreased fat metabolism, while the silencing of fruitless neurons only affected metabolic processes. In each case, the group was able to reverse the obesity by removing the neural inhibition.
The authors suggest that a signal with information about energy stores in the body, perhaps from the fat cells, is detected by the c673a and fruitless neurons in the brain. These particular target neurons then process the received information to control feeding behaviors and fat metabolism.
With the identity of fat-regulating neurons established in fruit flies, future research can now utilize this model system to determine how neural networks link together to process signals from the body and to identify the genetic components involved in the development and function of such a tightly regulated system. Because many of the molecules that control fat processing in the body are conserved between flies and humans, insights gained from experiments on the fruit fly brain may one day reveal interesting and useful information about our own noggins.
The bottom line: That old childish taunt “fat-head” might not be so far from the truth.
Reference: Al-Anzi et al. “Obesity-Blocking neurons in Drosophila” Neuron 63, 329–341, August 13, 2009 DOI 10.1016/j.neuron.2009.07.021
Weight gain is commonly a symptom of overeating combined with a lack of exercise. In some unfortunate cases, failure in an area of the brain known as the hypothalamus can lead to excess body fat. The hypothalamus responds to hormone signals from the body to regulate both hunger and metabolism. If the hypothalamus is compromised, abnormal eating behaviors as well as inadequate metabolic processing can occur. Due to the current obesity “epidemic,” there is an increased interest in understanding neural control over the factors that affect weight gain.
The ability to test predictions about brain activity and obesity in humans is limited due to the ethical problems generated by inhibiting human neural function. Clearly, another model is needed to study the association of brain performance and fat processing.
Both humans and fruit flies share many aspects of fat storage and metabolism. Each organism absorbs fat in the intestine, contains dedicated tissue for fat storage, and synthesizes new fat in specialized cells. In fact, many of the molecular factors required for each of these biological events is conserved between humans and flies.
Last week, a group of scientists lead by Dr. Bader Al-Anzi of the California Institute of Technology reported one more similarity: as in humans, there are neurons in the fruit fly brain that control eating behavior and fat metabolism.
Al-Anzi’s team adapted a chemical test, called rapid thin layer chromatography, to measure the total fat levels in the adult fruit fly body. The group screened the fat levels in hundreds of flies, each fly containing a brain with different combinations of neurons inhibited. His team successfully identified two populations of neurons, called c673a and fruitless, that when inhibited generated fat flies. Interestingly, when these same neurons were hyper-activated, the flies were significantly leaner!
Upon closer examination, Al-Anzi and colleagues determined that the inhibition of c673a neurons provoked increased food intake and decreased fat metabolism, while the silencing of fruitless neurons only affected metabolic processes. In each case, the group was able to reverse the obesity by removing the neural inhibition.
The authors suggest that a signal with information about energy stores in the body, perhaps from the fat cells, is detected by the c673a and fruitless neurons in the brain. These particular target neurons then process the received information to control feeding behaviors and fat metabolism.
With the identity of fat-regulating neurons established in fruit flies, future research can now utilize this model system to determine how neural networks link together to process signals from the body and to identify the genetic components involved in the development and function of such a tightly regulated system. Because many of the molecules that control fat processing in the body are conserved between flies and humans, insights gained from experiments on the fruit fly brain may one day reveal interesting and useful information about our own noggins.
The bottom line: That old childish taunt “fat-head” might not be so far from the truth.
Reference: Al-Anzi et al. “Obesity-Blocking neurons in Drosophila” Neuron 63, 329–341, August 13, 2009 DOI 10.1016/j.neuron.2009.07.021
Wednesday, August 12, 2009
Can all cells be stem cells?
We all want to live longer, escape disease, and experience life to its fullest. Our newspapers claim that stem cells will solve our medical problems. Michael J Fox pleads for support. Yet, debate surrounds stem cell research. We fear what we do not understand.
The controversial cells in question are known as embryonic stem cells (ES cells). Human ES cells are found in the very early four to five-day-old embryo. Their promise resides in the fact that they can become any cell type in the body. ES cells can transform into beta cells for a diabetic, neurons for a Parkinson’s patient, or heart muscle for an individual with cardiac trauma.
The majority of ES cells are harvested from unused embryos after fertility treatments. After isolation, ES cells can be maintained indefinitely in culture with good hands and rigorous care. Unfortunately, cellular contamination and naturally occurring mutations can affect the normal behavior of stem cells.
In a hotly disputed move, the Bush administration limited stem cell research to existing ES cell cultures. Researchers around the world began to pump laboratory manpower into finding ES cell alternatives.
In 2006, K. Takahashi and S. Yamanaka found that a mere four genes introduced into a differentiated mouse cell could coax adult cells back into a stem cell-state. Subsequently, other groups followed suit and had similar results with adult mouse liver, stomach, blood, and skin-specific cells.
A mature cell that is “re-programmed” into a stem cell is known as an induced pluripotent stem cell (iPS cell). Like embryonic stem cells, the iPS cells harbor the ability to differentiate into any cell type in the body. To prove that iPS cells are comparable to embryonic stem cells, they must pass a battery of tests. Only one test continuously stumped researchers – the tetraploid complementation test.
In tetraploid complementation, a flawed embryo serves as an empty vessel. Stem cell contribution to the faulty embryo enables the growth of an animal. Imagine a flowerpot. A flower will not grow from a pot of soil without planting a seed. In this test, the stem cells are like seeds. For iPS cells to be equivalent to ES cells, they must have the ability to grow into an entire animal when planted.
In what seems to be a tie finish, three independent groups successfully performed tetraploid complementation with iPS cells. Their work was released online in two prominent journals, Nature and Cell Stem Cell, last week.
The three teams, lead by Michael Boland of The Scripps Research Institute, Lan Kang of the Chinese Academy of Medical Sciences, and Xiao-yang Zhao of the Chinese Academy of Sciences Institute of Zoology, used mouse embryonic fibroblasts to generate iPS cells.
Fibroblasts produce the connective tissue between all cells in the body and have the ability to generate other cell types such as bone and smooth muscle. Because fibroblasts are primed for a transition to multiple cell types and grow beautifully in culture, they are an optimal choice for iPS cell studies.
To induce stem cells, the three groups each used a virus to deliver four genes, including Oct4, Sox2, Klf4, and c-Myc, into the embryonic fibroblasts. After a series of steps to verify the fibroblasts exhibited typical stem cell-like properties, the iPS cells were subjected to tetraploid complementation.
For the first time, each group successfully obtained at least one surviving adult mouse from their experiments. Importantly, the surviving mice were shown to be fertile, a critical requirement for the iPS cells to be considered equal to embryonic stem cells in this experiment.
While this is a major breakthrough in revealing induced pluripotent stem cell biology, it remains to be determined if cells isolated from adult tissue can have the same potency as the embryonic fibroblasts and if this same finding would hold true for humans. Indeed, for iPS cells to become a viable treatment for disease, we will need to understand the biology of re-programmed cells that are isolated from the human adult.
Finally, I want to ask my readers a question. If we can take a single cell that has already differentiated into its tissue specific form, activate a small set of genes, and use the induced stem cell to generate an entire animal, does this warrant a new area of bioethics in stem cell biology? If one considers human life to start with the potential to grow into an adult, then do all cells harbor this potential? Think about it. I’m happy to answer any questions and look forward to your comments on this controversial issue.
The bottom line: Stem cells generated from mouse embryonic fibroblasts are equivalent to embryonic stem cells in their ability to grow into a functioning adult mouse.
References:
Zhao, X.-Y. et al. Nature advance online publication doi:10.1038/nature08267 (2009).
Kang, L. et al. Cell Stem Cell doi:10.1016/j.stem.2009.07.001 (2009).
Boland et al. Nature advance online publication doi: 10.1038/nature08310 (2009).
A helpful site on stem cells for additional reading:
http://stemcells.nih.gov/info/basics/basics10.asp
The controversial cells in question are known as embryonic stem cells (ES cells). Human ES cells are found in the very early four to five-day-old embryo. Their promise resides in the fact that they can become any cell type in the body. ES cells can transform into beta cells for a diabetic, neurons for a Parkinson’s patient, or heart muscle for an individual with cardiac trauma.
The majority of ES cells are harvested from unused embryos after fertility treatments. After isolation, ES cells can be maintained indefinitely in culture with good hands and rigorous care. Unfortunately, cellular contamination and naturally occurring mutations can affect the normal behavior of stem cells.
In a hotly disputed move, the Bush administration limited stem cell research to existing ES cell cultures. Researchers around the world began to pump laboratory manpower into finding ES cell alternatives.
In 2006, K. Takahashi and S. Yamanaka found that a mere four genes introduced into a differentiated mouse cell could coax adult cells back into a stem cell-state. Subsequently, other groups followed suit and had similar results with adult mouse liver, stomach, blood, and skin-specific cells.
A mature cell that is “re-programmed” into a stem cell is known as an induced pluripotent stem cell (iPS cell). Like embryonic stem cells, the iPS cells harbor the ability to differentiate into any cell type in the body. To prove that iPS cells are comparable to embryonic stem cells, they must pass a battery of tests. Only one test continuously stumped researchers – the tetraploid complementation test.
In tetraploid complementation, a flawed embryo serves as an empty vessel. Stem cell contribution to the faulty embryo enables the growth of an animal. Imagine a flowerpot. A flower will not grow from a pot of soil without planting a seed. In this test, the stem cells are like seeds. For iPS cells to be equivalent to ES cells, they must have the ability to grow into an entire animal when planted.
In what seems to be a tie finish, three independent groups successfully performed tetraploid complementation with iPS cells. Their work was released online in two prominent journals, Nature and Cell Stem Cell, last week.
The three teams, lead by Michael Boland of The Scripps Research Institute, Lan Kang of the Chinese Academy of Medical Sciences, and Xiao-yang Zhao of the Chinese Academy of Sciences Institute of Zoology, used mouse embryonic fibroblasts to generate iPS cells.
Fibroblasts produce the connective tissue between all cells in the body and have the ability to generate other cell types such as bone and smooth muscle. Because fibroblasts are primed for a transition to multiple cell types and grow beautifully in culture, they are an optimal choice for iPS cell studies.
To induce stem cells, the three groups each used a virus to deliver four genes, including Oct4, Sox2, Klf4, and c-Myc, into the embryonic fibroblasts. After a series of steps to verify the fibroblasts exhibited typical stem cell-like properties, the iPS cells were subjected to tetraploid complementation.
For the first time, each group successfully obtained at least one surviving adult mouse from their experiments. Importantly, the surviving mice were shown to be fertile, a critical requirement for the iPS cells to be considered equal to embryonic stem cells in this experiment.
While this is a major breakthrough in revealing induced pluripotent stem cell biology, it remains to be determined if cells isolated from adult tissue can have the same potency as the embryonic fibroblasts and if this same finding would hold true for humans. Indeed, for iPS cells to become a viable treatment for disease, we will need to understand the biology of re-programmed cells that are isolated from the human adult.
Finally, I want to ask my readers a question. If we can take a single cell that has already differentiated into its tissue specific form, activate a small set of genes, and use the induced stem cell to generate an entire animal, does this warrant a new area of bioethics in stem cell biology? If one considers human life to start with the potential to grow into an adult, then do all cells harbor this potential? Think about it. I’m happy to answer any questions and look forward to your comments on this controversial issue.
The bottom line: Stem cells generated from mouse embryonic fibroblasts are equivalent to embryonic stem cells in their ability to grow into a functioning adult mouse.
References:
Zhao, X.-Y. et al. Nature advance online publication doi:10.1038/nature08267 (2009).
Kang, L. et al. Cell Stem Cell doi:10.1016/j.stem.2009.07.001 (2009).
Boland et al. Nature advance online publication doi: 10.1038/nature08310 (2009).
A helpful site on stem cells for additional reading:
http://stemcells.nih.gov/info/basics/basics10.asp
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