I probably take this blog too seriously. No, I definitely do. I am trying to make it like some serious review of the literature, and as a result, my true opinion is getting lost in the midst, and this is a shame. It should be what it is, and that is gloriously a blog.
I did some investigative reporting today. On what you may ask? Well basically what it would mean for me to be a PhD student in biostatistics. What it would mean in terms of what I could do, what the future challenges are for the field, and things like that.
What I found is that the PhD program would be course intensive at first, and from there it would move on to developing novel statistical methods. The novel part is important as it also counts for the “original research” requirement so often bandied about with that PhD (Doctor of Philosophy) thing. Yes.
But on the whole, the field of bioinformatics, biostatistics, what have you, appears to be one to me that is waiting for technology to happen. That is to say, the field is less likely to be advanced by nifty statistical methodologies that somehow can predict how the human genetic code is translated to create life, and is more likely to be advanced by cheaper more effective microchips and micropossessors which can capture all that cool RNA gene expression data which is working all the time in your body and making you, you.
Of course, this now brings on a daunting information technology job. One that demands high speed high capacity servers and brings a company like Google to mind in a hurry. But also, I must say, that it also appears to me to be an appealing entrepreneurial challenge, and one which could arguably have a greater impact on the field of genetic medicine than fancy statistical/computational techniques.
Of course, in fairness, I should also say that said techniques are yet vital, and that both should at least, develop at the same time.
Tags: bioinformatics, biostatistics, etc, Grad school, PhD
According to a recent article in U.S. News and World Report there are 3 paths in creating pills of youth. Here is a quick summary of each of them.
1. Find drugs which mimic the benefits of caloric restriction. This would be things like resveratrol, and work by Sitrus pharmaceuticals.
2. Looking for clues in the very old. Scientists can study a sample of the 1 out of 7 million people who reach the “supercentenarian” age of 110 with few bad health effects. Looking at their genes or other molecular markers can give us clues to new medicines.
While the exact causes of mammalian aging are not known, the decline in replicative capacity of cells appears to be a factor. Activation of a particular gene, p16INK4a, causes the cell to arrest in a state of senescence at once suppressing cancer while attenuating its ability to replicate. Thus p16 may function via aging as a cancer suppressor.
Previous research has already shown that levels of p16INK4a increase exponentially with age, and recent research shows that inactivation of p16INK4a alleviates progeriod (early aging) symptoms in mice, suggesting that p16INK4a expression has an effect in the aging process.
The data used in this model of p16INK4a is taken from blood samples of 170 individuals. The level of p16INK4a was measured in blood cells of a limited lifespan, as such the model had to account for declines in p16INK4a due to apoptosis or immune clearance. Two models were created for the level of expression, the first which viewed the level of p16INK4a in a synthesis/degredation dynamic and the second which only accounted for p16INK4a loss after saturation. Both models are designed to account for the exponential increase in p16INK4a, even at an early age, leading into what is seen as an asymptotic “saturation” of p16INK4a expression. Despite some attrition, not all p16 senescent cells are cleared and many remain in the body for years.
The model also contained clinical factors which all had an effect on p16INK4a expression. Namely: smoking, exercise, and the rs10757278 genotype (Single nucleotide polymorphism). As found previously p16INK4a expression is considerably higher in those who smoke and levels of p16INK4a are considerably lower if those who exercise, but the exercise works only till age 65. The reason for this is not clear. Whether exercise loses its effect or the amount of exercise people attempt after age 65 drops considerably. The rs10757278 SNP reduces the level of p16INK4a but the exact mechanism is not known. The authors speculate that it is by activating other cell cycle control mechanisms p15INK4b and ARF which increases the death rate of cells inactivated by p16INK4a.
The use of the model allows for a way to predict molecular aging on the basis of genetics and lifestyle factors. The authors conclude stating they will work to create a better model as the amount of their data increases.
Denis Tsygankova, Yan Liub, Hanna K. Sanoffb, Norman E. Sharplessb, & Timothy C. Elston (2009). A quantitative model for age-dependent expression of the p16INK4a tumor suppressor PNAS, 106 (39)
Specific organ functions rely on differentiated cells. How differentiated
cells are replaced is a fundamental question in biology
with important implications for regenerative medicine.
So begins a recent paper in Cell which has shown heart cells in rodents can be stimulated to proliferate, thus repairing any damage. Typically the heart stops proliferating or regenerating shortly after birth, so any event that causes death the heart cells, like a heart attack (myocardial infarction), is currently quite irreversible. Past research on heart cell regeneration focused on trying to manipulate stem cells to differentiate into new heart muscle cells(cardiomyocytes). The breakthrough in this paper was to focus on healthy differentiated heart cells and see if any proteins could stimulate them to start dividing and repair the damage.
The scientists (Kevin Bersell, Shima Arab, Bernhard Haring, and Bernhard Kühn) tested the signaling protein, neuregulin1 (NRG1)) which is known to stimulate heart cell growth in prenatal development and even in fetal tissue. The results showed that neuregulin1 stimulated proliferation in 30% of the heart tissue as compared with 1% proliferation in control groups.
The finding represents a major breakthrough in regenerative medicine. The protein, neuregulin1, is administered via injection, creating a noninvasive method of heart tissue repair. Kühn, one of the major investigators of the paper, is already looking for profitable potential therapies.
Bersell, K., Arab, S., Haring, B. & Kuhn, B. (2009). Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury Cell
Tags: regeneration, signalling protein, stem cells, therapies
I just got done reading a Nature interview of Elaine Fuchs, who does stem cell research at Rockerfeller University in NYC. Specifically she focuses on how skin stem cells act to maintain and repair the skin.
As I read the article, I found myself asking a lot of questions, that seem obvious but that I rarely think about. Questions like: How exactly does my body repair a cut on my skin? How does it know to do it? What does it have in reserve? Why doesn’t it use the same mechanism to keep my skin from looking wrinkled and scathed? How do scars form?
A sample passage:
In the skin, there are stem cells that exist within the bulge of the hair follicle and also in the basal layer of the epidermis. We still don’t know whether all of the cells within the basal layer can behave as stem cells or whether only a few stem cells exist that are scattered within this layer. It’s an open question of where along the lineage to differentiation is the point of no return where a stem cell becomes irreversibly committed to terminally differentiate. In the skin the point of no return has definitely passed in the dead hair cells or in the enucleated squames [squamous cells] that are sloughed off the skin. But can an epidermal cell that has exited the basal layer and begun its journey to the body surface go backwards under certain circumstances and become a stem cell again?
To answer this question, we need to have a firmer grasp of the key features of a stem cell that determine stemness.
What I suddenly realized reading the article is that all these questions of regeneration are very unknown, and the medical potential of finding out is huge, and beyond that, it would be hugely satisfying as a human to really understand how the mechanics of my body works. I would love to make a working molecular model of a human one day. (In computer simulation of course) 
As for the potential of stem cells? Well some wikipedians have put together a good image for that:
Tags: regeneration, stem cells
Before August Weismann, the explanation of how a human body developed and then later aggregated sexual material for reproduction was dominated by Charles Darwin’s theory of of Pangenesis. The theory basically stated that every cell in the body emitted hundreds of tiny germ like materials, called “gemmules”. These gemmules then aggregated in the reproductive organs, ready for reproduction.
In the early 1880s the imminent German biologist August Weismann took it upon himself to re-evaluate the problem of heredity and found that the recent research of the era came to serious odds with Darwin’s suppositions. The main change that Weismann proposed was that the body(or soma) is not responsible for governing the material of heredity(the germ line), but rather, that the germ line governed the soma, and then like any good aristocrat, isolated itself from the trials of the plebs as much as possible.
The net result of such a thought leads one to conclude that while the soma is vulnerable to damage over time, the germ line somehow remains untainted as it is passed down from generation to generation.
Another interesting result of Weismann’s finding is how often great thinkers have to come along and pull together current research to create a paradigm shift in the central dogma of the time…and perhaps more to the point, how important it is to have a central dogma to be overthrown.
Could Weismann have really reached his conclusions about the germ line had it not been for Darwin’s earlier (flawed) work? We can understand the appeal of Darwin’s somatic-driven logic: sexual reproduction is not reached until later in life, the somatic cells seem to come first, where else could germ line material come from? Thanks to the scientific method, observational data eventually proved Darwin’s logic wrong…however, it was perhaps Darwin’s incorrect theory which most prompted the search for observational data in the first place.
We see a similar situation in the history of cell theory where Theodore Schwann adamantly advocated that cells originated from a kind of Spontaneous generation of sugars in the body. Again, the theory has appeal, spontaneous generation is still our current explanation for the origin of life on earth. However, as microscopes improved and the process of cell division that we now call mitosis became elucidated Schwann’s work got set aside as an artifact of thought, and a new central dogma took its place.
This leaves us with two appealing questions:
- What current theories do we have today that will eventually succumb to observational evidence?
- What theories can we propose to challenge scientists to find observational evidence disproving our thoughts?
The theory I would like to suggest is that the stem cells of our body have the ability to fully regenerate every organ and system within the body. As the MIT tech review reported today such work at Fate Therapeutics is already underway. I can’t wait to see what they come up with.
The human body is a factory producing trillions of new blood cells daily, and replacing the lining of the small intestine on a weekly basis. The raw materials in production are stem cells, which have the ability both to create cells used by our body, and to create copies of themselves.
To ensure quality of production, the body creates various quality control measures expressed in the form of proteins and caps on DNA which will either cause the cell to be killed and catabolized (apoptosis) or cause the cell to enter a state of permanent irreversible growth arrest (senescence). Accumulation of these “frozen” cells leads to the eventual aging of our bodies. On the other hand, if quality control measures fail, cells can become pathological, often proliferating without control in a phenomenon known as cancer.
The result can lead one to theorize a trade-off between aging and cancer as is proposed by Norman Sharpless and Ronald DePinho in the Stem Cell Theory of Aging. It is a tantalizing theory as expression of cancer suppressing mechanisms p53, p16Ink4a, and shortened telomeres, also appear in older cells and tissues. The correlation provides good motivation to increase understanding of how these cell cycle check points work. In the meantime, Sharpless and DePinho will use expression of these proteins in epidemiological research so that better associations between lifestyle, aging, and cancer can be made.
In my mind, their paper raises a number of intruiging questions:
- Why don’t cell cycle check points lead to apoptosis as opposed to senescence?
- Why does the amount of stem cells in our body decline over time?
- Are there potential drug targets in the cell cycle that can prevent both aging and cancer?
I will look forward to research with the answers.
Sharpless, N. (2004). Telomeres, stem cells, senescence, and cancer Journal of Clinical Investigation, 113 (2), 160-168 DOI: 10.1172/JCI200420761
Tags: Aging, apoptosis, cancer, senescence
What makes a disease a disease? Why isn’t aging, a condition which results in the slow decline of the body, considered a disease? It seems so obvious.
Part of the problem is where to define the line between “good aging” (i.e. development) and “bad aging” (i.e. degeneration)? Looking at the Gompertz curve, one might say the body enters decline after reproductive potential has been reached, but this is still not a hard and fast line.
Another reason why people don’t recognize aging as a disease is because 100% of the population suffers from it. We just need one person with perpetual youth to ignite a massive outcry for an aging cure.
Finally, we need a new word for the disease. “Aging” is too confusing. People associate it with children growing, or with becoming wise and experienced. One could then use “senescence” but that is a biological term. So what then can we use? Senectitudeitis?
Enter Senectitudeitis, a disease characterized by:
- Somatic degeneration
- Wrinkling of the skin
- Macular degeneration
- Muscular degeneration
- Sexual decline
- Increased risk of Cancer
- and the dreaded Gothenburg Syndrome where people come to identify with the disease as being a normal part of life
We can even have a ribbon:
I just finished an entry for the SOA timeline on the 1970s discovery that nematodes collect inactive enzymes and molecules as they grow older. The main idea being that the body is unable to clear out the junk inside cells and that the energy cost of carrying this junk leads to senescence, or aging.
The theory reminded me of a similar finding by Coleen Murphy who found that long lived daf-16 elegans mutants lived longer in part because they encoded antimicrobial lysosomes, that helped to clear out microbes that would get “packed” inside the nematodes precipiating senescence and eventually their death.
As far as I know, the reason for the slow decline in enzyme activity and for the collection of intracellular junk is still unknown. Why isn’t our body clearing this stuff out and selling it on ebay? The SENS foundation, which is perhaps the biggest player in anti-aging research, is pushing forward with a solution anyway. Their strategy is to find enzymes manufactured by soil bacteria and fungi that can then be applied therapeutically to help clear junk out of cells. Such similar medications have already been discovered for people with Gaucher’s disease.
It is going to be interesting in the future to see what result comes of this. Both for understanding the chemical mechanism of the collection of junk, and the therapeutic solutions which can get rid of it.
Harriet Gershon, & David Gershon (1970). Detection of Inactive Enzyme Molecules in Ageing Organisms. Nature 227, 1214-1217
Murphy, C., McCarroll, S., Bargmann, C., Fraser, A., Kamath, R., Ahringer, J., Li, H., & Kenyon, C. (2003). Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans Nature, 424 (6946), 277-283 DOI: 10.1038/nature01789
In recent paper published in Aging Cell, Dr. Sharpless out of the UNC Medical School reported that expression of protein p16INK4a appeared to increase exponentially with chronological age. Expression was measured in human blood and was found highest in peripheral blood T-lymphocytes (PBTL).
The discovery is exciting as it creates a relatively easy way to measure molecular age as opposed to chronological age. Data was taken from 170 blood donors and analysis showed that a higher expression of p16INK4a correlated to patients who smoked and had a low level of physical exercise, but did not correlate to gender or BMI.
The lack of correlation of p16INK4a with BMI might tempt one to conclude the effects of calorie restriction in humans to be minimal, but it is important to remember that calorie restriction is theorized to act as a famine response mechanism, and also that caloric intake does not necessary correlate with BMI. What would be truly interesting is to measure expression of p16INK4a in individuals who have been on a calorie restricted diet.
Liu, Y., Sanoff, H., Cho, H., Burd, C., Torrice, C., Ibrahim, J., Thomas, N., & Sharpless, N. (2009). Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging
Aging Cell DOI: 10.1111/j.1474-9726.2009.00489.x
