Thursday, October 4, 2007
Monday, August 13, 2007
Thursday, August 9, 2007
If you’re ever out west, Rocky Mountain National Park (RMNP) is one of those places you really have to consider visiting. Last weekend, about 60 or 70 volunteers with Wildlands Restoration Volunteers (WRV) planted sedges and willow in RMNP.
The goal was to restore a former wetland that was demolished by a flood in 1982, when a man-made dam collapsed, sending flood waters down the
In 1996, the Park Service breached the debris dam that had formed as a result of the flood (and which trapped the water forming
To help restore the wetland, the Park Service rerouted the
Here’s a few pictures of the area taken by Desiree Holtz
You can see more pictures by Desiree of the area and the volunteers here.
Wednesday, August 8, 2007
Political interference with science (or just ignoring scientific findings altogether) has gotten a lot of attention under the Bush administration. An editorial in this week’s issue of Nature brings up an example of science ignored.
Apparently, in 2006, the Office of Management and Budget (OMB) drafted a new bulletin on risk assessment (including a new definition of risk assessment and new standards for its application). The National Academy of Sciences reviewed the draft at the request of the OMB and several other federal agencies. A two word excerpt from the NAS report sums it up: “fundamentally flawed.”
A press release issued in January of 2007 quotes the chair of the NAS committee that produced the review as saying:
“We began our review of the draft bulletin thinking we would only be recommending changes, but the more we dug into it, the more we realized that from a scientific and technical standpoint, it should be withdrawn altogether."
If this all happened months ago, then why is it the subject of an editorial in Nature? Because the draft bulletin is still alive and kicking. According to the editorial, the draft is under revision. I suppose that’s a good thing, but what kind of revision can fix something that’s fundamentally flawed?
The widget is available here.
Thursday, July 5, 2007
Meet the whippets (click for larger version):
Whippets are a breed of dog developed specifically for racing. They were officially recognized as a breed in the late 1800s and can reportedly run up to 35 mph.
Take another look at the photos of whippets above. See anything interesting? If you look close, you might notice that the dogs get bigger from left to right. The heavily muscled dogs in the right column are referred to as ‘bully’ whippets by breeders. Apparently, whippet breeders brought this trait to the attention of the National Human Genome Research Institute at NIH. Knowing about the role of myostatin mutations in producing other examples of double muscling, the researchers went looking for mutations in the myostatin gene of whippets.
The results are pretty nicely summed up by the pictures. Wild type whippets (lacking any mutation in the myostatin gene) are on the far left, heterozygotes (dogs that possess one copy of a normal myostatin gene and one copy with a mutation that produces a malfunctioning protein) in the middle, and individuals (bullies) with two copies of the mutation on the right.
If that was the end of the story, it would be interesting to scientists (and useful to dog breeders), but not much else. What makes this more newsworthy is that the researchers were able to connect the genetics with athletic performance.
I don’t know anything about dog racing, but racing whippets are apparently divided into four classes: A, B, C, D. Think of it like the system used in professional baseball in the US (or like soccer leagues in the rest of the world). The fastest dogs are A, the slowest in D. It turns out that dogs with the mutation make up a disproportionate number of dogs in the faster classes. We now have a quantitative connection between genes and performance. (I should point out that the faster dogs almost always possess only one copy of the mutation, not two. I don’t think dogs with two copies of the mutation generally are raced. Muscle bound perhaps?)
This brings me back to the boy in
Given that high level athletes have shown themselves willing to do lots of things to gain an advantage over the competition, and knowing that drugs are in the pipeline that would inhibit myostatin, how long will it be before athletes are trying to build muscle by blocking their myostatin? Or how long before the national Olympic training programs or college scouts start screening for these mutations to guarantee that funds for training are spent on athletes with the best genes?
As the authors of the whippet research note:
“Our findings have implications for competitive and professional sports. Here, we show that a disruption in the function of the MSTN [myostatin] gene increases an individual’s overall athletic performance in a robust and measurable way. …
The potential to increase an athlete’s performance by disrupting MSTN either by natural or perhaps artificial means could change the face of competitive human and canine athletics. Given the poorly understood consequences for overall health and well-being, caution should be exercised when acting upon these results.”
1. Mosher, D.S. et al. (2007). "A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs." PLoS Genetics 3(5): e79 (doi:10.1371/journal.pgen.0030079)
1. Mosher, D.S. et al. (2007). "A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs." PLoS Genetics 3(5): e79 (doi:10.1371/journal.pgen.0030079)
Wednesday, July 4, 2007
From the beginning, it was apparent to researchers that myostatin might provide treatment options for musculodegenerative diseases like muscular dystrophy. In 2002, researchers showed that by blocking activity of the protein produced by the myostatin gene with an antibody, mice from a strain used as a mouse model of Duchenne muscular dystrophy (known as mdx mice) had greater body weight, muscle mass, and muscle strength than mdx mice that did not receive the antibody. The same research group repeated the research in a study published in 2005 using a different method to block myostatin and got similar results.
[Note on figure: EDL = extensor digitorum longus. In humans, this muscle is located in your shin and is one of several muscles that acts in dorsiflexion of foot. (To do this, stand with your feet flat on ground and raise the ball of your foot off the floor.)]
Unfortunately, research on other strains of mice wasn’t so positive. Using a strain of mice (referred to as dyW/dyW) that acts as a model of a different kind of muscular dystrophy, researchers in southern
A year later, another research group (this time from
The outcome of this research emphasized the variability in blocking myostatin. Using mice that had received an antibody blocking myostatin beginning at 4 weeks old and other mice that began receiving the antibody at 20 weeks old, the researchers found that the younger mice received greater benefits than did the older mice. Also, reaction to the treatment varied depending on the particular muscle group under consideration. For example, the quadriceps (thigh muscle) was larger in the 20 week old mice that received the antibody blocking myostatin, but the gastrocnemius (calf muscle) was smaller than untreated mice.
Finally, to cloud the water even more, a recent study published in the Proceedings of the National Academy of Sciences indicated that bigger muscles may not mean stronger muscles. This study simply blocked the myostatin gene in otherwise normal mice, then tested the force of contraction of the muscles. It turns out that the force of contraction was not significantly different between mice without myostatin and control mice. And, since the muscles of the mice lacking myostatin were bigger, the force per unit mass of muscle was actually less than the force of contraction in control mice.
This research throws a cloud over the research described above that found mice with blocked myostatin had muscles that contracted with greater force than mice without blocked myostatin. The main difference between the two studies is the mice: normal mice without myostatin in the PNAS study, and mdx mice without myostatin in the other.
The upshot of all of this is that the effect of blocking myostatin seems to depend on age of the intervention, the strain of mice receiving the intervention, and the particular muscle under consideration.
Despite all this, pharmaceutical companies have completed clinical trials in humans (phase I/II). According to clinicaltrials.gov, Wyeth has completed phase I and II on stamulumab (MYO-029). The MDA website notes that the data are currently being analyzed.
We’ll have to wait and see if inhibiting myostatin turns out to be a workable treatment for any types of MD. But there’s one other aspect of myostatin’s usefulness that I haven’t really touched on. It will bring us back to the baby with mutations in his genes for myostatin. Stay tuned, sports fans…
- Bogdanovich, S. et al. (2002). "Functional improvement of dystrophic muscle by myostatin blockade." Nature 420: 418-421. (Nov. 28)
- Bogdanovich, S. et al. (2005). "Myostatin propeptide-mediated amelioration of dystrophic pathophysiology." FASEB J 19: 543-549.
- Li, Z. et al. (2005). "Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethality." American Journal of Pathology 166(2): 491-497.
- Parsons, S.A. et al. (2006). "Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdlemuscular dystrophy."American Journal of Pathology 168(6): 1975-1985.
- Amthor, H. et al. (2007). "Lack of myostatin results in excessive muscle growth but impaired force generation." PNAS 104(6): 1835-1840 (Feb. 6)
Friday, June 29, 2007
The child was also abnormally muscular. His quadriceps had twice the cross-sectional area as that of children of a comparable age and sex. His subcutaneous fat was half as thick.
In 1997, only three years before the child’s birth, researchers at the Johns Hopkins University School of Medicine had discovered a gene that, when expression of the gene was blocked, caused abnormally large muscle growth in mice. Mice lacking a functioning copy of the gene had muscles 2-3 times the mass of mice that did have a functioning copy. The gene, initially called GDF-8, belongs to the TGF-β gene family. (GDF stands for growth and differentiation factor; TGF is short for transforming growth factor.) The members of this family of genes regulate growth and differentiation. Because the normal function of GDF-8 was to limit muscle growth, the researchers named it myostatin (myo for muscle, statin because it seemed to inhibit muscle growth).
In their own words:
“GDF-8 null animals are significantly larger than wild-type animals and show a large and widespread increase in skeletal muscle mass. Individual muscles of mutant animals weigh 2-3 times more than those of wild-type animals, and the increase in mass appears to result from a combination of muscle cell hyperplasia and hypertrophy. These results suggest that GDF-8 functions specifically as a negative regulator of skeletal muscle growth.”
[In the photo, taken from McPherron et al (1997), normal (wild-type) mouse on top, mouse without myostatin on bottom.]
This discovery was perhaps a bit more than just another brick in the wall of molecular biology and gene function. As the scientists noted, manipulation of either the gene, its expression, or its signaling pathway in cells had potential implications for treatment of diseases like muscular dystrophy or the muscle wasting that occurs in patients immobilized for long periods or those suffering from cancer (cancer cachexia). However, they also commented that it might have agricultural implications (think chicken breast and beef cattle).
In fact, within months, of the discovery of myostatin, several research groups had sequenced the gene in cattle and identified the mutations that produced two breeds noted for their extraordinary muscle: Belgian blues and Piedmontese. In these cattle, the phenomenon was known as “double muscling.” In both breeds, mutations in the myostatin gene prevented the animals from produce enough (or any) functioning protein from the myostatin gene. As a result, the negative regulation of muscle growth was lacking and muscle was more massive. The meat of these breeds is reported to be more tender than other meat because it apparently has less connective tissue. On the downside, calves generally have to be delivered by C-section because they are so large at birth.
But the research on myostatin hasn't been all about agriculture. It also has been an active subject of research related to Duchenne muscular dystrophy. I’ll discuss some of that research soon.
- Schuelke, M. et al. (2004). "Myostatin mutation associated with gross muscle hypertrophy in a child." New England Journal of Medicine (June 24) 350: 2682-8. (I think it's available free with registration?)
- McPherron, A.C. et al. (1997). "Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member." Nature (May 1) 387: 83-90. (subcription required)
- McPherron, A.C. and SJ Lee (1997). "Double muscling in cattle due to mutations in the myostatin gene." Proc. Nat'l Acad. Sci. (USA) 94: 12457-61.
Friday, June 22, 2007
A recent study in the New England Journal of Medicine looked at atherosclerotic calcification of women in the 50-59 year-old cohort using computed tomography, comparing women who had received hormones and those that hadn’t. The women studied had been part of the initial WHI study (estrogen only trial - so all the women lacked a uterus). Technicians at a central lab scored all the scans for calcification. In the end, women that had received estrogen during the WHI trial had less calcification than women that received a placebo.
The authors conclude:
The new findings from WHI-CACS [CACS = Coronary Artery Calcium Study; the name of the follow-up analysis] indicate that estrogen therapy initiated in women at 50 to 59 years of age is related to a reduced plaque burden in the coronary arteries and a reduced prevalence of subclinical coronary artery disease, providing support for the hypothesis that estrogen therapy may have cardioprotective effects in younger women.The authors also provide a potential explanation for why estrogen might be cardioprotective in recently post-menopausal women (50-59 years old), but have negative effects on older women (70-79):
It is possible that estrogen could reduce coronary-artery calcium scores but still increase the risk of clinical CHD [coronary heart disease] events, owing to adverse effects on thrombosis and plaque rupture, which are more likely in older women with advanced stages of atherosclerosis. Such a duality of effects would not necessarily apply to younger women with lower burdens of atherosclerosis.
But nobody should get carried away with hormone replacement therapy; it still has significant risks. Any decision to initiate hormone therapy is still a balanace between those risks and the benefits:
In the meantime, hormone therapy should not be initiated (or continued) for the express purpose of preventing cardiovascular disease in either younger or older postmenopausal women. The current recommendations from many organizations that hormone therapy be limited to the treatment of moderate-to-severe menopausal symptoms, with the lowest effective dose used for the shortest duration necessary, remain appropriate.References:
1. Manson, J.E. et al. (2007). "Estrogen Therapy and Coronary Artery Calcification." New England Journal of Medicine 365: 2591-25602. (Available for free after 6 months)
2. WHI steering committee (2004). "Effects of Conjugated Equine Estrogen in Post-menopausal Women with Hysterectomy." Journal of the American Medical Association 291(14): 1701-1712. (Free with registration)
Thursday, June 14, 2007
Some of the most spectacular areas include
Much of the
Within the last month, the BLM approved the drilling of 2000 wells along the Atlantic Rim (located along the southeastern edge of the
One potential problem on the Atlantic Rim is methane seeps. These can occur naturally, but there is some evidence that pumping by test wells in the area has led to the formation of new seeps. These are dangerous because the methane is flammable but odorless and colorless. Be careful where you light your camp stove.
Larger concerns relate to wildlife in the area. Some of the areas of highest use by mule deer, elk, pronghorn, and sage grouse are frequently the same areas targeted for drilling. And, although the oil and gas industry claims that the disturbance to wildlife will cease once the wells quit producing, the scars of development tend to be long lasting in an area that gets less than 10” of precipitation a year. Wagon tracks from stagecoach lines used 150 years ago are still visible in places.
For more information on the
Maybe not the best photographs of all time, but here are some that I took from a recent trip to the Red Desert:
The White Mountain Petroglyphs:
And Honeycomb Buttes:
Tuesday, June 12, 2007
This is one of the exclosures. One mature willow was already present; the newly planted willows are just thin vertical lines.
Here's a view of the northern part of the refuge (looking west). The meandering stream is the Illinois River.
Tuesday, June 5, 2007
The title seems to imply that the article is just about what ion channel is involved in the regulation of glucagon release. It goes beyond this however, suggesting that blood glucose alone is enough to regulate glucagon (as the thing that influences the ion channel’s activity).
“We have now compared insulin and glucagon release and α- and β-cell Ca2+ responses in intact mouse, rat, and human pancreatic islets. We show that glucose retained the ability to suppress glucagon release from isolated islets during blockade of the Zn2+ and GABA paracrine pathways, and in the absence of stimulated insulin secretion or β-cell Ca2+ responses. Thus we now provide evidence in both rodent and human islets supporting the direct (intrinsic) glucose regulation of glucagon release from pancreatic α-cells.”
Recall that the review I discussed previously favored the ‘paracrine/endocrine’ hypothesis – specifically emphasizing the possible role of insulin (the β-cell ‘switch-off’ hypothesis). In fact, that review repeatedly downplayed any direct role for glucose in the regulation of glucagon:
“A direct inhibitory action of glucose on α-cell secretion seems to be of little physiological significance…”
In brief, MacDonald and colleagues systematically set out to (1) test whether glucose levels were sufficient to regulate glucagon secretion and (2) examine the electrophysiology of a-cells under different experimental conditions.
To demonstrate that glucose can directly regulate glucagon (without paracrine intermediaries), MacDonald measured glucagon secretion by mouse and rat islets at two different concentrations of glucose. In addition, they selectively blocked two known paracrines: GABA and Zn2+ ions. (Both of these chemicals inhibit glucagon release.) The results of these experiments are shown in the figure below.
To understand this figure, you need to know that Ca2+-EDTA removes Zn2+ from solution. Actually, the Zn2+ is still there, but it’s bound to the EDTA, so we’d say it is not biologically available. Similarly, SR-95531 blocks the activity of GABA. The pluses and minuses below the x-axis of each graph indicate the presence (+) or absence (-) of the EDTA and the SR-95531.
We can work through the graph in the following way (taking only the mouse data for simplicity). The first two bars basically show data from islets at low (left bar) and high (right bar) glucose. Based on normal physiology, we’d expect glucagon to be high when glucose is low and vice versa. Since neither EDTA nor SR-95531 are present, the reduction in glucagon secretion could be due to either glucose, GABA, or Zn2+. The next pair of bars again shows the response at two different concentrations of glucose, but now we’ve prevented Zn2+ from acting by adding EDTA to the mix. Even without Zn2+, however, we still see a reduction in glucagon production at high glucose concentrations. So, Zn2+, isn’t what’s causing the reduction. In the third pair of bars, the only difference is a change in glucose concentration – both Zn2+ and GABA have been blocked. What can we conclude? Glucose alone is sufficient to reduce glucagon secretion. Notice that the drop in glucagon secretion isn’t as great this time. This might signal that the presence of GABA magnifies the effect of glucose on glucagon secretion.
These data contradict the conclusions of the review paper, but they don’t deal with the β-cell ‘switch-off’ hypothesis. However, a subsequent experiment (panel A and B of Figure 2) shows that glucagon secretion (filled circles) increases well before insulin drops (open circles) to any significant degree (this is particularly apparent in the mouse data). Conclusion: it isn’t a drop in insulin that switches on the secretion of glucagon.
A similar effect can be seen in human islets (presented in Figure 5B in a slightly different format).
The evidence for the central role of KATP channels can be seen in Figure 2 above. Diazoxide is a chemical that opens the channels, and tolbutamide blocks them. Panels 2A and 2B show that glucagon secretion rises as the amount of diazoxide rises (and as more KATP channels open). Beyond a certain point, however, increased activity of the KATP channels actually leads to a reduction in glucagon secretion. (I’ll try to explain the authors’ interpretation of this in a second.)
For brevity and simplicity, I’ll skip the experiments that investigated ion channels for Na+ and Ca2+, and just say that the authors conclude that both channels involved are active at intermediate membrane potentials. As the membrane becomes either hyperpolarized (more negative than usual) or too depolarized (more positive than usual) these channels become inactive and close). The effect of this is inhibition of glucagon secretion.
Having said that, I’ll jump to the conceptual model that MacDonald and crew devise to explain what they think is going on. (As an aside, this is one of the things I really liked about this paper. Although the authors might be wrong in their interpretation of what the results of these experiments mean, the model will provide other researchers with some specific things to test.) The model is summarized graphically in Figure 10.
Panel A basically depicts what they think is going on in normal α-cells: at low glucose, the KATP channels are mostly open (as are the Na+ and Ca2+ channels - shown in the red and blue lines) and glucagon secretion is high (solid line at bottom of panel). As glucose levels rise, the KATP channels begin to close (due to the increase of ATP in the cell from glucose metabolism), and the cell membrane begins to depolarize (i.e., becomes less negative because fewer K+ ions are leaving the cell – keeping more positive charges in the cell makes the inside less negative). At some point the membrane is sufficiently depolarized that the Na+ and Ca2+ channels close, inhibiting glucagon release.
The other three panels basically explain what they think is happening to produce some of the results they saw in their other experiments. For example, if diazoxide opens more KATP channels, then why does glucagon secretion decline at high levels of diazoxide? The idea is that as more and more KATP channels open, the cell membrane becomes hyperpolarized (more negative because more K+ ions are leaving the cell). This hyperpolarized state causes the Na+ and Ca2+ channels to close, reducing glucagon secretion.
I have to say that the one thing that I don’t really understand about all this is the connection between the Na+ and Ca2+ channels and action potentials of the α-cell membrane that ultimately trigger the release of glucagon (by exocytosis). I would assume that other channels that are either not voltage sensitive or sensitive to different voltages (different from the particular Na+ and Ca2+ studied in these experiments) are also active. But experience suggests that I’m probably wrong.
- 1. MacDonald, P.E., et al. (2007). "A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans” PLoS Biology. Published May 15, 2007.
- Gromada, J., Franklin, I., and Wollheim, C.B. (2007) “α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains.” Endocrine Reviews 28(1):84-116. (Author manuscript pdf free here.)
Thursday, May 31, 2007
Sam Brownback, Republican senator from
The short summary of Brownback’s op-ed seems to be: science and faith are complementary as long as scientists come up with answers that my reading of the Bible supports.
First, Brownback on the complementarity of science and faith:
“The truths of science and faith are complementary: they deal with very different questions, but they do not contradict each other because the spiritual order and the material order were created by the same God.”
This sounds a bit like Stephen J. Gould’s non-overlapping magisteria (NOMA). The merits of this are strongly debated. Personally, I waffle. The bigger problem with Brownback’s statement is that science and faith absolutely do contradict each other. If faith is telling you that the planet is 6000 years old, then you have a very real conflict with science. Moreover, this seems to represent an over-reaching of faith into the magisterium of science. If you want to know how the natural world (the ‘material order’ according to Brownback) works, ask a scientist, not a priest.
“People of faith should be rational, using the gift of reason that God has given us. At the same time, reason itself cannot answer every question. Faith seeks to purify reason so that we might be able to see more clearly, not less. Faith supplements the scientific method by providing an understanding of values, meaning and purpose. More than that, faith — not science — can help us understand the breadth of human suffering or the depth of human love.”
At the risk of sounding uncharitable, what is rational about faith? And what does it mean to say that “faith seeks to purify reason”? Look, I’ll allow that values play a role in making all kinds of decisions – we’re not robots after all. But I’m not so sure I like the notion that reason has to be passed through a purifying filter of faith.
So much for the marriage of faith and reason. Now Brownback gets to what science is OK in his mind:
“If belief in evolution means simply assenting to microevolution, small changes over time within a species, I am happy to say, as I have in the past, that I believe it to be true. If, on the other hand, it means assenting to an exclusively materialistic, deterministic vision of the world that holds no place for a guiding intelligence, then I reject it.”
Is this how faith purifies science: if science contradicts my faith, then the science is wrong? (Didn’t
“Biologists will have their debates about man’s origins, but people of faith can also bring a great deal to the table. For this reason, I oppose the exclusion of either faith or reason from the discussion. An attempt by either to seek a monopoly on these questions would be wrong-headed. As science continues to explore the details of man’s origin, faith can do its part as well. The fundamental question for me is how these theories affect our understanding of the human person.”
Just what, exactly, is faith’s part in exploring human origins? This just sounds like the equal time argument to me. Go play in your own magisterium.
“While no stone should be left unturned in seeking to discover the nature of man’s origins, we can say with conviction that we know with certainty at least part of the outcome. Man was not an accident and reflects an image and likeness unique in the created order. Those aspects of evolutionary theory compatible with this truth are a welcome addition to human knowledge. Aspects of these theories that undermine this truth, however, should be firmly rejected as an atheistic theology posing as science.”
The first couple of sentences remind me of something in Daniel Quinn’s book Ishmael. It’s essentially a retelling of the history of life (as told by a jellyfish) except that it ends, “and then jellyfish appeared.” (I’m paraphrasing…I don’t have the book in front of me.) Obviously, if you look back on a path that you’ve traveled, it will look like that path leads to you. But the notion that the path was preordained is ridiculous. There is no basis for saying that humans are not an accident. This underscores why faith is so detrimental to knowledge: Brownback begins with an untried proposition and he rejects any evidence that puts his proposition in doubt. Knowledge stagnates in such an environment. And read the last two sentences by Brownback again. Can you get more anti-intellectual than that? Have people learned nothing from the colossal missteps of George Bush caused by his lack of respect for actual information about the real world? Believing something to be true in the face of evidence to the contrary is not a laudable position to take.
Wednesday, May 30, 2007
In the May 18, 2007 issue of Science, Paul Bloom and Deena Skolnick Weisberg write a short review about why adults sometimes have trouble accepting claims made by scientists. Specifically, they apply findings from developmental psychology to explain the resistance to scientific claims based on two lines of research dealing with “what they [children] know and …how they learn.”
The first line of research has uncovered naïve conceptions that children have about the world. These are things that come pre-wired (if I understand things correctly). Bloom and Weisberg write:
"These intuitions give children a head start when it comes to understanding and learning about objects and people. However, they also sometimes clash with scientific discoveries about the nature of the world, making certain scientific facts difficult to learn.”
This sort of thing comes up a lot regarding the teaching of science – the notion that before you can teach certain topics, you have to understand and deal with the preconceptions that students have about things. If you don’t, students might learn the material as you present it (and they may even give the correct answers on an exam), but if you ask them two weeks later, they will revert to their preconceived idea about the concept. In a video called “A Private Universe,” somebody went around asking Harvard graduates (immediately after commencement, I think) questions about science. One question had to do with where the matter to make plant tissue (wood) came from. Almost all the students said it came from the soil. Actually, it comes from CO2 in the air. (Makes you wonder about all those student loans you took out to pay the Ivy League tuition, huh? D’oh!) The point is that these students had a preconception, sat through some biology classes that taught something different, and came away without learning anything because the preconception wasn’t dealt with. Bloom and Weisberg also note that children have a natural inclination to see things “in terms of design and purpose.” They continue:
Bloom and Weisberg also note that children have a natural inclination to see things “in terms of design and purpose.” They continue:
“For instance, 4-year-olds insist that everything has a purpose, including lions (“to go in the zoo”) and clouds (“for raining”), a propensity called “promiscuous teleology” (15).”
David Gilbert, a Psychology professor at Harvard, wrote a nice little essay at Edge called “The Vagaries of Religious Experience” that dealt with this same sort of thing. (Not promiscuous teleology per se, but how our minds interpret certain events. I’d summarize his ideas, but you’re much better off reading his short essay.)
I wonder how much of this goes back to our ability to see cause and effect? We see what we consider an effect – the universe – and just naturally insert the cause – a bearded guy with grey hair that lives in space.
The second part of Bloom and Weisberg’s article deals with how we learn things. If someone makes a particular claim of truth, how do we deal with it?
“When faced with this kind of asserted information, one can occasionally evaluate its truth directly. But in some domains, including much of science, direct evaluation is difficult or impossible. Few of us are qualified to assess claims about the merits of string theory, the role of mercury in the etiology of autism, or the existence of repressed memories. So rather than evaluating the asserted claim itself, we instead evaluate the claim’s source. If the source is deemed trustworthy, people will believe the claim, often without really understanding it.”
Richard Dawkins wrote an essay published in his book “The Devil’s Chaplain” that addressed the difference in accepting a scientific claim vs. a religious claim, for example. How are the two different? Why is one appropriate (at least sometimes) and the other an indefensible appeal to received wisdom? Dawkins points out that although you, personally, may not independently verify a given scientific claim, it is possible to verify it. A scientific claim is public and open to criticism from anyone who wants to put in the time to verify it. Not so with a pronouncement by the Pope. Born of a virgin? If you say so.
Bloom and Weisberg conclude:
“These developmental data suggest that resistance to science will arise in children when scientific claims clash with early emerging, intuitive expectations. This resistance will persist through adulthood if the scientific claims are contested within a society, and it will be especially strong if there is a nonscientific alternative that is rooted in common sense and championed by people who are thought of as reliable and trustworthy.”
What we need to do now is learn how to break this resistance. Most of the education literature I’ve read suggests that you need to induce “cognitive conflict” in the students. They have to come face to face with the inadequacy of their preconception, then be shown how another explanation is better suited to explaining reality. Unfortunately, this is just very hard to orchestrate, especially with pressures to “cover the material.” And for some people, it's likely true that the only way to replace an emotionally held belief is with another emotionally held belief.
Note: a link to a pdf of the Science article is available online at Adventures in Ethics and Science. A modified version of the paper is available online here. PZ Meyers at Pharyngula also blogs about this article.
Tuesday, May 29, 2007
You might recall that hormone replacement therapy made the news in 2002 when a study by the Women’s Health Initiative (WHI) was shut down early because of unacceptable increases in breast cancer. I think there was concern about breast cancer going into the study, however. A more surprising finding was that coronary heart disease (CHD) was higher in women undergoing hormone replacement than those taking a placebo. This was surprising because pre-menopausal women have a much lower risk of heart disease than men, and this difference is thought to be due to some cardioprotective action of estrogen. If estrogen provides cardioprotection, then why were post-menopausal women on hormone replacement at a slightly greater risk for coronary heart disease than women taking a placebo?
One reason, known (or at least suspected) for some time, was that progesterone opposes the cardiovascular benefits of estrogen. (Progesterone – as medroxyprogesterone – was increasingly added to the hormone replacement mix because of an increased risk of uterine cancer. However, a 2002 editorial in the Journal of the American Medical Association cited statistics that in 2000, twice as many prescriptions were written for a pill with just estrogen than a pill with both estrogen and progesterone.)
The article in PLoS Medicine outlines another possibility. This study, which was not a randomized and controlled trial, searched a British database and looked at risks for heart attacks among women who had received (or were still receiving) hormone replacement therapy and those who hadn’t versus a group of “control” patients. This group isn’t really a true control, they were just randomly drawn from some population and matched to the study group by some criteria. They also looked at the use of NSAIDs for those same women.
So, we’ve got two groups of women: our study group and the controls. The authors compared the risk of heart attack (acute MI – myocardial infarction – to be fancy) for women that had undergone hormone therapy (HT) and those that hadn’t, as well as whether they took NSAIDs or not. The relative risks are shown in the table below (as odds ratios). An odds ratio of 1 indicates equal risk; less than one, less risk; and greater than one, a greater risk. The data indicate that the risk of heart attack is reduced for women currently undergoing hormone replacement, but that risk increases for women that are currently undergoing hormone replacement therapy and also taking NSAIDs.
Enough statistics. What’s the physiological reasoning behind this? Like most everything else, it comes down to proteins. Specifically, enzymes known as cyclooxygenases. There are 3 kinds: COX-1, COX-2, and COX-3. The enzyme of prime interest is the COX-2 protein. This enzyme catalyzes a reaction that produces a molecule called prostacyclin (PGI2). This molecule is a prostaglandin. PGI tends to decrease platelet activity (platelets play a role in blood clotting) and increase the diameter of blood vessels (vasodilation). Estrogen increases the amount of prostacyclin by activating the COX-2 enzyme. Traditional NSAIDs inhibit cyclooxygenases. Inhibiting COX-2 directly opposes the action of estrogen.
This doesn’t mean that women going through menopause should run out and start hormone replacement therapy. The authors of the study are quick to note its limitations. Chiefly, it wasn’t a randomized controlled trial. The data they analyzed wasn’t collected with this issue in mind, it was just a database of patient information. In other words, these data are suggestive but require more controlled studies to draw more definitive conclusions. In any case, hormone replacement therapy still increases risk of breast cancer, so any potential benefits related to minimizing the symptoms of menopause, heart disease or osteoporosis have to be weighed against the risks.
- Garcia Rodriguez, et al. (2007). “Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy:A Drug–Drug Interaction?” PLoS Medicine
- Writing Group (2002). “Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women's Health Initiative Randomized Controlled Trial” JAMA 288(3): 321-333. Available free with registration.
- Fletcher and Colditz (2002). “Failure of estrogen plus progestin therapy for prevention.” JAMA 288(3): 366-368. July 17. Available free with registration.
Thursday, May 24, 2007
One of the difficult things about teaching science (or any subject, I imagine) is deciding which details to leave out. On one hand, it’s often the details that make things interesting. On the other hand, each layer of complexity often requires more background for it to make sense, and the amount of information necessary for comprehension expands exponentially. As a result, we often present things as cut and dry when they are anything but. I imagine that this often gives students the impression that everything is known. Given that I’m teaching subjects that are a bit outside what I studied in graduate school, I sometimes get to experience this myself as I delve into the research literature. I’m often surprised to find out what we don’t know. As an example, take the regulation of the hormone glucagon.
Glucagon is a hormone produced and secreted by α-cells of the pancreas. The basic role of glucagon is to prevent low blood sugar – it helps maintain adequate levels of glucose in the blood. In effect, glucagon opposes the action of insulin. Insulin decreases blood glucose, glucagon raises it. It does this by triggering the release of glucose from the liver.
According to a common anatomy and physiology text (Tortora & Derrickson):
Decreased blood level of glucose, exercise and mainly protein meals stimulate [glucagon] secretion; somatostatin and insulin inhibit secretion.
From reading that, you might think the regulation of glucagon seems pretty straightforward. But if that’s true, then why did the Endocrine Society publish an article earlier this year by Jesper Gromada and colleagues titled “α-Cells of the Endocrine Pancreas: 35 Years of Research but the Enigma Remains.” (The paper is available online for free as an “author manuscript pdf” here.) Clearly, things aren’t as cut and dry as the textbook leads one to believe.So, what do we know about glucagon regulation? Before I answer that, perhaps I should mention why this is of anything more than academic interest. If you follow the news, you’ve probably heard discussions of a diabetes epidemic. NPR recently broadcast a story about type 2 diabetes showing up in people in their teens and twenties, much younger than once was common. Traditionally, diabetes is portrayed as a problem with the hormone insulin, but actually, high levels of glucagon also play a role. Moreover, problems with glucagon regulation in people with type 1 or advanced type 2 diabetes lead to problems with low blood sugar (hypoglycemia). In short, being able to control glucagon could help diabetics maintain normal blood glucose levels. (This is important because many of the complications associated with diabetes are a result of chronic high blood glucose.)
Back to what we know about glucagon regulation. From the article in Endocrine Reviews:
The control of glucagon secretion is multifactorial and involves direct effects of nutrients [like glucose and amino acids] on α-cell stimulus-secretion coupling as well as paracrine regulation by insulin and zinc as well as other factors secreted from neighboring β- and δ-cells within the islet of Langerhans. Glucagon secretion is also regulated by circulating hormones and the autonomic nervous system.
Some of that bears explaining. Paracrines can be thought of as local hormones that affect cell types different from the type of cell that made and secreted the paracrine. A regular hormone (as opposed to a paracrine) can be thought of as a circulating hormone – meaning that it circulates throughout the body, not just a local area. β- and δ-cells are other cell types in the pancreas. β-cells release insulin and δ-cells release somatostatin (somatostatin was mentioned in the textbook description of glucagon regulation). Lastly, the islets of Langerhans are clusters of cells including α-, β-, and δ-cells that make up the endocrine pancreas. It’s referred to as the endocrine pancreas because it’s the part of the pancreas that releases hormones (as part of the endocrine system). The rest of the pancreas (the exocrine pancreas) releases digestive enzymes into the small intestine.
If we know all of these things influence glucagon regulation, then what’s the enigma referred to in the article’s title? The uncertainty lies in the relative influence of the factors:
Since the early 1970’s, the mechanism underlying the regulation of glucagon secretion by glycemia has puzzled scientists. The debate continues whether α-cells directly sense and respond to fluctuations in plasma glucose or whether the response is mediated by the autonomic nervous system and/or the paracrine/endocrine effects of secretory products from other islet cell types. Currently, a large body of research favors the latter ‘paracrine/endocrine’ hypothesis.
The ‘paracrine/endocrine’ hypothesis can be summarized briefly as the idea that a drop in insulin triggers the release of glucagon. This portion of the broader paracrine/endocrine hypothesis is often called the β-cell ‘switch-off’ hypothesis because insulin is secreted by β-cells. High levels of insulin inhibit glucagon, so the decline of insulin in the blood will free α-cells from inhibition.
The rest of the paper goes over the evidence for the various controlling factors, explaining why the authors think the ‘paracrine/endocrine’ hypothesis is most likely the major factor regulating glucagon release. One complication seems to be that research conducted on different species can be difficult to compare. Apparently, there are subtle species-specific differences in glucagon regulation. Just because α-cells of mice react a certain way doesn’t necessarily mean that rats (or humans) will too. So, research on one organism doesn’t necessarily translate perfectly to other organisms.
Having written all this, however, I haven’t really gotten much beyond what the textbook said. (Perhaps a good indication that the extra detail isn’t worth going into at the level of class I teach.) But there is something that an inquiring mind still might be wondering: How does insulin prevent the α-cells from secreting glucagon?
This post is already far too long to delve into that in much detail, but the CliffsNotes version is this. The membranes around cells are impermeable to ions like potassium (K+), sodium (Na+), and calcium (Ca2+). It’s still possible for these ions (and others that I haven’t named) to enter cells, but they need passages (called ion channels) through the membrane. Using these channels, cells can control which ions get in and which ions get out. In doing so, the cells set up concentration gradients. For example, K+ ions are generally more abundant inside cells than outside them. The reverse is true for Na+. A result of this is the generation of an electrical potential across the cell membrane. Changes in the electrical potential can trigger changes in the activities of a cell. (A nerve impulse – the transmission of an action potential – is an example of what can happen when the electrical potential of a cell changes.)
So, to get to the point, insulin opens an ion channel in the membrane of α-cells. The opening of this ion channel changes the electrical potential of the cell, and this indirectly prevents the vessels containing glucagon inside α-cells from releasing the hormone. When insulin levels in the blood decrease, those ion channels close. This changes the electrical potential of the α-cells, and allows the vessels containing glucagon to release the hormone from the cell.
Next week, when I get some time, I’ll take up a new research paper that deals with this issue and comes to conclusions that differ from the ‘paracrine/endocrine’ hypothesis.
Wednesday, May 23, 2007
Monday, May 21, 2007
The willows will hopefully provide habitat for migratory songbirds. Previous use of the land resulted in the loss of willows in some areas, and high elk and moose populations have prevented willow regeneration. This is where WRV comes in. They provided the labor to plant willow cuttings and to fence them off so that elk and moose can't browse them down to the ground. The idea is that the exclosures will allow the willows to grow large enough so that parts of the shrubs will be above the reach of herbivores.
I spent Saturday working on building up a fence around one of the exclosures. I can say that my fence building skills are a bit lacking, but I managed not to hurt myself (or anyone else), so that's encouraging. On Sunday, I planted willow cuttings in pots that some high school students in Walden, CO ("Moose watching capital of Colorado") will take care of before planting them at the refuge either this fall or next spring. Other volunteers planted freshly cut or recently cut willows into the exclosures. It will be interesting to see how well the willow cuttings fare over the summer; I think the survivorship of cuttings is fairly low.
In any case, it was good to be outside after being cooped up in my office all spring. The breeding season for birds on the refuge isn't in full swing yet, but there were some snipe around to add entertainment value to the weekend. I'll add a few pictures of the refuge in a week or two. (See what I mean about behind the curve? I don't even own a digital camera.)
Tuesday, May 15, 2007
I think that's cool. And, it serves as a nice metaphor for what's likely to go on here: No one should expect much in the way of quality from a blog that is named for a process that churns shit.