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November 2013 Archive

Posted by Chris on November 14th, 2013  ⟩  0 comments

Antibiotic resistance is certainly more of a rule than a question and one which I have discussed several times (here, here, here and here). The relatively simple genetic structure of bacterial and fungal pathogens and their fast population turnover rate make resistance mutations both likely and common. So it should be exceptional to find a drug that is resistant to such resistance. And that’s exactly the kind of drug Amphotericin B seems to be.

Amphotericin B was discovered in 1955 and extracted from the bacteria Streptomyces nodosus, which was originally found in a Venezuelan riverbed. Amazingly, in its nearly 55 years of use, it has generated relatively few resistant pathogens. That’s contrasted with the usual fate of other antibiotics which seem to have an ever decreasing efficacious life-span. For instance, the antifungal drug Fucytosine was introduced in the early 1960’s and saw resistance in strains of Candida in less than 20 years. In fact, it’s estimated that up to 50% of all Candida specimens isolated from new patients are already resistant to Fucytosine. So what makes Amphotericin B so resilient in the face of such odds? Well, there are lots of theories.

For instance, Amphotericin B targets lipids and not proteins. So therefore, it might not be as susceptible to genetic substitutions in drug-binding pockets which is common in drugs that do target proteins. Additionally, Amphotericin B targets the plasma membrane, so it might not be susceptible to resistance through increased drug efflux. Also, Amphotericin B is typically administered intravenously and for short time frames. So it might not be as susceptible as more typical, oral antibiotics that offer greater chance of resistance through their extended treatment periods.

However, Susan Lindquist’s group from MIT believed there might be something more. Wanting to finally piece together the remarkable puzzle of this anti-resistance, the group spent considerable time sequencing the full genome of several rare varieties of AmB-resistant Candida patient specimens that they could find, some evolved, resistant strains grown in the lab and some targeted, site-directed resistant strains created through recombination. They found that the most common sources of genetic resistance derived from mutations in the ERG2, ERG3, ERG6 and ERG11 loci. They also discovered that AmB resistant mutants depends critically on the Hsp90 chaperon protein (similar to that previously seen with Fluconazole resistant strains), and that even small inhibitions of Hsp90 eliminated inherent AmB resistance (Hsp90 is a protein which helps promote the proper folding of other proteins and stabilizes them from heat stress). Since Hsp90 is key in the stabilization of a number of proteins required for tumor growth, Hsp90-inhibitors are also popular in anti-cancer investigations.

AmB resistant strains - Hsp90 functionPerhaps the most surprising part for Lindquist’s group though, was that the Hsp90 inhibitors completely blocked all growth of AmB resistant strains all by themselves, even in the absence of AmB and was effectively cytocidal! This would suggest that, contrary to mutations in other fungicidal resistant strains, the growth of AmB mutant strains rely on a critical level of Hsp90 just to survive. It would also seem that these resistant-mutant strains are simply doomed from the beginning. In effect, the act of becoming resistant to Amphotericin B makes them susceptible to a host of other, normal immunological responses and all but renders them avirulent.

So even though the point of this study was to discover the mechanism of anti-resistance in Amphotericin B, the bigger story is likely the position that Hsp90 plays in the enabling of new mutations and phenotypes to survive. Even more, this finding shines a light on the prospect of treating resistant strains with chemicals that antagonize and exploit the resistance mechanism. As fungal infections often turn deadly in the face of immuno-compromised cancer treatment and are cause for nearly as many deaths as the cancers themselves, this might be a path of investigation worth traveling.


Vincent, B. M., Lancaster, A. K., Scherz-Shouval, R., Whitesell, L., & Lindquist, S. (2013). Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B. PLoS Biology, 11(10), e1001692.

Category Code: 79102 88221 79101

Posted by Chris on November 21st, 2013  ⟩  0 comments

The growth and development of plants are governed by the induction, suppression or transmission of phytohormones such as Indole-3-acetic acid (IAA), sometimes known as auxin. The sessile nature of plants demands some kind of chemical response to all manners of external stress as opposed to the physical response which animals typically make. Those chemical responses, whether responding to living organisms (biotic stress) such as insects, bacteria, fungi, etc. or to environmental conditions (abiotic stress) such as drought, salinity or cold, must occur repeatedly over the plant’s entire lifetime and help determine its ultimate survival or death.

Since this is such a critical part of the plant’s existence, it stands to reason that any sensible plant would harbor a multitude of redundant pathways, and also a variety of phytohormones, in the event that any one specific pathway or hormone fails to work adequately. I have found this redundancy to be one of the most amazing aspects of plant physiology, and definitely one of the most frustrating as well. Discovering that your model plant is fully capable of working around every one of your knockout mutations, convoluting your hypotheses on molecular pathways and mechanisms, helps explain why there is never any beer left over after an academic plant symposium.

Even though IAA was first discovered in 1937, plant scientists are still befuddled to many of the ways in which IAA functions in the plant and to what extent and in relation to which types of stress. We know how it moves and where it moves. We know that IAA is unique in that it is the only phytohormone that moves both long distances through the phloem of the plant as well as short, cellular distances utilizing polar auxin transport (which requires the use of specific auxin efflux carriers on the plasma membrane). We know that a little bit goes a long way, and that too much is a very bad thing (See 2,4-D). We even know a lot about what IAA does in the plant specifically; driving root tip initiation, apical dominance, flower initiation and fruit growth or even the suspension of fruit senescence. But from a physiological standpoint, that barely scratches the surface of what is actually going on.

Environmental stress is one of the most debilitating effects on cereal crops from an economic perspective. Early freezes or summer droughts run roughshod over grains and fruit/vegetable farms, dealing hundreds of millions of dollars in lost revenue every year. So there’s a strong financial incentive to understanding what’s really going on behind the scenes of abiotic stress on some of the world’s biggest cash crops. Perhaps not so unexpectedly, the results are complicated.

Rice Roots Gravitropism Cold StressHao Du et al. published a paper last month, in the online journal Frontiers of Plant Science, studying auxin levels during abiotic stress in rice. Their results showed that the regulation of IAA changes in response to different types of abiotic stress. In drought conditions, the level of IAA was reduced 18% after 3 days, but exposure to either heat stress or cold stress caused the level of IAA to increase up to 1.6 fold after 3 days. They also saw that root tip gravitropism could be inhibited by cold stress nearly to the same effect as the auxin transport inhibitor TIBA (2,3,5-triiodobenzoic acid). Additionally, they looked very closely at a number of the genes (such as OsYUCCA and OsIAA genes) encoding these molecules and their overexpression or suppression during abiotic stress conditions.

Arab root tips Cold Stress IAASo what does all that mean, exactly? First, it confirms that the homeostasis of auxin levels is tightly related to tolerance of these three stress conditions, at least in rice (and maybe other monocots as well). More importantly, it starts pointing a putative finger toward the genes that need to be regulated in order to develop plants which are tolerant to these specific stress conditions. Of course, that’s no guarantee of success…any plant molecular biologist knows that. But it is a start, and just like when dealing with any clump of plant roots, the only way you can begin to see the entire root system is to tease the root tendrils out one by one.


Du, H., Liu, H., & Xiong, L. (2013). Endogenous auxin and jasmonic acid levels are differentially modulated by abiotic stresses in rice. Frontiers in plant science, 4. doi: 10.3389/fpls.2013.00397

Shibasaki, K., Uemura, M., Tsurumi, S., & Rahman, A. (2009). Auxin response in Arabidopsis under cold stress: underlying molecular mechanisms. The Plant Cell Online, 21(12), 3823-3838.

Rahman, A. (2013). Auxin: a regulator of cold stress response. Physiologia Plantarum, 147(1), 28-35.

Category Code: 88221 79101

Posted by Chris on November 27th, 2013  ⟩  0 comments

In the US, we are once again preparing for that glorious day of turkey, Thanksgiving. The stuffing is being prepared, the cranberry sauce just as Grandma would have wanted it, the pies are getting baked…and the search engines are alight with thousands (if not millions) of Tryptophan queries as curious dinner guests wonder if eating the traditional turkey will excuse their post-dinner slumber. The answer is still no.

However, tryptophan is one of the essential amino acids that we need to consume to maintain a healthy life. In fact, the lack of tryptophan in a diet was seen in a dire way in the 19th and early 20th century epidemics of pellagra. Pellagra is a devastating illness caused by a chronic deficiency of niacin, which is a natural product of tryptophan. Symptoms such as dementia, skin lesions, ataxia, diarrhea, and ultimately death were only restrained through the work of doctors like Joseph Goldberger and Tom Spies (among others) who pieced together the puzzle of this very avoidable disease. Contrary to some popular belief, turkey (or even meat) is not the sole source of tryptophan. This amino acid can be found in a wide variety of foods including, eggs, soybean, fish, meat, milk/cheese, oats, wheat, potatoes and various vegetables and fruit. So in the event that you might a vegetarian, you don't have to worry about having to take additional supplements in order to include tryptophan into your diet.

But what if there’s even more to the story? Adrian Williams and Robin Dunbar seem to think so. In the International Journal of Tryptophan Research (Really! Tryptophan has its own journal!), they outline a fascinating hypothesis concerning the historical implications of increased ingestion of meat, and therefore tryptophan, creating a surplus of niacin and nicotinamide which may have helped to fuel our pre-historic, evolving brains. Oh…and tuberculosis may have been a beneficial symbiont way back then. Williams and Dunbar believe that TB acted in a symbiotic relationship with humans for thousands of years, producing nicotinamide as a byproduct and bolstering the human vitamin demand during occasional meat famines. This advantage meant that humans, in a hunter/gatherer society, would not immediately suffer the pains of vitamin deficiency such as pellagra during such lulls in food availability. The side effect was that if meat could not eventually be found, TB would cause eventual death. But if the famine subsided, the side effects of TB could again be reduced to its quiet, symbiotic relationship.

That’s a remarkable hypothesis for the tryptophan metabolic pathway and I’ll be very interested to see if Williams and Dunbar can back up their pilot claims with some kind of experimental proof. Until then, might I suggest that you partake in some extra turkey this Thanksgiving holiday with the full knowledge that you are contributing to the brain-enriching habit of niacin production and human brain evolution. Really! Go ahead! Your genetically superior, genius-level descendants will thank you…probably on their future version of Thanksgiving.

Happy Thanksgiving!!


Williams, A. C., & Dunbar, R. I. (2013). Big Brains, Meat, Tuberculosis, and the nicotinamide switches: co-evolutionary Relationships with Modern Repercussions?. International journal of tryptophan research: IJTR, 6, 73.

Category Code: 88221 79101

Posted by Chris on November 7th, 2013  ⟩  0 comments

Since the early 1990’s, there has been an explosion of research and discovery around the problem of preeclampsia and the correlated growth factor, VEGF. Preeclampsia has been a menace of pregnancies for ages and still affects anywhere from 2-10% of pregnancies world-wide. It’s a disease that strikes most often in first-time mothers, marked with high blood pressure and proteinuria, can be debilitating and can also lead to even more serious complications. But despite that, it is also a disease that is poorly diagnosed, or only properly diagnosed once the symptoms have been alleviated, i.e. the baby was delivered.

In the last 20 years, scientists have accumulated a massive amount of information about the Vascular Endothelial Growth Factor (VEGF) family and its role in preeclampsia. VEGF is a signal protein that is strongly involved in angiogenesis, building new blood vessels during embryonic development or after injury. It’s also very important in the implantation of the placenta to the uterine wall, wherein during preeclampsia, there is a shallow implantation, with reduced arteriole development and a subsequent immune response by the mother’s antigens. Research has shown that pregnancies resulting in preeclampsia show a significantly reduced level of VEGF, as well as its Placental Growth Factor (PlGF), an integral member of the VEGF family during pregnancy. They’ve also shown an increase in the soluble form of VEGFR1, called sVEGFR1 or sFlt-1. sVEGFR1 binds VEGF and prevents it from hooking up with the normal VEGFR1 and continuing its proper course. This results in a decrease in available VEGF which appears to be causative to preeclampsia.

There are a lot (and I mean a LOT) of papers dedicated to, or relating to, finding a marker protein or system to predict when preeclampsia will occur. In fact, there were so many duplications of the same work (I will continue to assume that they were all terribly unaware of previously published work), it was difficult to find a novel paper that went BEYOND simply reporting the problem and the symptoms. But I did! Allessandro Rolfo et al., from the University of Turin, took one step further back to see what was originally causing the sVEGFR1 to overexpress and cause the cascade of VEGF problems and the eventual preeclampsia.

Preeclampsia MSCsRolfo’s group found that mesenchymal stromal cells (MSCs) contribute to the pathophysiology of the preeclampsia condition through the irregular overproduction of a host of proimflammatory cytokines in PE placental mesenchymal stromal cells (PE-PDMSCs) as opposed to normal PDMSCs. Some of the elevated growth factors included IL6, IL8, TGFB2, LIF and TNF-alpha, just to name a few. Even more interesting was that they were able to take PE-PDMSC conditioned media and entice the same overproduction of those cytokines in normal explant systems! It’s a remarkable find, and if the results prove true, a definite boon to medical research. Pushing back to find the root cause of the problem is necessary to treating the disease and the next step for Rolfo’s group is to find out if the preeclampsia process can be reversed. Stay tuned. I'm sure there will be some amazing discoveries in the future!


Rolfo, A., Giuffrida, D., Nuzzo, A. M., Pierobon, D., Cardaropoli, S., Piccoli, E., Giovarelli, M. & Todros, T. (2013). Pro-Inflammatory Profile of Preeclamptic Placental Mesenchymal Stromal Cells: New Insights into the Etiopathogenesis of Preeclampsia. PloS one, 8(3), e59403.

Category Code: 79105 


PS. At Gold Bio, we’re always interested in finding things that interest our customers (and readers here at the Blog). If there’s a topic you’d like us to cover or an article that you think we should review, please email me at:! We’d love to hear more from you!