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December 2013 Archive

Posted by Chris on December 18th, 2013  ⟩  0 comments

One of my favorite holiday traditions as a child was watching the amazingly adorable (and horrible claymation) Christmas special, “Rudolph the Red-nosed Reindeer” which always aired every December on one of the three prime-time networks (this was way back in the dark ages of television when there were only ever 3-5 channels to watch anyway). The tale of that poor, little, “mutant” deer overcoming the adversity of the bullying he received, forgiving the culture that ridiculed him, and finding his place in their world was, and still is, an uplifting storyline. As I watched it again last night with my son, I was reminded of the clear message it wrought and the cultural changes that have occurred since I was a kid (as my son commented that “if HE were Santa, HE wouldn’t have treated Rudolph like that in the first place). Of course, my son was also less impressed with the show than I had ever been at his age since the movie “didn’t really have a bad guy that the hero needed to catch/fight/overcome/whatever” and that the Abominable Snowman didn’t count.

However, since I am a science geek, I began to wonder exactly why or how a reindeer might be born with a red nose in the first place. Reindeer typically have large, black noses (as you can see to the right here) and it’s not really a light bulb type of nose either, set up to hi-beam around in a blizzard. So barring the physics involved (as I’m not much of an engineer), I was still biologically curious to know if this could have been a wild mutation, random and unlikely to occur, or if there was, in fact, some kind of genetic underpinning that could have led to this marvel of evolution.

Serendipitously, I received a random email this morning pointing me toward a fun, little research article from a group in the Netherlands, led by Can Ince, entitled “Why Rudolph’s nose is red: observational study”. According to the paper, reindeer have a “rich vascular anatomy with a high functional density of microvessels” in their noses, which leads to a continuous level of sensitivity and function even as the reindeer spend enormous amounts of time with their noses buried in the snow, searching for food. Ince and colleagues found that the microcirculation of the nasal mucosa in reindeer is 25% denser than humans and can actually be visualized as areas of higher temperatures in thermographic pictures! In a related comparison, another group from Sweden (the Mammalian Rhinarium Group) is using a thermographic camera to study mammals and why some developed the rich, blood-filled noses while others (like dogs) evolved wet, cold tipped rhinaria (that’s that hairless, outer tip of the nose of many mammal species like dogs or cats).

Still, according to Ince, ALL reindeer have this blood-dense mucosa…and their noses remain black as coal. But I am reminded that there are animal species which have evolved specialized blood vessels in various parts of their anatomy. For instance, alligator snapping turtles use the blood coursing through their bright, red, pulsating tongue to act as a lure for unassuming fish to be drawn closer to the turtle’s gaping mouth. Such an evolutionary leap might have been possible due to a rich density of blood vasculature already present in the species from which the mutation was able to springboard. One small bit of evolutionary pressure later, and VOILÀ! We have turtles with pulsating worms for tongues!

So does that make the possibility of a bright, shiny reindeer nose more probable? Well, evolution has certainly produced stranger things. It may be that Rudolph has an evolutionary advantage over the other reindeer. With a brightly glowing nose, it may be easier for female reindeer to locate him in blizzard like weather. Or, with even more blood pouring through his nose than a normal reindeer, it may be easier for him to locate snow-buried food. Or maybe the original story was only partially right, and the truth is that Santa has been carefully cross-breeding his reindeer for years in order to eventually develop an eight-reindeer team of fog-busting reindeer. It’s difficult to discover the truth. And only time will tell if this is a genetic advantage worth perpetuating.

But my guess is that we will start seeing herds of red-nosed reindeer at some point in the future.

 
 

Ince, C., van Kuijen, A. M., Milstein, D. M., Yürük, K., Folkow, L. P., Fokkens, W. J., & Blix, A. S. (2012). Christmas 2012: Research: Why Rudolph’s nose is red: observational study. BMJ: British Medical Journal, 345.

(Bonus video below is from an interview with Professor Ronald Kröger with the Mammalian Rhinarium Group in Sweden!)

Happy Holidays!

Category Code: 79101
 

Posted by Chris on December 4th, 2013  ⟩  0 comments

In the universe of cancers, there are an overabundance of different types. Not just in terms of where a particular cancer tends to show up (such as ovarian cancers, prostate cancer, etc.), but in how the cancer grows or spreads. In fact, apart from the obvious broader categorization that doctors have assembled over the last century and some smaller, subcategorizations that have happened more recently, it could be argued that every single instance of cancer is as unique as the person who has it. And why wouldn’t that be the case, after all? Every individual person has a unique genetic structure, and cancers are caused by defective genes gone awry, so it stands to reason that each cancer is technically as unique as any one person’s individual DNA.

Of course, there are millions of genes that are virtually identical in everyone…the genes that make my intestines work are probably 99.99% identical to the genes that make your intestines work. That’s just good evolutionary conservation. That also explains why cancers can be categorized at all. In the larger framework of things, our bodies are not so different. The metabolic pathways in me are mostly the same as in everyone else and any single, specific gene in one person will get upregulated or downregulated by the same growth factors as the next person.

However, that uniqueness that encompasses each one of us DOES change something in the equation. It answers (without really answering at all) why treatments respond for with some and adversely for others. It explains why cancer can sometimes be annihilated fairly easily while other times relapsing over and over again.

Compounding that penchant for variety is the problematic approach to screening new therapeutic agents. Typically, new drugs are tested first on in vitro cancer cells that have been propagated extensively over decades. But these same cell lines are far removed from the malignant tumors they are derived from. The development of the soft agar assay did wonders for our ability to study cancer outside of a patient and far removed from the threat of death. However, at the same time, they have created an artificial environment which is non-similar to the complicated mass of tumors, their supportive stromal and hematopoietic cells, and their entire vasculature. This dissimilarity makes for a large drop-off rate between in vitro and in vivo trials, eats up valuable resources and takes time away from patients who need viable options.

More recently, some doctors have grown adept in a procedure called Patient-Derived Xenograft (PDX). In a PDX, a graft of the tumor is transplanted directly into a recipient host; usually an immunocompromised mouse or rat. These PDX are usually transplanted somewhere generic, such as the subcutaneously near the hind quarters of the animal and can more closely recapitulate the biological environment that the tumor required to subsist. Current PDX methods aren’t perfect though. Some cancer varieties, such as breast cancer, are resistant to the act of xenotransplantation for some reason while others, like melanoma or lung, are much easier to graft. Regardless, PDX is providing an excellent opportunity to study and screen potential therapies on a growing variety of cancers, in something very similar to their natural setting.

In late 2011, a group from the John Hopkins University School of Medicine, led by Gary Gallia, managed to successfully transplant Chordoma into athymic mice! All by itself, that was a remarkable achievement. Chordoma is an insidious type of cancer, a bone cancer, but one that only grows in the skull or spinal portions of our body. It forms from remnants of our vestigial notochord and grows slowly and is usually diagnosed only in an adult. It is currently treatable only with surgery to remove the tumor, followed with radiation therapy to deal with what was missed in the surgery. Metastasis occurs in about 20% of patients and the 10 year survival rate is only about 46% with a median survival of patients of 6-7 years.

Then, earlier this month, Gallia’s group trumped their earlier chordoma PDX with a chemotherapeutic inhibition of the chordoma-grafted mice using either erlotinib or gefitinib, two popular EGFR (Epidermal Growth Factor Receptor) inhibitors, demonstrating the efficacy of this approach for chordomas. Overall, they saw a 70-75% reduction in tumor size after nearly double the time post-PDX.

As good as PDX is for replicating cancers in vivo, ultimately it is more useful in an academic setting than a clinical one. It will never produce results fast enough to provide the magic pill that will rid a patient of their immediate cancer. But it is an important step in the research of cancer and one I believe will continue to shed light onto a dark and convoluted metabolic pathway.

Chordoma Xenograft

 
 

Siu, I. M., Ruzevick, J., Zhao, Q., Connis, N., Jiao, Y., Bettegowda, C., & Gallia, G. L. (2013). Erlotinib Inhibits Growth of a Patient-Derived Chordoma Xenograft. PloS one, 8(11), e78895.

Siu, I. M., Salmasi, V., Orr, B. A., Zhao, Q., Binder, Z. A., Tran, C., & Gallia, G. L. (2012). Establishment and characterization of a primary human chordoma xenograft model: Laboratory investigation. Journal of neurosurgery, 116(4), 801-809.

For some additional, informative reading on PDX:
Williams, S. A., Anderson, W. C., Santaguida, M. T., & Dylla, S. J. (2013). Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Laboratory Investigation, 93(9), 970-982.

Category Code: 88221 88241 88231

Posted by Chris on December 11th, 2013  ⟩  0 comments

Sometimes, the smallest of things have the biggest impact on our lives. Bacteria inundate every crevice of every larger crevice of our existence. They sustain us, enrich us, immunize us, and sometimes, they kill us. It’s really hard to consider yourself a “top-predator” and all-conquering master of the universe while also recognizing your utter dependence on organisms that can literally number in the millions along the edges of your fingernails.

However, these kinds of numbers also make it hard for us to study individual bacterium. The masses obfuscate the individual. We treat bacteria as a collective, discuss them as a collective and assign their traits as a collective. In fact, most non-biologists probably don’t even realize that the singular form for bacteria is bacterium. But not all bacterium are the same. In our 50-year war against bacterial disease, scientists and doctors have come to realize that some of the bacterium in a culture are different, more…resilient…persistent even.

These “persister” bacterium appear to have some sort of natural resistance to antibiotics, despite being nearly identical to the rest of the colony. But it can be devilishly hard to study persisters since they usually account for a tiny fraction of the total culture and they’re indistinguishable from the whole. This seems like a problem just begging for innovation and invention. So somebody complied.

A group from the engineering department of the University of Japan, led by Hiroyuki Noji, created a femtoliter droplet array system to Femtoliter Droplet Arraystudy individual bacterium cells, explaining their system recently in the Frontiers of Microbiology. (Yes, femtoliter…that’s 10-15 of a liter, 1 billion times smaller than a µl (microliter)!) I can’t even begin to understand some of the engineering that went into building their amazingly tiny “plate”, but the end result was that they were able to monitor individual bacterium grow and replication, even under the selective pressure of antibiotics such as Carbenicillin.

Imagine using a system like this to develop drug treatments or programs in which you can know, statistically, the efficacy of any one treatment versus any bacterial strain. Imagine the convenience of a dose response curve that illustrates the exact limit which is necessary to kill off persisters. Imagine being able to see acquired bacterial immunity as its happening, cell by cell. There are just so many tangible benefits from a system such as this. Hats off to Dr. Noji’s group for creating this fantastic, engineering marvel! I look forward to awesome discoveries using the femtoliter droplet array in the future.

 
 

Iino, R., Matsumoto, Y., Nishino, K., Yamaguchi, A., & Noji, H. (2013). Design of a large-scale femtoliter droplet array for single-cell analysis of drug-tolerant and drug-resistant bacteria. Frontiers in microbiology, 4.

Category Code: 88241 88231