Dogs saving lives: Better at detecting small molecules than mass spectometry!

It is probably obvious that Sarah & I have an (unhealthy) obsession with our dogs, so much so that we made a specific tab for their pictures on our non-dog related science blog. Aside from being the most amazing creatures that DNA & protein have combined together to make, ever, I recently ran into a (understated) field that researches canine olfactory detection. I first learned about this field while listening to NPR and blew it off for pseudo-pet-lover science – but today one small Google search (& one more pubmed search to back it up) unveiled a substantial (& peer-reviewed!) area of research dedicated to canine detection of cancer.

Though dogs have been sniffing things for the government for decades – the 2006 article “Naturalistic quantification of canine olfactory sensitivity” by Dianne Walker, et al. is the first comprehensive research that identifies a dog’s threshold to detect molecules at an astonishing parts per trillion. This work was begun with the intention of understanding & quantifying the elusive canine detection of cancer. They studied canine detection of very low odorant concentrations of n-amyl acetate (nAA) using an air dilution olfactometer (to the left) and found there were stable concentration thresholds at 1-2 parts per trillion (ppt). I will add that this study only included two dogs – with an n of 2 things start to get murky, but there have been many holes in studying this phenomenon & I think this is a great jumping off point.

More recently, there have been publications on canine detection of multiple cancers including melanoma, bladder, lung, breast & ovarian. In 2006 Michael McCulloch, et al. propose canine detection of breast cancer as an alternative or addition to mammography screening (generally inconsistent) or the (just-now-FDA-approved) search of cancer through biomarkers identified through testing blood samples. This paper presents evidence that a dog’s nose not only detects very low concentrations of molecules, but it can discriminate between complex chemical mixtures, such as would be found in exhaled human breath. It has been previously shown that “volatile organic compounds potentially diagnostic of cancer, such as alkanes, methylated alkanes, aromatic compounds, and benzene derivatives, have been identified using gas chromatography/mass spectroscopy (GCMS) in the exhaled breath of patients with lung and breast cancers”. It took 2 to 3 weeks to train ordinary dogs to distinguish breath samples of lung & breast cancer patients from those of healthy controls. Although they have an idea of what molecular compounds the dogs might be sniffing – I think there’s potential that the dogs might not be responding to the cancer itself, but possibly to the inflammation, infection, or necrosis (associated with cancer).

January 31, 2011 there was a press release in Gut (An International Journal of Gastroenterology & Heptology – may sound like a very specific journal but they have an impact factor of over 9) stating that in patients with colorectal cancer (CRC) and controls, the sensitivity of canine scent detection of breath samples and/or stool samples compared with conventional diagnosis by colonoscopy (with 0.91 & 0.99 specificity, respectively)! In addition, they mentioned that not only was this method as specific as current diagnostics, it was also temporally sensitive – with detection even higher for early-stage cancers! One more amazing thing, the detection was not disrupted by benign colorectal disease, inflammatory disease or the presence of human haemoglobin or transferrin (this is obviously in the stool samples). This might negate my point about the dogs actually smelling inflammation.

In all of these diagnostic studies using breath detection, they have also ruled out smoking as a factor, eating & drinking.

The next step in this research needs to be identifying what compounds or molecules the dogs are detecting – I think this will be the hurdle for the field because we are limited to detection of molecules by gas chromatography/mass spectroscopy (GCMS) – therefore the molecules that slip under the radar cannot be accounted for…

This is where my dream of dogs speaking English would really come into handy.

Walker DB, Walker JC, Cavnar P, et al. Naturalistic Quantification of Canine Olfactory Sensitivity. Forthcoming (2006).

McCulloch M, Jezierski T, Broffman M, Hubbard A, Turner K, & Janecki T (2006). Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers. Integrative cancer therapies, 5 (1), 30-9 PMID: 16484712

Sonoda H, Kohnoe S, Yamazato T, Satoh Y, Morizono G, Shikata K, Morita M, Watanabe A, Morita M, Kakeji Y, Inoue F, & Maehara Y (2011). Colorectal cancer screening with odour material by canine scent detection. Gut PMID: 21282130


Science Highlights this week:

Surprise! Dumping antibiotics leads to microbial resistance.

Nature news reported this week, “high levels of antibiotic resistance have been found in bacteria that live downstream from a waste-water treatment plant in Patancheru, near Hyderabad in India”.

When bacteria are exposed to low levels of antibiotics (ie: diluted drugs from a waste-water treatment plant) they need to quickly adjust to their environment so they do not parish. Bacteria are known for trading groups of genes on mobile genetic elements like transposons, or “jumping genes”, and plasmids, circular extra-chromosomal genes. Given a dynamic environment of several different species of bacteria, that contain different resistances to a variety of antibiotics, these resistance genes can be easily transferred from one species to the next. The stronger & now resistant strains will outlive the weaker strains – and this is the basis of developing bacteria that are antibiotic-resistant.

This dumping of low-level antibiotics into our environment seems outrageous, but in the states we use low levels of streptomycin & tetracycline to crop dust organic produce (replacing pesticides) – so wash your fruits & veggies.

(Original Nature News article)

5 Black Bears: Insight into space travel like in Alien?

After 5 “nuisance” black bears were picked up by the Alaska Department of Fish & Game they found their second calling – being aids for studying mechanisms in hibernation. They were fitted with sensors to record their temperature & heart rate and monitored by infrared cameras (catching even their tiny little bear snoring). With this data researchers found that unlike ground squirrels, bears’ body temperature drops only by 6 degrees Celsius. In addition, they show that bears only take 1 or 2 breaths/minute and their heart rate is about 4 beats/minute. They also found weeks before & after hibernation bears entered an “intermediate metabolic state: wandering around and eating like normal but with lowered metabolism”. The mechanism behind this new intermediate metabolic state would be fascinating to discover & could be extremely helpful for long-term space travel by humans…

(Original article: Science)

Watch footage of black bears hibernating.


Neutron Stars shown to be probably pretty normal, for neutron stars

When I was a kid, I thought that I was going to become a theoretical particle physicist. Then I learned enough to know that that thought is hilarious.

But, you know, some people actually do have to grow up to be theoretical particle physicists. I've never met any of them, but I know they exist, because I see their theories that they make about the physics of particles.

One set of theories is about the behavior of matter that has been condensed so far that I doubt even the people who made the theories can truly have a mental model for how dense this denseness is. Does extremely dense matter decompose itself into free quarks? Does it become more like a kaon condensate, or a happy set of hyperons? Or is the result less exotic than that--do the atoms' protons and electrons, when pushed up against each other, simply fuse to become plain old neutrons and nothing else? Or is it a combination of these scenarios? How will we ever know, and how will we live without knowing?

We here on planet Earth do not have the ability to prove any of the theories right or wrong, because how are we supposed to crush matter to densities extreme enough to condense atomic nuclei? We can't. So we have to look elsewhere.

Luckily, astronomers have found us these dudes called 'neutron stars,' which get their name from the idea that proton+electron+pressssssssssssssssssssssssssssssssssssure=(just) neutron. But that idea has been challenged, a lot, by theorists who say that more exotic states of matter will appear.

Well, since we can't schlep to a bunch of neutron stars, and even if we could, taking close-up measurements would kill us dead, how are we going to figure out what they're made of? How are we going to cross some of these competing theories off the List of Stuff with Scientific Validity (a real list)?

The trick lies in 'constraining' the equations of state predicted by the theories. Equations of state (EOS) describe relationships between the important parameters within a system, basically telling you how all the significant aspects of an object or substance behave together. They, like all good equations, can be plotted.

If you take measurements of the parameters described in the EOS, you can put your measurements on the plot and see how the reality and the theory mesh or don't mesh.

So guess what? I'm not the only one who knows that. Some astronomers have heard of this technique too. In particular, here, I'm talking about Demorest, Pennucci, Ransom, Roberts & Hessels and their ApJ Letter "A two-solar-mass neutron star measured using Shapiro delay," a title that kind of steals the thunder of the disclosures that follow.

Neutron star background in one minute or less: Massive star goes supernova; remnant of star, material that hasn't been blown away, is compressed and retains much of the magnetic field and angular momentum of the original star, although this remnant is only the size of Washington, D.C. This D.C., though, weighs more than the Sun.

a) it's very dense ('very' being the understatement of 2011 so far)
b) if you think about how 'conservation of angular momentum' means that when an ice skater is spinning and then pulls her arms in and then she (or he, or he) spins faster, and then you think about how that would apply to a star that used to be massive star-sized and is now city-sized...that's one fast rotater (sometimes more than 600 rotations a second)
c) the intense magnetic field causes intense radiation to be beamed from the poles, which is how we typically find neutron stars. When we can see a beam of radiation from a neutron star (which we see once per rotation, when it's pointed at us), the neutron star is also a 'pulsar.'

Sometimes pulsars are in binary systems. Sometimes they are in binary systems with other massive objects. Those other massive objects affect the spacetime around them, curving it. The pulses from the pulsar must travel along this curve, which takes longer than traveling across a straight line. Because of this time difference, the pulses are delayed, an effect that is shown in this graphic (credit: Bill Saxton, NRAO).

Though the delay, called the Shapiro delay, is not large, it is large enough: pulsars' signals are so regular and we are able to measure them so accurately that we can latch on to very small deviations.

Once the delay is measured, astronomers can calculate how much mass is required to create the spacetime dip that would cause that delay. Then, based on the orbital parameters of the system, they can use regular-old Keplerian dynamics to determine, given one known mass, what the other mass must be. In this case, the companion was a white dwarf half the mass of the sun, while the neutron star/pulsar was 1.97 times the mass of the sun. Turns out this is by far the most massive neutron star known and BAM (roundhouse kick) defeats some proposed equations of state.

On this graph (from the paper) of radius versus mass, the EOSs are the ones that look like snakes; each snake represents the predictions of a different theory of what is inside a superdense object.

We only know the mass--not the radius--of the heaviest neutron star, so we don't actually know its density. However, the simple statement "A neutron star can be up to 1.97 solar masses" results in a horizontal line (red), which results in a lot of the snakes being trapped underneath. These trapped snakes represent theories that can never produce 1.97-solar-mass neutron stars.

Turns out that these low-lying snakes are the ones that predicted more crazy interior states, such as the aforementioned kaon condensates, which I just like saying.

Isn't it strange that finding something so strange (even for a neutron star) resulted in the ruling out of the strangest possibilities for its interior state?

And isn't it reassuring that observations still have the power to confirm or deny theories, even if we can never create the necessary observational conditions in a lab? It is a relief to me. I sleep better at night...whereas (to make this a neatly circular blog post) if I had become a theoretical particle physicist, I would probably never sleep, especially not if my EOS was a buried snake.

Demorest, et al. Nature, 467: 1081–1083, 28 October 2010)


Science Brief Today:

Nature reported today that Obama resisted the proposed cut in research funding! The proposed budget for 2012 is $66.8 billion, a 6% increase in overall current funding & even more for specific agencies (graphs of specific agencies & their budget increases). NIH & NSF are on their way up again!

(original Nature News article)

In addition, if anyone is home tonight at 7:30pm (eastern) Watson, the IBM computer, is playing the second half of its Jeopardy game against 2 of the most famous players. Watch Ken & Brad flinch as Watson wipes the floor with them.


What came first - the chicken's DNA or the chicken's proteins?

Tonight I was watching Teen Mom and contemplating evolution. Rough night. But… the idea of natural selection, though hard to grip with shows like Teen Mom, is generally accepted and understood. The question that is harder to answer is how did we come from amino acids floating in the primordial soup to typing on a lap top talking about Teen Mom? That’s a big question (and this is smaller questions) but a good place to start looking is “The RNA World”, or the theory that RNA was the egg that came before the DNA chicken.

The RNA World hypothesis implies that there was life based solely on ribonucleic acid (RNA) that predated the world we live in now, based on deoxyribonucleic acid (DNA). This hypothesis includes the idea that genetically encoded proteins (made of amino acids) were not involved in RNA replication or synthesis. When I first heard this hypothesis it completely blew my mind – my whole biology knowledge stemmed from the idea that life was created by DNA & DNA replication (DNA to DNA), transcription (DNA to RNA) & translation (RNA to proteins) and they were all carried out by proteins & enzymes – but in the origin of life… how do you replicate DNA without DNA polymerase? What came first, the DNA or the polymerase?

For the RNA World hypothesis you have to go deeper (like Inception) – if DNA is required for protein production & proteins are required for DNA production, than we’re not looking in the right place. RNA is a likely candidate for the origin of life because it not only stores information like DNA, it can act as an enzyme like proteins. EUREAKA!

Though there is not universal belief that RNA was the first form of life on Earth, in the last 10 years there has been ground breaking evidence. With the structure of the ribosome (required for translation – RNA to protein) being solved in 2001 we can see that the primordial ribosome might have been made completely from RNA. Although, this theory requires the assumption that there were free forming activated nucleotides that joined together to make polynucleotides that were self-replicating. This is where our new data comes in - published in Science, Self-sustained replication of an RNA enzyme (Tracy Lincoln & Gerald Joyce, 2009).

They answer “a long-standing research goal […] to devise a nonbiological system that undergoes replication in a self-sustained manner, brought about by enzymatic machinery that is part of the system being replicated”. They show the “RC3” RNA enzyme can self-replicate by binding two RNA molecules to produce another copy of itself. This form of self-replication was inefficient so they modified the RC3 RNA enzyme so that two enzymes catalyze each other’s synthesis from a total of 4 polynucleotide molecules. These cross-replicating RNA enzymes showed exponentially growth in the absence of proteins or other biological materials. To introduce the complexity aspect of life as we know it they hypothesize they would need to create a genetic system that takes enzymes that can create different daughter enzymes. The next NEXT step would be to introduce an enzyme with a broad range of functions, beyond self replication. Oh the possibilities!

This has come a long way since mentioning Teen Mom, so far that now Brian Green is on the Colbert Report. If anyone has any opposing ideas of the origin of life, I'd be really interested!

Lincoln, T., & Joyce, G. (2009). Self-Sustained Replication of an RNA Enzyme Science, 323 (5918), 1229-1232 DOI: 10.1126/science.1167856