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Sugar-Coated Nanomachines Cure Cancer

March 10, 2019

An idea going back to Fantastic Voyage is that physicians can shrink to microscopic size and travel through the blood vessels to treat the site of a patient’s illness. Today, we’re not shrinking human physicians, but nanomachines. This research team at University of Tokyo focuses on a particular challenge for nanomedicine, getting the therapeutic agents across the blood brain barrier. The blood brain barrier is especially challenging to fight brain tumors, such as glioblastoma, the kind that Senator McCain had. Dr. Kataoka discusses his work here.

Kataoka’s group used an ingenious trick to get their device across the blood vessel membrane. The capillaries into the brain exclude lots of things, but need nutrients—especially the sugar called glucose. The brain has one of the highest glucose uptake rates found in the body. The glucose is taken up by a protein called GLUT1 that is embedded in the membrane of the capillary cells. So the researchers built a delivery device called a “micelle” (basically a highly engineered soap bubble). The micelle contains sugar molecules attached to a carbon chaine (hydrocarbon) that dissolves into the micelle membrane. Now the whole sugar-coated object can bind to GLUT1 molecules in the capillary, and dissolve through the membrane.

How do we know it works? This micrograph shows the capillaries within the brain of a mouse. The sugar-coated micelles have a tagged molecule that fluoresces red. In the first image, we see the micelles only found within the capillary vessels. But after 60 minutes, the micelles have leaked out of the vessels into the surrounding tissue; a process known by a mouthfull of a term, “extravasation.” Extravasation is something that white blood cells normally do all the time, in most parts of the body, but not the brain.

If that’s not strange enough, at ICFA “Clone with Joan” Saturday breakfast we’ll hear more about how gut bacteria may take up residence in the brain (a controversial report) and how bacteria can treat human genetic diseases. Sounds more and more like the microbial aliens of Brain Plague.

Infrared Mice. Wait, What?

March 3, 2019

Perhaps the most curious thing about this story, of how mice were made to see infrared, is that it represents a collaboration amongst three Chinese universities plus the University of Massachusetts Medical School. Wait, what? So our leading universities are engineering our soldiers plus the Chinese to see each other glow in the dark?

The human visual spectrum spans red through violet. Red light has longer wavelength and smaller energy per photon; violet has shorter wavelength and higher energy. Recall how the protagonist of Brain Plague had one mutated gene that enabled her to see infrared, the wavelength beyond red color, shading into thermal radiation (heat). What Chrys could see might look something like this:

What animals can see infrared? Some snakes, mosquitoes and bedbugs can detect infrared. Humans can detect infrared photons—but only as bursts of many photons coming together, so pairs of them can add up. To see individual infrared photons is not possible for mammals, because we are “warm-blooded.” Because we maintain a higher temperature, our thermal energy generates “noise”; that is, random firing of the opsin proteins that absorb each photon.

But the Chinese and Massachusetts investigators made use of an optical trick with nanoparticles. The nanoparticles show a form of fluorescence called “upconversion.”

Fluorescence, the simple kind, involves a material that absorbs light at a short wavelength (lambda 1); dissipates some of its energy as heat (broken line); then emits the rest of its energy as a photon of longer wavelength (lambda 2) with lesser energy. For example, absorb blue, emit red.

Suppose however your detector absorbs infrared: Could it emit light at a shorter wavelengh, which your retina can see? Not by plain fluorescence. But upconversion means that the electron cloud absorbing the first infrared photon then absorbs a second one, and is raised to an even higher energy state. Now the electron cloud can release all its energy in one photon of shorter wavelength (lambda 2).

So the researchers injected upconversion nanoparticles into the retinas of mices. The nanoparticles coated the mouse photoreceptor cells, where they could absorb infrared and emit light in the visible range (green). When the mice were given green light (535 nanometers wavelength) they produced electrical signals. And when the nanoparticle-injected mice were exposed to near-infrared light (980 nm) them also produced electrical signals–in response to the green light emitted by upconversion of the nanoparticles.

The infrared response was imperfect, but it was good enough for the mice to distinguish patterns and shapes formed by infrared. Perhaps this kind of approach could engineer new kinds of color vision in the future. If you don’t mind your retina getting injected.

Arsenic and Old Lace–Actually, Bacteria

February 24, 2019

Ultraphyte welcomes you back!

The past two years of my break from the blog have yielded ever more reasons to thank your hardworking gut bacteria. From brain control to jet lag, bacteria on their way to poop manage to control just about everything. Microbes invented us metazoans to house them—more on that in a future post. We look more like Brain Plague all the time.

Arsenic poisoning is the stuff of plays and forensics—and all too real a hazard in ground water, particularly the western USA. Chronic exposure leads to skin problems, deterioating organs, and cancers. Yet surprisingly, individuals can vary in their sensitivity. What deterimines arsenic’s effect on our bodies?

Bacteria may play a huge role. As in Brain Plague, microbial inhabitants actually do collect arsenic and protect us from it. Michael Coryell and other in Seth Walk’s lab at Montana State conducted fascinating experiments with mice. They used mice treated with antibiotics to kill much of their normal gut bacteria. The mice (plus untreated controls) were given drinking water with arsenic. (I know, those cruel scientists.) Antibiotic-treated mice excreted more arsenic in their urine than controls (a). And the antibiotic-treated mice retained more arsenic in their organs (b). Looking at the graph, the (b) result is less convincing than the excretion result, but still intriguing, especially the dramatic difference in the lungs.

How could our bacteria protect us? The bacteria metabolize arsenic—that is, they add various chemicals to it, such as sulfurs and carbons (thiols and methyl groups). Arsenic metabolism is extremely complicated, but some chemical conversions make it more soluble and less toxic, whereas other conversions do the opposite.

Even more interesting, the researchers took germ-free mice (reared in isolation from birth, like the bubble boy) and added human gut microbiota. The so-called “humanized mice” survived arsenic much better than the germ-free mice. In fact, the researchers zeroed in on one particular species, with the mouthful name of Faecalibacterium prausnitzii.

The germ-free mice survived arsenic about five days longer if they hosted this F. prausnitzii.

I still wouldn’t drink arsenic water regularly, but it’s good to know our gut residents are looking out for us—one wonders what all else they are up to.

If you’d like to reward your helpful gut friends, remember to eat some chocolate because bacteria tell us they want it.

Hope to see you at ICFA in sunny Orlando! Remember our traditional Saturday 8:00am breakfast, Clone with Joan.

 

 

From Skin to Eggs

May 18, 2017

Now that grades are turned in, I can take a moment off from the Indivisible site that’s occupied my blogging since November, to highlight a momentous event, long foreseen: Conversion of skin cells to eggs. For the first time, molecular biologists have converted mouse fibroblasts (a type of skin cell) into pluripotent stem cells (cells that have lost the skin-type specialization) which then were converted into egg cells. The eggs were then fertilized in vitro (IVF) with normal sperm, and produced viable mouse pups.

For humans they say skin-to-egg is maybe five years away. If every skin cell could be a baby, will we outlaw dandruff?

The details are more intriguing yet, as describe by Katsuhiko Hayashi in his original report.

The full process actually required two types of cells: embryonic stem cells (providing helper genes), and the skin cell-derived stem cells to become eggs. The requirement of embryonic helpers is one aspect that will prove challenging to perform in humans.

For egg production, the two types of cells are aggregated to form ovary-like tissues, “ovaries in a dish.” Within these artificial ovaries, the skin-cell derived cells differentiate (become specialized) to form functionally normal oocytes (egg cells). Remarkably, the egg cells undergo normal development including exclusion of one set of chromosomes within a tiny polar body. The successful fertilization rate is about

The study’s author describes further implications of their work here. The timing of human egg production will involve several months, and the requirement for supporting embryonic cells is a hurdle. But in the past such requirements for stem cell procedures have been superseded by chemical treatments that mimic the cells’ developmental signals.

What medical applications could this technique have, if developed in humans? Such techniques might lead to uniparental humans (the egg and sperm derived from one person); or to humans with multiple parents providing different chromosomes. One thing is clear, the role of conception in human biology would be shifted, with unknowable results for our concept of what is human.

Microbes of 2016

December 30, 2016

From Syria to Trump Tower, this year has not been the greatest for human beings. Yet our microbial communities have flourished. Even the White House (perhaps with prescience) announced the National Microbiome Initiative, predicting that microbes would accomplish some of the year’s most noble and memorable achievements–from CRISPR/CAS (bacterial antiviral defense applied to human gene editing) to the ancient invention of multicellular life. We can all appreciate that one; or regret it, as the case may be. My own lab has been a romp through bacteria reversing our drug resistance, to Haloarchaea evolving for Mars. Why send Mars our humans, when we can send our microbes?

One last salute to microbial scientists: What’s lurking in your showerhead? As you might guess, recalling our famous old shower curtain, the answer is, quite a crowd. Robb Dunn’s lab works at identifying microbes and meiofauna (microscopic invertebrates) in all parts of your home, from your undusted furniture to the antiperspirant of your armpit. Perhaps most intriguing is the great Showerhead Microbiome Project.

Do you ever unscrew the cap of your showerhead to find out what’s growing inside? Not very often. Yet you use the showerhead every day. A daily inoculation–just like all our evolution projects at Bacteria Lab Kenyon. You are running a lifelong evolution project, with your self as culture medium. All you need to do is swipe your scalp now and then, run a DNA prep, and send the contents to MR DNA.

Alternatively, you can send your showerhead water to Dunn Lab project. They plan to sample showerheads from “around the United States and Europe”–rather parochial, I suppose, but they might be persuaded to expand.

So what might we expect to find in the showerhead community? One quaint hypothesis is that we might find amebas, gobbling up the “nontuberculous mycobacteria” (the ones that don’t cause TB but do infect immunocompromised people). More prosaically, we might just find assorted pollen grains from pines and cedars. An early finding of Dunn Lab: the fungi in your home depend more on geography, whereas your home’s bacteria come from you. You may recall the microbial air print–that we can now identify who’s been in a room based on the bacteria they left in the air.

After showerheads, you can move on to the Sourdough Project. Find out the real reason different bakers make different tasting bread. (Hint: Do you have earwax?)

From our own microbiome to yours, we wish you all a Happy New Year.

 

Ross Sea: Protecting Antarctica

November 6, 2016

While some of us up North endure elections and Brexits, down under in  Australia the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) has been busy protecting one of Antarctica’s great treasures, the Ross Sea.

CCAMLR is a commission of 36 nations founded in 1982  to protect Antarctica and preserve this continent for science and future generations. This monumental agreement is all the more remarkable when you consider the size of Antarctica (larger than the USA) and the lousy state of the year 1982 (height of Reagan and AIDS). This commission has largely succeeded in protecting Antarctica from mining and harvesting operations. It has allowed the National Science Foundation (backed by unobtrusive US military forces) to largely administer access for biology, geology, and climate science.

But off the coast, it’s been another story, with fishing and whaling threatening the ecosystems of the Southern Ocean. This week, however, CCAMLR has reached agreement to put off limits an enormous swath of ocean known as the Ross Sea.

The Ross Sea is familiar as the region I crossed in the C-17 cargo hold on our way to McMurdo Station. McMurdo sits on the lava spit of Ross Island; in the above map, located at the edge of the ice shelf just below the words “Ross Sea Shelf.” The edge of the ice shelf is a magical region attracting thousands of penguins, seals and killer whales. On our final helicopter flight back from Taylor Valley, the pilot dipped and buzzed the shelf, startling pods of Adelies, Emperors and others for our last good look. The new CCAMLR agreement will protect more than a million and a half square kilometers of this ecosystem.

Meanwhile, back at Kenyon our own bit of Antarctica in our -80 freezer is yielding up secrets to the science of our supercomputer. Current projects include:

  • Discovering life forms capable of living half the year at forty below (where centigrade equals Fahrenheit)
  • Mining the microbial genomes for enzymes that make new antibiotics
  • Growing purple bacteria that store sunlight as hydrogen fuel–a stowaway colony from the mat stuff we picked up off the ice.

 

Nose Snot Antibiotic

October 8, 2016

lugdunin

Usually we look for antibiotics in exotic places such as Antarctica, aiming to find new drugs that no human pathogen has ever seen. But what if an antibiotic could be hiding in plain sight–or nearer yet, up your nose?

That’s what Alexander Zipperer and colleagues found, at the University of Tübingen. They focused on a pathogen Staphylococcus aureus, cause of serious skin infections including drug-resistant varieties such as methicillin-resistant Staph (MRSA). But S. aureus  has a surprising ability to hang out up the nose of healthy, unsuspecting carriers–that’s about one in three of us. Look to your right, then your left: One of you three’s got it.

So what keeps some of us healthy, despite this pathogen? The German researchers proposed there might exist some other nose-loving bacterium, part of our nasal snot microbiome–some bacterium that defends us from the bad ones. To find this white-knight defender, the researchers screened a collection of previously isolated nasal bacteria, cultured on a synthetic nasal medium (i.e. standardized snot). They tested individual isolates by dropping each culture upon a lawn of the tester strain Staph aureus. One isolate Staphylococcus lugdunensis showed a clear halo, a region where the tester Staph failed to grow.

The new S. lugdunensis was shown to produce a novel antibiotic, which they named lugdunin. Lugdunin (above) is a nonribosomal peptide; like vancomycin, the antibiotic is formed by a factory-modular enzyme that generates peptide bonds. Unlike ribosomal proteins, however, the nonribosomal peptide can contain all kinds of amino acids, beyond the canonical twenty. Lugdunin actually includes a thiazolidine, a unique five-membered ring including a sulfur atom.

So we may have a new antibiotic; or even a new probiotic, in the form of S. lugdunensis to inoculate our noses.