2 kinds of mole rats, 2 different cancer-fighting techniques

Did you know there are two (at least) kinds of mole rats? I didn’t until recently. Here they are:
Blind mole rat
Naked mole rat

Beautiful creatures, aren’t they?

Well, they’re fascinating anyway. Naked mole rats have been shown to be cancer-resistant. Their cells are programmed to cease division when they sense they are getting too crowded. So any cancerous cells that develop will eventually crowd themselves out of dividing any further, “contact inhibition,” as the shop talk goes. Basically, the cancer cells keep quiet about their identity, and do no harm.

Recently, in a paper by a team at the University of Rochester, blind mole rats are shown to also have cancer-fighting properties. However, it seems their potential cancer cells take a different tack. When they sense they have divided more than a normal amount of times, they kill themselves with their form of a cyanide capsule: a protein, IFN-beta. Rather than risk wreaking havoc on their sister cells, they take themselves out of the picture.

It’s exciting to think that perhaps these discoveries will help us unleash  hidden knowledge our own cells have. Or to simply help develop a novel drug.

Of course, it’s absurd to think the cells have “free will” as I have analogized. Nonetheless, I couldn’t help thinking about Battlestar Galactica when thinking about cells discovering they were something else. By the way, if you haven’t seen it, don’t wait around, just do it.


Protein Folding

I’m currently in the process of going through a monstrous stack of periodicals I’ve accumulated, including the magazine Physics Today, which comes with my APS membership.

This article by Ashley Smart is simply a research summary on experiments on proteins.

But Smart evoked a lot of thoughts about proteins. We need them to be folded correctly to work, but how are they folded? How is this the minimum energy state.

Smart’s description of various denatured (unfolded) proteins reminded me a lot of the language used in the glass/jamming community. A fried egg consists of proteins denatured by heat. A similar transition happens for
“glassy” systems: raise the temperature and the material will flow.

Mechanical stress can cause also cause the protein in egg white to denature, resulting in a foamy, stiff, meringue. In jammed systems, like mayonnaise, mechanical stress (i.e. using a butter knife) causes the material to unjam (i.e. deform and spread on the sandwich).

The third variable discussed in the jamming community is volume fraction, which I won’t delve into here. The third variable for the egg example is acidity, mixing egg whites with lime juice will also cause the proteins to denature. Completely different, can’t win ’em all.

What also drew me into this simple piece was the description of the experiments. (Smart does a commendable job of trying to explain the math in words.) There are two processes that contribute to the overall signal the researchers measure, only one of which relates to protein folding. But if you change the temperature, each process responds on a vastly different timescale.Taking measurements at the right frequency and using a trick of derivatives, they can isolate the process of interest. An experiment like this would be a great lab in a biophysics class.

Naked Mole Rats FTW

I have seriously been told I resemble a naked mole rat when I’m roused from sweet, sweet slumber. My eyes refuse to open, and I burrow under the sheets. I’m pretty pale and mostly hairless, too.

While I hope I don’t resemble a naked mole rat in all ways (a bit on the uncomely side) I think there’s reason to hope my cells act like their’s.

Naked mole rats never get cancer.

It appears they don’t get cancer because their cells experience “contact inhibition.”

Humans get cancer quite a bit, and the odds increase as we age. The chances of a cell switching to cancerous increase, simply because we’ve given them more chances to do so. Lab mice get cancer about 70% of the time, if allowed to live for several years.

Human and mouse cells experience this contact inhibition phenomenon as well. Cells divide and fill up the space they’re in. Once they touch, they generally slow down their division; there are enough cells.

Cancer cells don’t have this contact inhibition, and grow wildly, unchecked.

Naked mole rat cells, when studied in the lab, exhibit a super kind of contact inhibition – cell division completely stops when cells touch.

In the future, perhaps we can identify what causes this, and turn on a switch in our own bodies if we suspect we have cancer.

Real nanobots !!!! (???)

With fancy chemicals being developed for new medicines, a question remains: how can we deliver the most bang for the buck? It would be ideal to have a microscale delivery truck, capable of delivering the drug to the precise location needed. This would also eliminate many side effects experienced through a general delivery of the drug.

 Catalytic nanoswimmers are being researched as potential cargo vehicles. They are tiny spheres, with one half coated with a reactive material. This side reacts with chemicals in the environment, and the energy of reaction is transmitted into motion forward. Attach a blob of drug to them, and they can move medicine. But questions remain about how to get them to go a specific direction, without having to babysit them. Can we make these trucks driverless?

One way to direct these particles is to establish a fuel concentration gradient. The particles will be ‘attracted’ to the hot spot, though they have no free will.

In a recent paper, researchers say while this approach is interesting, it can’t be the solution. After all, the fuel molecules are not necessarily always the signal you want the swimmers to react to.

They explore another signal: a pH gradient.

Hydrogel particles can swell or shrink in size when the acidity of the environment changes. Particles are  smaller in high acidity, and larger in low acidity. By exposing hydrogel catalytic swimmers to a pH gradient, the team was able to accumulate the swimmers in high pH regions. Cancer cells, as an example, can cause acidity changes.

So why does this accumulation happen? First, the high pH makes the particles larger, which makes their diffusion – the random motions experienced at the microscale – slower. Thus (smaller) particles in low pH regions will be kicked out more often, and settle in the high pH region. The smaller particles also undergo more (random) rotational motion, and this ends up being a double whammy for remaining happy in low pH regions.

I was struck by this paper as it was in nice contrast-and-compare to the run-and-tumble motion of E. Coli. bacteria, as is mentioned in the paper. Both systems are governed by the same physics, at the same scales. E. Coli turns its motor off to tumble and rotate, and figure out where the food is. It then turns the motor back on when it finds somewhere to go.  The catalytic swimmers have no such on/off switch, but can still get to where they need to go.

Adhesion, Geckos, and Technology

One of our earlier experiences with science comes in kindergarten. The teacher brings out the Elmer’s glue and we put macaroni on construction paper. The white viscous stuff acts to permanently bond the paper and pasta. As children we’re ignorant of the science beneath this and view glue as magic stuff. But if we could zoom in to resolve the detail, we’d see the long squiggly polymer molecules in the glue are grabbing onto the fibers in the paper as well as the starch fibers in the macaroni. The glue acts as an adhesive.

Adhesion refers to whether or not two different surfaces stick together. [Aside: cohesion refers to how molecules within a substance are attracted to one another, one might think of it as ‘self-stickiness.’] In our glue example, there are actually two interfaces of adhesion, the glue/paper and the glue/macaroni. There are different varieties of adhesion. There is chemical adhesion, which involves actually forming a new bond between the molecules of each surface. There is the physical, grabbing adhesion of glue mentioned before. There is adhesion due to electric charge. That static cling sticker dedicated to your alma mater on your car window uses this kind of adhesion. There is even yet another type of adhesion. Even if there is no chemical bond, polymer grabbing, or charge attracting two surfaces, there is still likely to be a force of adhesion called “van der Waals” adhesion. The precise details of van der Waals adhesion will not be explored here, but it is the same van der Waals interaction (sometimes referred to as ‘London dispersion force’) many learn about in high school chemistry. Van der Waals adhesion can be surprisingly strong, as we will see.

Geckos are quite amazing in their ability to perform seemingly impossible feats of climbing. They can even easily climb up and down a smooth glass aquarium cage, a surface with no obvious footholds! Yet if you hold a gecko in your hand their feet don’t feel especially sticky. Each of their toe pads is covered with about 100,000 setae, basically short hairs. The setae then split into hundreds of tips, each about 200 nanometers in diameter. These setae tips are what touch the glass, so there must be some type of adhesion between the tips and the surface to support the gecko’s weight. Autumn and coworkers [1] cleverly demonstrated the exact nature of this adhesion. Since they produce no glue, chemical and physical mechanisms were not on the table. However, there were two dry adhesion candidates: charged and van der Waals. The team let the geckos crawl up and down smooth surfaces that were charged differently. They performed equally well on both surfaces, pointing to van der Waals adhesion as the culprit.

However, since this adhesion is strong enough to keep the gecko firmly affixed to a wall, then how do they unstick? Geckos can crawl quite quickly, so there must be an unsticking mechanism in place. The same group came forth [2] to answer this question. With a series of experiments (including forcing a gecko to hang by one toe) the team showed that the setae tips are angled. This has the net effect of increasing the adhesion forces when at they are on surfaces at steeper angle: the setae tips become stickier as needed! Further, the angled attachment affords easy detachment: there is essentially no force required to move the foot up. They also have a “reverse gear” in their back feet for moving down surfaces, where the tips are oriented in the opposite direction.

Recently, Suh and coworkers [3] have been trying to recreate this remarkable gecko adhesion synthetically. After all, this adhesion has many desirable qualities. It’s strong, yet completely reversible. It can adhere to various degrees of surface roughness and any surface orientation. These qualities are especially suited to precise tasks such as moving and manipulating sensitive electronic components. The group was able to fabricate 200 nanometer plastic ‘hairs’ on a flat surface, resembling the setae tips of the gecko. These hairs were angled as well, and a 1 inch patch of them was capable of transporting a piece of glass that was 300 times that large! However, this system relies on needing to hit the hairs at the correct angle, and so is really a passive adhesion mechanism. While the gecko uses the same basic mechanism, it is actively controlling the contact with its muscles. Unfortunately, the synthetic version would not be suited to any complex task.

So while originally inspired by the gecko, the group ultimately developed a better system for practical use [4]. They stretched out a thick sheet of rubber and treated it with a reactive gas, so only the top surface was modified and became stiffer. When the sheet was allowed to relax, it went back to its original size. However, the top surface was no longer happy in this state, and created a wrinkly pattern on the surface, like a shallow egg crate. They then stretched it again, and put small (1/50th of a millimeter) pillars on the surface. So, when the sheet is relaxed, the pillars do not stick straight up, rather they are at odd angles due to the wrinkling, and when stretched they stick straight up. This creates a simple on/off adhesion mechanism. In the stretched state, the top of every pillar can make good contact with another surface, and in the relaxed state, none of the pillars can. They were able to pick up and move the same piece of glass in a complex choreography, all without leaving the even the slightest trace on the surface.

[1] Autumn, K. et al. PNAS 99, 12252 (2002)

[2] Autumn, K. et al. Journal of Experimental Biology 209, 3569 (2006)

[3] Suh, K.Y. et al. PNAS 106, 5639 (2009)

[4] Suh, K.Y. et al. Langmuir 26, 2223 (2010)

How DO bacteria swim with no arms?

You had to skip breakfast today. To compound your misery, a delicious smell
permeates the office. Who ordered pizza? Your stomach growls. You wander around
the hallways and follow your nose to the source of the smell. A few boxes sit unat-
tended in the conference room. A sign in your boss’s handwriting threatens, “DO
NOT EAT.” You sneak a slice anyway, undetected. How do bacteria find food when
they are hungry? It turns out, even though they don’t have noses, they use a simi-
lar tactic. They sense the direction of nutrients by sampling their external chemical
environment, then swim in the appropriate direction. The entire process is called
chemotaxis. While the process of bacterial “smelling” is interesting on its own, the
simple act of swimming is also worth studying.

In a recent issue of the journal Proceedings of the National Academy of Sci-
ences, researchers at the University of Pittsburgh led by Professor Xiao-Lun Wu
reported on the swimming of the bacterium Vibrio alginolyticus and contrasted it to
the swimming of the well-known E. coli bacterium. V. alginolyticus is a species of
marine bacteria. You may be come infected with it if you eat some bad sushi. The
team took high-speed videos of the swimming motions of both bacteria and found
intriguing results.

The swimming of E. coli bacteria has been studied for quite some time, and
the team found nothing surprising there. E. coli bacteria are quite familiar to us as
they live in our lower intestinal tract. Each bacterium has a cigar-shaped head and a
bundle of corkscrew shaped tails called flagella. The bacterium propels itself forward
by turning the corkscrews counterclockwise together. To change direction, some of
the corkscrews start turning clockwise, ending the forward “run.” The bacterium then
rotates or “tumbles” randomly due to external kicks from its environment. During
this tumbling, it “smells” each angle and finds the best direction to run next. If it’s
already near a source of food, the bacterium alternates between these two motions in
a complicated dance to keep itself close.

This run-and-tumble pattern works for E. coli, but cannot work for all forms
of bacteria. Some bacteria, such as V. alginolyticus, are cursed with only one tail.
At face value this may not seem like too much of an impediment. However, due to a
mathematical constraint (the scallop theorem) these bacteria can only propel them-
selves forward or backward, and so cannot enter the neutral tumbling state to change
direction. So singly-corkscrewed bacteria must alternate forward and backward steps
until they happen to be in the right direction they want to be. It’s similar to wiggling
out of a parallel parking space. Since turning is theoretically so inefficient, one would
expect chemotaxis to be a slow process for these bacteria.

But Dr. Wu’s research team found a surprising result when they studied V.
alginolyticus. While the bacterium undergoes run-and-reverse motion as expected, it
also undergoes a previously undiscovered third motion: the flagellum flicks quickly
like a whip, which reorients the bacterium in a random direction in less than 1/20
of a second. This active reorientation is much faster than the passive tumbling of E.
coli. Also, since these bacteria can move backwards (unlike E. coli ) they can precisely
regulate their position more easily: if they overshoot, they can always go back. In
fact, when they compared V. alginolyticus and E. coli head-to-head, V. alginolyti-
cus reached the nutrients about three times faster than E. coli. Additionally, since
they can control their position more carefully, swarms of V. alginolyticus are able to
congregate in much tighter groups (about 7 times as dense) and so maximize their
nutrient dose per organism.

But don’t feel sorry for E. coli. It lives in the relatively utopian environment
of our intestines. Food is plentiful and there are no fast flows disrupting the bacteria
or the nutrients. Contrast this to the native environment of V. alginolyticus. Food is
scarce and harsh ocean currents can wash it away in an instant. The bacteria abso-
lutely must be efficient in order to live. In short, both species seem to have adapted
solutions appropriate to their natural habitat.

The research team does not currently have an explanation for the mechanics
of the novel flicking behavior of V. alginolyticus. However, they do propose that this
could be a widespread feature of marine bacteria due to the previously mentioned
need for efficient scavenging. Finally, while these details of bacterial motion are
interesting from a fundamental research perspective, this work also carries greater
consequences. If we can gain a better comprehension of how bacteria move, we can
possibly come up with new ways to keep them from spreading. Perhaps in the future
we can simply introduce physical obstacles that prevent bacteria from swimming,
as opposed to resorting to antibiotics. And as bacteria can develop a resistance to
antibiotics, humans can easily become desensitized to threatening notes. So, if your
boss really wanted to prevent you from stealing that pizza, a simple locked door would
have been a more suitable countermeasure.

How do you make a nanobot?

Here is an essay I wrote while reflecting on and researching a lecture I heard by Yale Goldman, Professor of Physiology at the Pennsylvania Muscle Institute, and associate director of the NBIC at Penn.

How do you make a nanobot?

Imagine you are playing with a set of Legos. This set is one of the newer

ones. It has all kinds of blocks, gears, wheels, pulleys, batteries, etc. Put different

combinations of them together and you can build a house or maybe if you’re feeling

clever, a machine. Suppose you make a small battery-powered car. Imagine shrinking

this car. As it shrinks, the number of atoms in each Lego block must become fewer.

Eventually, you may reach the limit where each block is one atom. What if we could

make machines like this?

Eric Drexler had this vision in his 1987 book Engines of Creation: The Com-

ing Era of Nanotechnology. He imagined if we could manipulate atoms like Legos,

we could build nanomachines from the ground up, atom by atom. One could create

different kinds of machines by simply using different assemblies of atoms. Drexler

hoped that these “nanobots” could be used to do all sorts of things, like deliver drugs

to specific sites within the body. Micheal Crichton in his 2002 novel Prey envisioned

these nanobots existing, but in a typical Crichton ending the bots take over and kill

us. While Drexler’s vision is intriguing (and Crichton’s vision is scary), these hopes

(fears) should be looked at skeptically. For starters, it’s simply not possible to build

nanomachines using Drexler’s scheme.

Why is this? Consider a Lego block floating in a cup of water. This block is

surrounded by water molecules. The water molecules are constantly jostling about

due to a phenomenon called Brownian motion. You won’t see the effect of this phe-

nomenon with the Lego. Change the Lego to a speck of dust. The dust is much

smaller than the Lego and so is more affected by the jostling of the water molecules.

(You can actually see the dust being randomly jiggled around if you do this experi-

ment.) Now, imagine changing the speck to a single sugar molecule, comparable in

size to the water molecules. What was gentle jiggling of the dust translates into vio-

lent jostling of the sugar molecule. In fact, the sugar molecule collides with the water

molecules about a trillion times per second! So we really can’t place atoms together

in an orderly fashion like we can with Legos: the wind is too strong. In brief, the

nanoscale is a much harsher environment than the macroscale.

Despite the seemingly impossible construction challenge of Brownian motion,

nanomachines are ubiquitous. They are around us and already inside of us! Fear not,

as they are supposed to be there. They are naturally occurring biological molecules

that keep us functioning. So in order to make artificial nanomachines, we might need

to steal ideas that nature is already using. Biological nanomachines make use of a

few tricks, that scientists one day hope to copy. First, their molecular makeup is pre-

programmed by a DNA sequence. Secondly, they undergo self-assembly to make up

their final shape. Lastly, they use the Brownian motion of the surrounding molecules

to their advantage rather than detriment.

One example of a natural nanomachine is myosin. There are several different

varieties of myosin. They are all motor proteins that “walk” along long actin fibers.

All myosins are actuators, machines that convert one form of energy to another. Like

the motor in a battery-powered car converts electrical energy into motion, myosin con-

verts the energy of a chemical reaction (ATP to ADP) into motion. Clearly myosin

is a great model nanomachine to study for future technology. One common variety

of myosin (II) is responsible for flexing our muscles by sliding the filaments against

each other. One variety (V), is responsible for moving large amounts of cargo along

actin fibers. Myosin V has two “hands”, and seems to move hand-over-hand along

actin, similar to a child on monkey bars [Corrie, J.E.T., et. al. Nature 422, 399

(2003)]. However there does seem to be a key difference. The child on monkey bars

releases one hand, then does a power stroke with the free hand to get to the next

rung. Myosin does the same motion, but its power stroke only takes it 2/3 of the

way. It then lets the Brownian motion of the surrounding water push the rest of the

way [Shiroguchi, K. et. al. Science 316, 1208 (2007)]. By taking advantage of this

Brownian motion the efficiency of the system is about 50%, very comparable to an

electric motor!

While artificial nanomachines are still only a vision, it’s clear that natural

nanomachines are excellent prototypes. Unfortunately, our technology is not at the

stage where we can really imitate them. What scientists can do (and are doing now)

is try to understand more deeply how these fascinating natural nanomachines work,

and use this understanding to inform future technologies.

[1] Drexler, Eric. Engines of Creation: The Coming Era of Nanotechnology, 1987

[2] Crichton, Micheal. Prey, 2002

[3] Goldman, Yale. “Nature’s Nanotechnology: Biomolecules Explored One at a Time” Penn Science Café Lecture, 20th October 2010.

[4] Corrie, J.E.T., et. al. Nature 422, 399 (2003).

[5] Shiroguchi, K. et. al. Science 316, 1208 (2007).

Cartoon of still SEM images of myosin processing along actin from: Matthew L. Walker, Stan A. Burgess, James R. Sellers, Fei Wang, John A. Hammer III, John Trinick & Peter J. Knight. Two-headed Binding of a Processive Myosin to F-actin. Nature, 405, 804-807 (2000).