The scale is small, but the problem is huge. Most of your organs are locked in place – your heart never needs to be in your thigh – but the immune system has to be everywhere. When you cut your toe, breathe a virus into your lungs or eat a piece of contaminated spinach, the immune system needs to be johnny-on-the-spot with the inflammatory response.

Thankfully, there’s already an organ system that reaches just about every place in the body: the circulatory system. In fact, the red blood cells that carry oxygen through your blood vessels and the white blood cells that make up the immune system develop from the exact same precursor cells in the bone marrow.

A schematic of how different blood cells develop from a common stem cell

The blood vessels act as highways, rapidly moving cells around to the various locations in your body. For red blood cells, this is enough. They’re able to absorb oxygen in the lungs and dump it off in tissues that need it all while staying confined within the vessel wall. And a red blood cell is a red blood cell – there are a lot of them and they need to go everywhere, but it’s not important to get a particular red blood cell to a particular organ. But immune cells need to go to particular locations. It does you no good to send a macrophage to your lungs when you get a cut on your foot. In addition, immune cells can’t just fly by, they actually need to exit the bloodstream and move into the tissue to carry out their function. Both of these problems – getting to the right location and getting out of the bloodstream – are solved by the same set of 3 proteins.

Let’s start with the second problem: slowing down and getting out.

It’s tough to appreciate in the beginning of this video, but the blood flow is astonishingly fast – those vessels are packed with red blood cells moving so fast that you can’t see them. If you’re still thinking of blood vessels like a highway, the problem the immune cells contend with is like trying to take an offramp while traffic is moving at a few hundred miles per hour – they need to slow down.

To accomplish this, the cells lining the blood vessels can express special proteins on their surface called “selectins,” that are able to grab onto special sugars present on the immune cells. My apologies for the mixed metaphors, but you can think of this process like velcro – the immune cells are lined with the fuzzy stuff, and the blood vessel cells have the bristles that let them adhere. This interaction slows the immune cells down and allows them to roll along the vessel well, but it’s not enough to bring them to a halt. For that, the immune cells deploy another type of protein: integrins.

Integrins can exist in two different shapes. When they are inactive, they are folded over, and unable to interact with anything. But when the cell receives a particular signal (which I’ll get to in a minute), the integrin unfolds, and is able to latch on to specific partner protein.

The inactive integrin (left) is folded over and unable to interact with it's partner (ligand), but the active integrin (right) has an open conformation and can bind tightly

This binding between an integrin and its partner ligand (expressed on the blood vessel wall) is strong enough to fully arrest the immune cells, which can then squeeze through the gaps in between the cells that make up the walls of the blood vessel.

The final piece of the puzzle that you need to understand is what causes the activation of the integrin. Chemical signals called “chemokines” are produced by inflammed tissues, and these chemokines interact with receptors on the immune cells, telling them to extend their integrins in order to dock onto the vessel wall.

To recap: cells lining the blood vessel express selectins that bind sugars on immune cells, slowing them down and letting them roll along the vessel wall. Chemokines then signal to the immune cells that it’s time to activate their integrins, which can then grab tightly to the vessel wall, allowing the cell to stop and migrate across and into the tissue.

What I haven’t mentioned yet is that there are many different kinds of selectins, chemokines and integrins, and each of these different kinds have specific partners. This is the key to directing the immune response to a particular area of the body. First of all, only inflamed tissues will express the selectins necessary to get immune cells rolling. In the following video, blood vessels are black, and immune cells are white. In the vertical vessel, you can see immune cells slowing down and rolling, but if you watch carefully, you can see immune cells fly by in the two horizontal vessels, which don’t have the right selectin/sugar pair*.

Selectins and migration

The same principal holds true for chemokines and integrins as well – chemokines pair with specific chemokine receptors, and integrins pair with specific integrin ligands. Imagine you’re a T-cell that needs to get into the lung to do your job. You’ll express selectins that look for inflammation, chemokine receptors indicative of T-cells and a lung-specific integrin. On your way through the blood stream, you pass by a cut on the toe. The toe is inflamed, so your selectins bind and you start to roll, and the toe is looking for T-cells, so they express the right chemokines to activate your integrins, but there’s no ligand for your integrin. Since the integrin won’t bind, you won’t stop, and once you pass that area of inflammation, you’ll fly through the blood vessel again looking for the right combination.

Like a telephone area code, all three units have to be right to get where you’re going. In my example, the foot is San Diego (619) and the lungs are Boston (617) – two out of three parts are the same, but they take you to very different places. Using an almost endless combination of these three factors, the immune system has evolved to send the right cells to the right place, almost every time.

Prof. Benjamin Geiger of the Weizmann Institute and Prof. Joachim Spatz of the Max Planck Institute for Intelligent Systems, Germany are leading an unusual collaboration. One is a biologist, the other a materials scientist. Together, they are working on models that incorporate the whole gamut from completely man-made materials to 100% biological cells. In between, they are creating synthetic cells – artificial lipid membranes with a handful of proteins added in.

Of course much of human biology – growth and development, and cancer metastasis are the big ones – rely on these sensing and adhesion mechanisms, but Geiger and Spatz bring up some others: How certain cells sense blood flow, for instance, might affect the sticky buildup of plaques on artery walls. And they suggest that even before primitive cells began sticking together to form multicellular organisms, they probably formed some version of these complexes to adhere to other things – food sources, for instance.

The second article describes the postdoctoral research and future plans of Dr. Sarel Fleishman, who recently joined the Institute. Fleishman was in the protein design lab of Prof. David Baker at the University of Washington, Seattle, where he designed a protein that is able to block a wide range of flu viruses.

“Designed” is the operative word here: Fleishman and his lab mates showed that one can predict what is needed to selectively bind to a virus protein’s active site, create a detailed plan for a new protein structure to carry this out, and then actually shape that new protein according to plan on an existing protein base and even test it to see if it works. (Clearly, this one-sentence description makes it sound a lot simpler than it is.)

Geiger and Spatz have been moving toward synthetic cell adhesion models for several years – beginning with putting live cells on precisely designed synthetic substrates to see how they react. So the synthetic cells, in one sense, are the next logical step in their investigations. They are betting that this step will be a significant one, however, and the European Research Council is laying down bets too, in the form of a hefty grant.

Fleishman is now putting together his lab at the Institute. The protein he designed in his postdoctoral research is already on its way from the basic research bench to pharmaceutical R&D. We can’t tell you what the next protein to come out of his new lab will be, or even whether the designer anti-flu protein will eventually end up on pharmacy shelves. But we can tell you that this is just the beginning.

(via Ark in Space.)

(Also on FtB)

In 1993, convicted murderer Joseph Jernigan was executed in texas and his body donated to science. It was preserved in gelatin and sliced into 1,871 sections. Scans of these sections were strung together into an animation, and played back on a computer screen as it was swept across the field of a long-exposure camera shot. The result is these strange and haunting images of Jernigan’s ghost, floating in the twilight. More images can be found here, created by Croix Gagnon and Frank Schott.

Via Mo Costandi

Prof. Atan Gross has, for the past several years, been focusing on a pair of cell suicide proteins – BID and ATM. The more Gross studies these proteins, the more complex the picture appears. First, he found that the two are involved in both initiating cell suicide and preventing said suicide. His latest research shows that the same two proteins are also active in a completely different part of the cell’s life cycle – either preventing blood stem cells from differentiating or prompting them to differentiate. And there are hints that a much more convoluted set of connections may be lurking just outside the scope of his present framework.

Yet at the very heart of the story is a simple switch – an on-off connection between BID and ATM. ATM acts as a physical restraint on BID: When it stays around the cell nucleus, the status quo is maintained. When the two don’t connect, the unleashed BID molecule goes off to another organelle – the mitochondrion – where the small, destructive molecules known as reactive oxygen species are produced.  An excess of reactive oxygen species both kills the cell and initiates the differentiation of new replacement cells. To use an engineering concept, Gross describes the BID-ATM mechanism as a rheostat that senses the condition of the cell and regulates reactive oxygen species production accordingly.

That would seem to indicate a neat, elegant suicide mechanism. (Though not terribly simple: The cell nucleus and mitochondria are apparently in cahoots, and two very different activities – suicide and stem cell differentiation – are controlled by the same switch.)

Now for the real complexity: The various proteins in question, including the ones on the mitochondria involved in producing the reactive oxygen species, all have “day jobs,” working to maintain such metabolic functions as fat regulation. And here, says Gross, is where the idea of a unique suicide mechanism starts to get fuzzy. Rather than a special “cyanide pill” kept especially for the purpose of self-destruction, the cell does itself in by overdosing on everyday substances. Instead of simple switches, the molecules involved are something like people – they behave differently in different situations and are occasionally driven to desperate acts.

When mild-mannered BID exits the cell nucleus, it initiates cell suicide and saves the organism. But is that the whole story? Illustration: Elite Avni

Does this mean that the elegant model of a rheostat flies out the window? Not exactly. But it might be useful to think of it less as a component – something that can be isolated from a larger piece of machinery – and more as a cycle within a cycle.

Elegant engineering or a small part of a large, highly complex cycle? The question becomes especially relevant once we start to think about fixing or adjusting the mechanism to treat disease. Gross believes that the inherent connection he and his team are uncovering between the suicide switch and cell metabolism may eventually lead to new thinking about treating all sorts of ailments.

I was amazed to find out that there are bacteria in the ocean floor that have metabolisms roughly 10,000 times slower than those living at the surface of the seabed. This extremely slow lifestyle allows them to live for thousands of years. In fact, these microbes were found in a core sample of clay collected up to 20 meters beneath the seafloor of the North Pacific Gyre, just north of Hawaii. This depth means that the microbes settled on the ocean floor about 86 million years ago! While these as yet unidentified microbes rely on oxygen for survival, very little nutrients are available due to the large ocean currents in this area. Therefore, researchers have suggested they are still persisting off of food that arrived during the time of the dinosaurs.

Sources:
Scientific American

Roy H, Kallmeyer J, Adhikari RR, Pockalny R, Jorgensen BB, D’Hondt S. Aerobic Microbial Respiration in 86-Million-Year-Old Deep-Sea Red Clay. Science 18 May 2012:
Vol. 336 no. 6083 pp. 922-925.