BY ACCIDENT and by design, human bodies are hard to break into. They are surrounded by defensive walls (the skin, the lining of the gut, the barrier between the bloodstream and the brain), patrolled by sentries (the cells and antibodies of the immune system) and filled with mazes, such as the intricate network of blood capillaries that connects the arteries to the veins, delivering food and oxygen to cells as it does so.

In a healthy body, all these things are good. But they can be obstructions to the treatment of an unhealthy one. The glamour of medical science tends to surround the process of devising and testing new therapies. But a therapy is worthless if it cannot be delivered. Researchers must therefore deal with the obstructions that evolution—unable to anticipate the advances medicine has made in recent years—has placed in the way of administering the therapies they have devised.

One of the greatest advances of the “heroic” side of medicine over the past few decades has been transplant surgery. Some 70,000 lives are saved every year by kidney transplants, and 30,000 others by heart, lung, liver and pancreas transplants. But recipients of such new organs have to pay a price. They must take drugs which suppress the activity of their immune systems—and thus their propensity to reject foreign tissues. Although these drugs keep them alive, they open their bodies to infection. A better way of subverting the defences put up by the immune system would thus be welcome.

Joseph Wu and Jeremy Pearl of Stanford University think they have come up with one. Past work on immune rejection has shown that a group of immune-system cells called T cells play a crucial role in alerting the immune system to the presence of transplanted organs in the first place. Using this insight, Dr Wu and Mr Pearl focused their attention on disrupting T-cell activity.

Disabling the sentries

For a T cell to become active, it must receive signals from another part of the immune system called an antigen-presenting cell. Antigen-presenting cells collect fragments of proteins from foreign bodies (normally pathogens, such as viruses and bacteria, but also transplanted organs) and show these to T cells, in order to tell them what to attack. However, before the alarm can be sounded in this way, proteins on the surface of the antigen-presenting cell and the T cell must bind together in what is called a cellular handshake.

Dr Wu and Mr Pearl realised that if they could stop the handshake happening, they would have a way of dampening the immune system's ability to detect transplanted organs. To do this, they used antibodies designed to bind to and thus decommission the molecules on T cells that are used to shake hands with antigen-presenting cells.

To test the effectiveness of these antibodies, the two researchers injected cells that belonged to one genetic population of mice into the leg muscles of mice from a different genetic population. The injected cells were genetically engineered to glow when exposed to ultraviolet light, for ease of detection.

In theory, the immune systems of the recipients should have rejected the transplanted cells, and among mice that were not treated with the antibodies this was indeed exactly what happened. However, the injected cells remained healthy in animals that were treated with the antibodies, and three months after drug treatment had ended these transplanted cells were even found to be replicating in some of the animals. Most importantly, when the drug-treated mice were later presented with other types of foreign material their immune systems responded rapidly. They had not, in other words, been permanently damaged by the antibody treatment.

Having proved that the technique works in mice, Dr Wu and Mr Pearl have now moved on to monkeys. If those tests go well, human trials should follow. But many mysteries remain. The biggest is why the new technique is able to make T cells unresponsive to just the specific tissues that are initially transplanted. For reasons that are not yet clear, when the T-cell-presenting system is reactivated by the gradual disappearance of the antibodies, it no longer seems to perceive the transplanted tissue as foreign. A lucky break, then, that may make organ transplants easier to carry out. However, tinkering with T-cell function is only a small part of what is being done to overcome the body's often-cursed refusal to be medicated. Doctors are also working to devise ways to smuggle drugs into the brain.

Are you member of the club?

In the early 20th century researchers realised that although simple injections into the bloodstream could get drugs to most parts of the body, the brain was almost always an exception. This led to discussion of the idea that the brain is protected in a special way and to the discovery of what is known today as the blood-brain barrier.

This barrier is the result of unusually tight junctions between the cells lining those blood vessels (particularly the capillaries) that run through the brain. Its role is to be exceedingly picky about what it lets through. Glucose and oxygen are permitted to pass quickly and easily, as are a handful of other proteins that are found on the barrier's exclusive members' list. Just about everything else, though, including the active ingredients of most medicines, is prohibited from entering.

“Defences protect a healthy body. But they can be obstructions to the treatment of an unhealthy one.”

William Pardridge, an endocrinologist at the University of California, Los Angeles, is trying to change that. He has spent years developing ways to breach the barrier so that medicines can be carried through it. His latest attempt is intended to provide protection against the damage caused by strokes.

In normal circumstances, when a stroke takes place, the flow of blood to a particular section of the brain is cut off. Starved of glucose and oxygen, brain cells in this section die, and that part of the brain stops working. In recent years, however, a protein called erythropoietin has been found to behave in a protective manner towards brain cells that have been cut off from blood flow. Exactly what it does is something of a mystery, but the result of its presence near brain cells that have been temporarily denied nutrients is that far fewer of them die.

Unfortunately, erythropoietin is not on the blood-brain barrier's membership list, so it has been impossible for doctors to use it as a drug to help stroke patients. Dr Pardridge and his colleagues have therefore been looking for a way to disguise it as a trusted member of the club, to enable it to gain admission to the brain.

They have looked at a number of proteins that are on the list and tried to identify one that they can attach erythropoietin to. And they think they have succeeded. They found what they were looking for in the form of an antibody to a substance called insulin-receptor protein. This is a chain-like molecule that has a cluster of atoms, called a carboxyl group, at one end of the chain. The researchers found that they could attach erythropoietin to the carboxyl group, and thus to the antibody.

And it works—in monkeys, at least. In a study on macaques, half were given erythropoietin on its own and half were given it attached to the antibody. Erythropoietin on its own could not, as expected, enter the monkeys' brains. When attached to the antibody, however, it was able to cross the blood-brain barrier and get to the cells that would need it in the event of a stroke.

Squeezing through the cracks

The blood-brain barrier, of course, is a deliberate defence, honed by millions of years of evolution. Some of the body's obstructions to treatment, however, are just accidents. Many drugs, for example, are not properly soluble, and tend to travel round as lumps of molecules. Such lumps are frequently too large to squeeze through the blood capillaries that carry food and oxygen into tissues, and carbon dioxide and other waste products out of them.

This is particularly true of a number of anticancer drugs, including paclitaxel, camptothecin, resveratrol and tamoxifen. When these drugs are crushed and mixed with liquids, they often form clumps inside blood vessels. This clumping tendency forces doctors to keep doses lower than would otherwise be desirable, to prevent a blockage from forming.

Yuri Lvov, a chemist at Louisiana Tech University, and Vladimir Torchilin, a pharmacist at Northeastern University in Boston, think they have found a way round this. They blast the drugs into small pieces with sound waves, then wrap the pieces up in chemical blankets so that they cannot reform into larger lumps.

The two researchers, along with a team of colleagues, took powdered paclitaxel, camptothecin, resveratrol and tamoxifen and put them in water. They then blasted each mixture with powerful sound waves for up to an hour, to break the drugs up into tiny bits. At the beginning of this process, the drugs were mixed with a solution of positively charged polymers that were expected to wrap around the smashed-up bits of drug and prevent them from reaggregating. Towards the end of the sonic battering, the researchers added a different set of polymers—negatively charged ones. They hoped that these would interact with the positive polymers to form a stable shell. Sure enough, they did.

The upshot was to reduce the size of the drug particles as much as a thousandfold—from microns to nanometres across. They were then small enough to travel through the tiniest blood vessels in the body, and were thus able to penetrate to the very heart of a tumour. More importantly, the particles did not re-aggregate. Each was kept separate from the others inside its two-layered polymer bubble.

Initial tests on animals indicate that these bubbles (or nanocapsules, as the team calls them) are safe and effective. If human trials confirm this, it will allow doses of anticancer drugs to be optimised. And another barrier, both literal and metaphorical, to the effective treatment of disease will have been overcome.