h+ Magazine

Winter 2009.

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Page 51 of 89

ARTwORk COURTESy Of dERyA UnUTMAz Md 52 winter 2009 Swine Flu. Spanish Flu. SaRS. almost every year, it seems, there is a new virus to watch out for. Roughly thirty thousand americans die annually from a new flu strain — meaning roughly one flu fatality for every two victims of car accidents — and there is always the possibility that we will do battle with a much deadlier strain of flu virus, such as the one (cousin to the current swine flu) that killed 50 million people in 1918. Currently, our bodies' responses are, almost literally, catch as can. The immune system has two major components. Innate immunity responds first, but its responses are generic, its repertoire built-in and its memory nonexistent. On its own, it would not be enough. To deal with chronic infection and to develop responses targeted to specific pathogens the body also relies on a second "acquired immune system" that regulates and amplifies the responses of the inbuilt system, but also allows the body to cope with new challenges. Much of its action turns on production of antibodies, each of which is individually tailored to the physical chemistry of a particular alien invader. In the best case, the immune system creates an antibody that is a perfect match to some potential threat, and, more than that, the acquired immune system maintains a memory of that antibody, better preparing the body for future invasions from the same pathogen. Ideally, the antibody in question will bind to — and ultimately neutralize or even kill — the potentially threatening organisms. Alas, at least for now, the process of manufacturing potent antibodies depends heavily on chance, and a type of lymphocyte known as B cells. In principle, B cells have the capacity to recombine to form a nearly infinite variety of antibodies: roughly 65 different "v regions" in the genome can combine with roughly 25 "D regions" and 6 "J regions," which further undergo random mutations. In practice, getting the right antibody depends on getting the right combination at the right time. Which combinations emerge at any given moment in any given individual is a function of two things: the repertoire of antibody molecules a given organism has already generated, and a random interplay of combination and mutation that is much like natural selection itself — new B cells that are effective in locking onto enemy pathogens persist and spread; those that do a poor job tend to die off. unfortunately, there is no guarantee that this system will work. In any given individual there may be no extant antibody that is sufficiently close. If there is a hole in a given individual's repertoire, that individual may never develop an adequate antibody. Even if there is an adequate starting point, the immune system still may fail to generate a proper antibody. The most useful mutations may or may not emerge, in part because the whole system is governed by a second type of immune cell known as the T cell. The job of T cells is to recognize small fragments of viral proteins as peptides and then help the B cells produce antibodies. like B cells, T cells also have a recombinative system, generating billions of different receptors, only a few of which will recognize a given viral antigen. In effect, two separate systems must independently identify the same pathogen in order for the whole thing to work. At its best, the system is remarkably powerful — a single exposure to a pathogen can elicit a protective antibody that lasts a lifetime; people who were exposed to Spanish flu in 1918 still retain relevant antibodies today, 91 years later. (See Resources) But the system can be hit-or-miss. That same Spanish flu claimed 50 million lives, and there is no assurance that any given person will be able to generate the antibodies they need, even if they are vaccinated. IMMUnITy 2.0 For now, the best way to supplement the body's own defenses is through vaccines, but vaccines are far from a panacea. Each vaccine must be prepared in advance, few vaccines provide full protection to everybody, and despite popular misconception, even fewer last a lifetime,. For example, smallpox vaccinations were lifelong, but tetanus vaccines generally last 5-10 years. There is still no vaccine for HIv infection. And when it comes to bacteria like tuberculosis, current vaccines are almost entirely ineffective. What's more, the whole process is achingly indirect. vaccines work by first stimulating B cells and T cells in order to induce production of antibodies. They don't directly produce the needed antibodies. Rather, they try (not always successfully) to get the body to generate its own antibodies. In turn, stimulation of T cells requires yet another set of cells — called dendritic cells — and the presence of a diverse set of molecules called the major histocompatibility complex, creating still further complexity in generating an immune response. Our best hope may be to cut out the middleman. Rather than merely hoping that the vaccine will indirectly lead to the antibody an individual needs, imagine if we could genetically engineer these antibodies and make them available as needed. Call it immunity-on-demand. Re-engineeRing thehuman immuneSyStem DERYA uNuTMAz AND GARY MARCuS

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