Biomedical Science is Awesome

As this academic year comes to a close, I want to highlight some recent discoveries in the wonderful world of biomedical science. As I sit at my lab bench, bent over an ice bucket cluttered with FACS tubes, trying to make some small discoveries of my own (and get a PhD before I’m 30?), I’m motivated by all the awesome discoveries that are helping humanity live longer and healthier lives. I’ve said before that today’s transformative technologies are driving the future toward us at a ferocious pace; I believe this is equally true of our understanding of the biology of human health and disease.

The Awesome Side Effects of Vaccination

We know that vaccines work. They’re well-designed immune-training disease-defeating warriors. Recent studies have shown that, on top of teaching the immune system to defeat one specific disease, childhood vaccination can indirectly provide protection against additional diseases. Vaccination is the gift that keeps on giving!

One example of this phenomenon is the measles vaccine, which was first administered to children about fifty years ago. As intended, the rates of childhood measles plunged. What’s perhaps more interesting is that overall childhood mortality decreased up to 90 percent in the poorest areas of the world, a stunning number that cannot be accounted for by measles incidence alone.

The two major hypotheses for this observation were: (a) the measles vaccine stimulates an immunological gain of function that can provide off-target protection, and (b) the measles virus itself is somehow immunosuppressive, and the vaccine simply prevents that suppression from occurring.

De Vries and colleagues demonstrated evidence for the latter hypothesis in macaques in a 2012 publication in PLOS Pathogens (an open-access article if anyone wants to read it). They found that the measles virus preferentially infected macaque memory T cells and follicular B cells, both of which are important for immune memory (the heightened ability to fight a repeat infection). As soon as the immune system was able to mount an anti-measles response, all those infected cells were killed off, and with them memory of any pre-measles infection. The authors termed this systemic depletion of memory cells,  “immunological amnesia.” They also noted that the reason we might have missed this effect in the past was that a rapid expansion of measles-reactive T cells would have masked a global T cell depletion. Quality over quantity: the number of T cells in someone who has survived measles may be high, but the global repertoire is gone.

Fast-forward to a May 2015 publication in Science by Mina and colleagues from Princeton University. Using population data from England, Wales, the United States and Denmark from the decades surrounding measles vaccine introduction, these authors set out to find human epidemiological evidence that would support or refute the two opposing hypotheses: does the measles vaccine provide an off-target gain of immune function, or does it prevent the measles virus-associated loss of immune function?

The authors found that in the pre-vaccination decades of all four countries, childhood measles infection associated significantly with mortality from other infectious diseases for a prolonged period of 2-3 years. This association was tight enough that the rates of measles infection year to year could predict fluctuations in mortality rates from other infections. The authors argue that while the gain-of-function hypothesis cannot explain the pre-vaccine disease rate correlations, the prevention-of-immune-suppression hypothesis explains both pre- and post-vaccine rates of childhood infection and mortality.

In further support of this claim, these correlations did not exist when the authors applied the same analysis to the introduction of the pertussis vaccine; this makes sense, given that pertussis (whooping cough) is not known to have any immunosuppressive effects.

The authors conclude that: “Measles vaccination is one of the most cost-effective interventions for global health.” My conclusion – and I’m no statistician – is that in this case, getting the vaccine is basically a million times better than getting the disease.

Sources: Science, PLOS Pathology, NPR

But Wait, There’s More!

A really cool paper just came out of the Müschen group at UCSF, published in the May issue of Nature Immunology. They were interested in the origins of childhood pre-B cell acute lymphoblastic leukemia (pre-B ALL), as well as the observation that the common childhood vaccine against Haemophilus influenzae type B (Hib), which cause ear infections and meningitis, also protects against childhood ALL.

As they develop, T and B cells undergo genetic recombination events that can produce an unlimited diversity of receptors (in B cells, these are antibodies). This adaptive immunity allows one to prepare for unforeseen infectious attacks that one must survive in order to reach adulthood. If errors occur during these recombination events, genetic abnormalities can turn a B cell into a pre-cancerous cell, which can then expand into leukemia.

It turns out that very high levels of inflammation in infancy can contribute to the expansion of these pre-cancerous cells. This group showed that the enzymes involved in B cell genetic recombination events were hyperactive in the presence of the inflammatory cytokines of chronic infection. Early vaccination against Hib, and perhaps other bacterial and viral infections, prevents such aggressively inflammatory diseases – and, as an added benefit, cancer.

Sources: Nature Immunology, UCSF News

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