On the State of the Species: pushing ahead in the race against infectious diseases

by Charles de Bourcy

Lush is the diversity of life forms on Earth, unrelenting their struggle for survival.

From the fluorescent pygmy scorpion hiding in tree bark to an underwater feeding frenzy in front of the island of Nusa Lembongan, all observations on our naturalist expedition to the Malay Archipelago in August 2014, led by Rob Phillips from Caltech, point to this truth. We are in the region of the world where Alfred Russel Wallace first wrote down his thoughts “on the tendency of varieties to depart indefinitely from the original type” more than 150 years ago: spontaneously occurring differences between organisms may facilitate or impede their survival, and if these variations are heritable then the selection imposed by environmental pressures will cause the advantageous traits to become more prevalent among the population. As we embark on a boat to cross the Strait of Lombok, retracing Wallace’s itinerary, one question occupies me. Have humans elevated themselves above this paradigm, the paradigm of natural selection?

Lush is the diversity of life forms on Earth, unrelenting their struggle for survival: shoal of fish near a coral reef in Indonesia. (Photo courtesy of Rob Phillips.)

We like to think that the answer is Yes in some respects. Two examples: women with unreceptive cervical mucus and men with low sperm count may reproduce thanks to artificial insemination; individuals who would be unfit to procure food by foraging in the wild can survive thanks to farming and food distribution systems. Ignoring for a moment the catastrophic unevenness of access to the resources afforded by modern technology, we can ask which fundamental challenges to our existence we are still facing.

The Ebola virus outbreak in West Africa is a recent and horrifying reminder that we do have some last remaining natural enemies: disease-causing viruses and bacteria. In what follows, we examine how they affect humans and how we may assist the human immune system in protecting us against them.

As far as bacterial infections are concerned, current generations have been lucky to live in a slice of history in which antibiotics have been effective, making formerly deadly diseases like pneumonia, tuberculosis and childbed fever curable. However, disease-causing bacteria are in a never-ending evolutionary arms race with us. They naturally come in different varieties and acquire random genetic mutations as they multiply. Whenever we use antibiotics on them and do not succeed in killing every last one, we will have selected the ones that are most resistant to the antibiotic for proliferation. The penicillin drug that saved so many lives from Staphylococcus aureus infections following its introduction around 1930 has become ineffective against these bacteria in most cases, and it is becoming clear that resistance even to our current “antibiotics of last resort” is spreading, calling urgently for more research into new types of antibiotics and adoption of better usage practices.

Rapid evolution occurs not just in bacteria, but also in viruses. For example, the replication and mutation rate of HIV is so rapid – of the order of billions per day per patient – that there is tremendous viral diversity even within a single infected patient when left untreated. Because the virus is constantly changing its characteristics, most infected patients’ natural body defenses are unable to get a hold on the infection; combinations of drugs interrupting the virus’s life cycle at different stages and via different mechanisms are necessary so that mutations resisting one of the drugs will still be kept in check by the other drugs and vice versa. The viruses that cause influenza also evolve rapidly from year to year, which is why in each flu season we are at risk of getting sick anew even if we are protected against past strains.

How can we gain the upper hand on infectious pathogens? Well, the human body already has a natural set of defenses, called the immune system. In particular, the adaptive immune system produces a highly diverse set of long molecules, called antibodies, that can bind to appropriate regions of specific pathogens, interfere with their functioning and tag them for destruction. When presented with a new disease agent, the adaptive immune system evolves by trial and error to produce better and better antibodies against the intruder, and these can then be recalled in future encounters with similar agents. Thus, one way to gain an advantage in the race against infectious diseases is to seek an in-depth understanding of both the disease agents and the human immune system, and prepare the immune system to better deal with the most dangerous pathogens by means of vaccination.

DNA sequencing and mathematical-computational analyses are ever such promising tools in this endeavor.

Figure 2

Example visualization of a small subset (some 30000 molecules) of a human antibody repertoire. Each spot corresponds to a particular antibody (with its own DNA sequence); the size of the spot indicates in how many copies the antibody was present. Antibodies that are so similar that they are believed to form a lineage originating from one and the same initial blood cell are connected by lines. The colors serve to distinguish between different categories (“heavy-chain classes”) of antibodies. (Image courtesy of Felix Horns.)

For example, in order to improve the efficacy of flu vaccine design, one would need to be able predict the evolution of flu strains from one year to the next – a formidable task considering the randomness and complexity inherent in the process. However, now researchers have taken a step in just this direction: having devised a mathematical model incorporating the fitness advantages and disadvantages of mutations in certain regions of a flu virus, they were able to correctly predict in most cases which groups of related strains would become more or less common in any given year by training their model on data from the previous years.

In the Quake laboratory, we use genetic sequencing to access the highly personal repertoires of antibodies found in the blood of volunteers, determined by genetic factors and history of pathogen exposure. Such an approach allows quantitative characterizations of adaptive immune responses at an unprecedented level of detail, down to the compositions of the antibodies and the ancestral relationships between them. For example, we can see which antibodies are produced in response to flu vaccination, which ones are recalled from one year to the next even when the vaccines differ, and how the responses of young and elderly patients compare. By analyzing and modeling these personal antibody repertoires using mathematical, computational and statistical techniques, we hope to identify the parameters that determine immune health and develop new ways of assessing the state of a patient’s immune system. This could point to new avenues for engineering the structure of the immune system so that it is neither overactive (as in diseases in which immune cells attack the patient’s own body) nor underactive (which increases susceptibility to infectious diseases).

By complementing the mechanisms of the immune system with the power of reasoning, we may just be able to outsmart bacteria and viruses in our evolutionary struggle against them, and come closer to rising above natural selection.

Charles de Bourcy is a 2012 fellow of the Fulbright Science & Technology Award, from Luxembourg, and a PhD Candidate in the Applied Physics Department at Stanford University.

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