Throughout my research career, I have evaluated a variety of forcing functions (e.g. anti-orthostatic tail suspension, centrifugation, spaceflight, and radiation) for their effects on immunology. These areas of interest, particularly that of spaceflight, have derived primarily from my background in aerospace engineering. However, as specialized as this focus appears upon first glance, my research has involved a surprisingly wide array of technical fields. There are at least four ever-present and currently inescapable aspects of the spaceflight environment that may be responsible for changes in immune status. These include mission-related psychological (e.g. isolation, danger) and physiological (e.g. microgravity, changes in inertia) stress, low-dose/low-dose-rate radiation, and potentially dangerous levels of microbial contamination. Each of these concerns are already familiar to immunologists and clearly have terrestrial correlates.

As a student in the Department of Aerospace Engineering Sciences at the University of Colorado in Boulder, I was involved with several Space Shuttle, Space Station, and KC-135 experiments. Through this work, I was able to combine my interests in engineering and biology. The high point of these experiments, in terms of my dissertation work, was an experiment involving rats on the Space Shuttle. After graduating from CU, I started as a postdoctoral fellow in the Radiobiology Program (within the Department of Radiation Medicine) at Loma Linda University and Medical Center (LLUMC). Some years later, I was promoted to an Assistant Research Professor.

At LLU, I shifted the emphasis of my work toward the low-dose radiation environment, gaining experience with the proton accelerator at LLUMC and the high-energy physics facilities at Brookhaven National Laboratory. To date, my colleagues and I have completed and published a growing body of work characterizing basic immune parameters (e.g. population distributions, hematology, and blastogenesis) after whole-body exposure to a variety of radiation types ranging from g-rays and protons to carbon and iron, for time points ranging from 4 to 120+ days post-irradiation. We have also started working with a fairly accurate model of a solar particle event (SPE) based on “worst case scenarios.”

Additionally, I have had opportunities to continue some of my gravitational work. For example, I was involved with the first Space Shuttle flight to ever use a mouse model using NASA’s Animal Enclosure Module (AEM). The major goal of each of these studies paralleled those of my radiation work (i.e. to evaluate lymphoid cell and organ status). Ultimately, we would like to combine the two environmental stressors to more accurately model the spaceflight environment. We were honored and delighted when the manuscripts describing the spaceflight work were highlighted by the Journal of Applied Physiology in their Genetic Models in Applied Physiology series.

Now that this basic, mostly descriptive work has been completed, we have begun to explore the impact of radiation-induced changes on the ability to respond to a pathogenic challenge. Although I am only in the initial stages of this work, it has already proven to be both interesting and rewarding. I am primarily interested in system models that include radiation and E. coli challenge as forcing functions. Because the immune system is, by definition, a distributed system, any predictive model will necessarily be a distributed agent model. The effects of radiation on cell populations, cell-cell interactions, as well as cell-bacteria interactions, will be the primary agent actions. As the field of radiotherapy is growing, the need for such modeling will become more and more necessary. However, before such models can be developed, the biological effects of radiation must first be characterized. The two research areas below will provide much of the biological data necessary to begin to modeling the local and systemic effects of radiation on immunity.

Radiation and Innate Immunity: Microbes that present the most serious threat to immunocompromised individuals include Gram-negative intestinal coliforms such as E. coli, Klebsiella, and Enterobacter. These bacteria are also very common in nosocomial infections that often progress to septicemia. For these reasons, as well as the accompanying wealth of relevant literature, I selected a bacterial challenge as my disease model for all subsequent work. Because the response to E. coli typically involves innate immunity, I have limited the scope of my work to responses involving the macrophage. Ongoing work, using in vitro and in vivo models, suggests that radiation could impact several macrophage functions ranging from oxidative burst and phagocytosis to cytokine production and macrophage-T cell communication.

Out-of-Field” Effects: I am interested in the effects of brain-localized irradiation on peripheral immunity. Clearly, there are clinical implications for this work. In the last decade, proton radiotherapy has grown in popularity as a treatment modality for malignancies and other pathological conditions. Due to the physical properties of protons, clinicians are able to focus a beam of these charged particles on specific targets, more precisely defining treatment volumes (e.g. tumor mass, arteriovenous malformation). As a consequence, it is possible to safely deliver a higher dose to the desired target volume. The advantages of proton radiotherapy make it an ideal treatment option for primary brain tumors, as well as intracranial metastases from other tumor sites.

A critical concern of proton radiotherapy is the limited exposure to normal tissue surrounding treatment site. Given the high doses used to treat tumors or AVMs, the tissue adjacent to the treatment site will inevitably be exposed to at least low doses of radiation. Inclusion of a ≥1 cm margin around the known tumor mass, a procedure frequently implemented in radiation protocols for brain tumors, greatly increases the volume of exposed normal tissues. Furthermore, despite the ability to localize and minimize the treatment locus, clinicians would be well advised to keep “out-of-field” effects in mind when designing patient treatment plans. Through a variety of mechanisms (e.g., blood flow through the treatment area during exposure), radiotherapy will likely influence tissues beyond the limits of the site of exposure. We already have a series of studies planned, involving head-localized radiation and innate immunity, which will compliment the whole-body work described above. The next step will be to characterize and model the mechanisms involved in any radiation-induced changes in CNS-immune communication.