Systems biology and red cells.

n engl j med 364;4 nejm.org january 27, 2011 376 The remarkable advances in molecular and cell biology over the past half century have revealed layer upon layer of biologic complexity. It has even been suggested that we are reaching a stage at which further progress may be beyond the scope of human imagination, that these branches of science — like physics in its endless search for a unifying theory for the basis of the universe — may be at an impasse.1 A more optimistic view suggests that if we apply the mathematical approaches of systems biology, many of these problems may be solvable, although Sydney Brenner has criticized this approach, suggesting that we first try to understand the organization and regulatory biology of individual cells.2 The relevance of systems biology to the interplay between the basic and clinical medical sciences was recently highlighted in a report by Higgins and Mahadevan.3 They used a systemsbiology approach to analyze the physiologic and pathologic population dynamics of circulating human red cells. The mechanisms that regulate the number, size, and hemoglobin concentration of normal red cells in circulation — and how these go awry in anemia — are not well understood. It has been established, however, that after their release from the bone marrow red cells undergo a reduction in their volume and total hemoglobin content. To approach this problem, Higgins and Mahadevan used theory from statistical physics together with standard red-cell indexes derived from electronic cell counters to develop a master equation for the maturation and clearance of red cells. Their mathematical model implies that the total number of red cells added to the circulation equals the number removed and suggests that there is a threshold for the mean cellular hemoglobin concentration below which most red cells are cleared from the circulation (Fig. 1). Quite remarkably, this model appears to clearly distinguish the dynamics of red-cell populations in normal persons from those in persons with anemia of chronic disease, iron deficiency, or αor β-thalassemia trait. Higgins and Mahadevan suggest that in persons with iron deficiency or thalassemia trait, the persistence of red cells with smaller volumes and lower hemoglobin content, which would not normally be retained, may reflect a compensatory delay in clearance as a result of the less efficient red-cell production characteristic of these anemias. This mechanism does not, however, explain the difSystems Biology and Red Cells