Abstract
Hemoglobin is an essential protein to the human body as it transports oxygen to organs and tissues through the bloodstream (Looker et al., 1992). In recent years, there has been an increasing concern regarding the global supply of this vital protein, as blood availability cannot currently meet the high demands in many developing countries. There are, in addition, several risks associated with conventional blood transfusions such as the presence of blood-borne viruses like HIV and Hepatitis. These risks along with some limitations are presented in Figure 1 (Kim and Greenburg, 2013; Martínez et al., 2015). As an alternative, producing hemoglobin recombinantly will eliminate the obstacles, since hemoglobin-based oxygen carriers are pathogen-free, have a longer shelf-life, are universally compatible and the supply can be adjusted to meet the demands (Chakane, 2017). A stable, safe, and most importantly affordable production, will lead to high availability of blood to the world population, and hence reduce global inequality, which is a focus point of the World Health Organization for the millennium (WHO, 2018). Synthetic biology and metabolic engineering have created a unique opportunity to construct promising candidates for hemoglobin production (Liu et al., 2014; Martínez et al., 2016). This review sets out to describe the recent advances in recombinant hemoglobin production, the societal and the economic impact along with the challenges that researchers will face in the coming years, such as low productivity, degradation, and difficulties in scale-up. The challenges are diverse and complex but with the powerful tools provided by synthetic biology and metabolic engineering, they are no longer insurmountable. An efficient production of cell-free recombinant hemoglobin poses tremendous challenges while having even greater potential, therefore some possible future directions are suggested in this review.
Highlights
Specialty section: This article was submitted to Synthetic Biology, a section of the journal Frontiers in Bioengineering and Biotechnology
Recent breakthroughs in the fields of synthetic biology and metabolic engineering have substantially boosted the development of the so-called oxygen carriers, which can be divided into two main categories: perfluorocarbon-based substitutes (PFC) and hemoglobin-based oxygen carriers (HBOCs) (Mozafari et al, 2015)
The Crabtree-positive nature of S. cerevisiae is one of the challenges in recombinant hemoglobin production for several reasons: (i) lower yields as carbon is diverted into ethanol production (Dai et al, 2018) and (ii) yields of hemoglobin are lower on ethanol than on glucose (Liu et al, 2014)
Summary
Since the first recorded blood transfusion in the ancient Inca civilization (fifteenth century), there have been countless attempts to create alternative blood substitutes to further improve the chance of surviving anemia (Sarkar, 2008). The societal and medical need to find an alternative to conventional blood transfusion has escalated in recent years, especially in developing countries (Kim and Greenburg, 2013; Moradi et al, 2016). This is due to factors such as population growth, natural disasters, decreasing donor number, population aging, terror attacks, and the risk of blood-borne pathogens threatening the supply-demand balance of human blood (Looker et al, 1992; Varnado et al, 2013; Alayash, 2014; Moradi et al, 2016; Chakane, 2017). The development of blood substitutes has the potential to get rid of logistical barriers for pre-hospital use in acute emergency situations and remote civilian locations, by enabling long-term storage, eliminating blood type matching, supplying adequate quantities, be “pathogen-free,” and providing immediate availability in catastrophic scenarios (Chakane, 2017)
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