Challenges and opportunities for enhancing biotechnology and technology transfer in developing countries.

Biotechnological innovation is gaining increased recognition as an important tool for improving global health. The challenge, however, lies in defining the role of technology transfer to develop therapies for diseases prevalent in developing countries. During the past decade, a large disparity emerged between the developed and developing world in accessing affordable medicines because of the pharmaceutical industry's focus on health areas bearing greatest profits. Discussed herein are several mechanisms that provide partial solutions to this challenge. The Office of Technology Transfer of the US National Institutes of Health has increased its technology licensing pertaining to neglected diseases to partners in developing regions. Establishing partnerships through the transfer of technologies and assisting indigenous institutions build R and D capacity may positively impact policies on protection of intellectual property rights and increase multinational company investments in lesser-developed countries. This will most probably result in the development of more accessible therapies for those in need.

Intrinsic role of polysialylated neural cell adhesion molecule in photic phase resetting of the Mammalian circadian clock.

The suprachiasmatic nuclei (SCN), the location of the mammalian circadian clock, are one of the few adult brain regions that express the highly polysialylated form of neural cell adhesion molecule (PSA-NCAM). A role for the polysialic acid (PSA) component of PSA-NCAM, which is known to promote tissue plasticity, has been reported for photic entrainment of circadian rhythmicity in vivo. The in vivo results, however, do not discriminate between PSA acting upstream or downstream of the glutamatergic synapses that convey photic information to the SCN. To address this key issue, we exploited an in vitro rat brain slice preparation that retains robust circadian function. As in the intact SCN, PSA levels in the isolated SCN are rhythmic, with higher levels during the early subjective day and lower levels during subjective night. Importantly, bath application of glutamate to SCN slices rapidly and transiently increases PSA levels during both the subjective day and night. Pretreating the slices with endoneuraminidase, which selectively removes PSA from NCAM and thereby prevents this increase, abolishes glutamate- and optic chiasm stimulation-induced phase delays of the SCN circadian neuronal activity rhythm. These results support the hypothesis that PSA expression in the SCN is controlled by both the circadian clock and photic input to the clock and that expression of PSA in the SCN is critical for photic-like phase shifts of the clock. Together, these results establish that such actions of PSA are manifested downstream from presynaptic retinohypothalamic terminals and therefore are intrinsic to the SCN itself.

Removal of polysialic acid from the SCN potentiates nonphotic circadian phase resetting.

The adult suprachiasmatic nucleus (SCN) expresses a polysialylated form of neural cell adhesion molecule (PSA-NCAM) that modulates cell interactions. Previous studies have shown that PSA is important for photic entrainment of the SCN circadian clock, suggesting that changes in cell-cell interactions may contribute to the phase-resetting capacity of this system. A possible role for PSA in nonphotic circadian phase resetting was evaluated using the enzyme endoneuraminidase (endo N) to selectively remove PSA from the SCN. Pretreatment of rat brain slices containing the SCN with endo N enhanced the daytime phase-advancing effects of the serotonin agonist, 8-hydroxy-2-dipropylaminotetralin [8-OH-DPAT] (41% greater than inactivated enzyme controls; P<.05). Similarly, removal of PSA from the Syrian hamster SCN in vivo potentiated the daytime phase-advancing effects of behavioral arousal (sleep deprivation) and of systemic application of 8-OH-DPAT (61% and 220% greater, respectively, than inactivated enzyme controls; both P<.05). While endo N perturbation of both photic and nonphotic phase resetting suggests that PSA plays a central role in clock regulation, it is striking that the effects on the two inputs are opposite in direction. This difference could reflect the antagonistic relationship between photic and nonphotic signaling pathways. It could also be explained by a permissive role of PSA common to both inputs, which in and of itself would not specify direction of response. Such a bidirectional control mechanism, based on PSA's attenuation of cell-cell interactions, is well documented in the developing nervous system, and may be retained in plastic regions of the adult brain.