Acheiving instantaneous control of G-protein coupled receptors using light as a ligand

能够影响人类行为和生理的药物的发现和发展，在上个世纪发生的医学巨大进步中发挥了关键作用。然而，未来的进展很可能在很大程度上取决于我们是否有能力克服这种治疗疾病的药物方法的一些固有限制。使用药物的一个众所周知的问题是副作用，发生这种副作用是因为药物通常会对身体的多个部位产生影响。许多原本有效的药物因为需要将这种不良影响降至最低而被遗失。药物的另一个问题是，与它们希望调节的生理自然变化相比，它们的影响积累得相当慢，可能会持续很长时间。这导致了我们对药物变得不敏感的倾向，也阻止了在我们想要更直接和可逆的效果的情况下使用药物。出于这些原因，迫切需要开发新的方法来调整我们的生理，而不仅仅是药剂学的成就。我们建议开发这样一种技术。我们的方法将是修改一组名为GPCRs的蛋白质，使其对光敏感。GPCRs几乎存在于我们身体的每一个细胞中。他们的工作是根据邻近细胞和身体其他部位释放的信号来微调细胞的活动和生理。由于它们的影响力如此之大，它们长期以来一直被认为是治疗疾病症状的好方法。事实上，目前超过一半的处方药是为了改变它们的活性而设计的。通过使GPCRs变得感光，我们将能够使用光而不是药物来调节它们的活性。与毒品不同，光可以非常迅速地开启和关闭。高剂量的光也可以照射到一组细胞上，而不会影响身体的其他部分。这些功能意味着我们将能够使用新的GPCR来实现非常精细的生理变化，远远超出目前使用药物的可能。首先，我们将在动物实验中使用这项技术，以增加我们对常见医学疾病(包括肥胖、抑郁和失眠)发生的了解。假以时日，它将成为治疗疾病的一种全新方式。

The discovery and development of drugs that can influence human behaviour and physiology has played a crucial role in the huge advances in medicine that have occurred over the last century. However, future progress is likely to depend in large part upon our ability to overcome some of the inherent limitations in this pharmaceutical method for treating disease. A well known problem with using drugs is that of side effects, which occur because drugs commonly have effects on multiple parts of the body. Many otherwise effective drugs are lost because of the need to minimise such adverse effects. An additional problem with drugs is that, in comparison with the natural changes in our physiology that they hope to regulate, their effects build up rather slowly and can hang around for a long time. This contributes to our tendency to become desensitised to drugs and also stops them being used in conditions in which we would like more immediate and reversible effects. For these reasons, there is a pressing need to develop new ways of adjusting our physiology that go beyond the achievements of pharmacy. We propose developing such a technology. Our approach will be to modify a group of proteins called GPCRs to make them light sensitive. GPCRs appear in practically every cell of our body. Their job is to fine tune the cell?s activity and physiology according to signals released from neighbouring cells and other parts of the body. Because they are so influential they have long been recognised as a good way of treating the symptoms of disease. Indeed more than half of currently prescribed drugs are designed to alter their activity. By making GPCRs photosensitive, we will be able to use light rather than drugs to tweak their activity. Unlike drugs, light can be switched on and off very rapidly. Light can also be applied at high doses to a single group of cells without influencing the rest of the body. These features mean that we will be able to use the new GPCRs to achieve extremely fine tuned alterations in physiology way beyond what is currently possible using drugs. In the first instance we will use this technology in animal experiments that increase our knowledge of how common medical conditions (including obesity, depression and insomnia) come about. In time, it will become a completely new way of treating medical conditions.