An industrial standard cancer drug development platform using human induced pluripotent stem cell technology

我的职业目标是成为一名独立的研究领导者，在与行业的界面上研究真正的患者问题，通过非动物技术和解决方案减少和取代动物的使用。英国内政部的数据告诉我们，在英国，每年有超过18.3万例动物手术用于癌症研究。此外，当我们研究来自内政部和主要癌症研究资助慈善机构的数据时，每年有9000多只老鼠被用于研究白血病。研究人员正在用老鼠培养白血病细胞，研究它们的生物学特性，并开发更好的药物。这种动物手术可以达到中度严重程度；这些老鼠经常表现出痛苦的迹象，比如体重减轻、驼背和毛发凌乱。癌症研究和癌症药物开发已被NC3Rs确定为实现动物替代的战略重要领域。目前，儿童癌症治疗包括2-3年的治疗方案，有严重的副作用，如因感染而死亡、肾脏损伤、心脏问题和骨骼破坏。因此，迫切需要更好的药物，并且有理由在这一领域进行大量研究。对儿童癌症的研究是紧迫和重要的，这一领域将在近期和遥远的将来继续扩大。只有通过研究直接从患者身上提取的癌细胞的生物学特性，才能开发出更好的药物。这种患者来源的细胞忠实地复制了白血病生物学，在仔细检查白血病细胞特征方面是不可或缺的。这反过来又对开发更好的药物至关重要。虽然白血病是一种侵袭性很强的疾病，但这种患者来源的癌细胞在体外会迅速死亡。因此，目前这些细胞只能在小鼠模型中生长和研究。我的目标是开发一种技术，使研究人员和制药行业能够在不使用小鼠的情况下研究白血病细胞并开发出更好的药物。我已经开发了一个平台，在支持白血病的人类骨髓细胞的帮助下，病人白血病细胞现在可以在培养皿中生长。鉴于这些骨髓细胞不能在培养皿中存活很长时间，它们必须不断地从不同的个体中获取。因此，它们在不同实验室的表现不同，导致高度可变性和不一致的药物开发数据。为了解决这个问题，我已经开发了一种新的解决方案，通过这种解决方案，我们现在可以使用干细胞来产生具有统一生物学特性的人类骨髓细胞。这些骨髓干细胞将提供一种环境，使白血病患者细胞可以生长，并且无需使用小鼠就可以研究它们的生物学。这意味着在儿童癌症研究中对动物的依赖将减少，因为开发更好的癌症药物需要更少的老鼠。此外，我的非动物解决方案适用于影响儿童和成人的其他几种类型的癌症。我将建立一个工业标准的生物测试，将有一个明确的工作流程管道和质量控制方案。我与癌症研究技术公司建立了联系，并与一个多学科团队合作，我将确保我的测试在国内和全球不同实验室的任何时候都表现出高度一致性。总而言之，我将设计一种技术，帮助科学家和制药公司测试和制定治疗癌症的新药，而不必严重依赖动物模型。我的平台的定义特征是将其建立在标准化的工业水平上，具有经过验证的协议和经过验证的质量控制措施。该奖学金的成果将取代和减少癌症研究中的动物实验，也将降低药物失败率，这是目前制药经济中的一个大问题。

My career intent is to become an independent research leader working on real patient problems at the interface with industry, reducing and replacing animal use through non-animal technologies and solutions. Home Office figures tell us that more than 183,000 animal procedures take place every year in cancer research in the UK. In addition, when we study figures from the Home Office and major cancer research funding charities more than 9000 mice are being used every year to study leukaemia. Mice are being used by researchers to grow patient-leukaemia cells, to study their biology and to develop better medicines. Such animal procedures can reach moderate severity; these mice often show signs of distress such as weight loss, hunched back and dishevelled fur-coat. Cancer research and cancer drug development have been identified by the NC3Rs as a strategically important area to bring about animal replacement. Currently, children's cancer treatment comprises a 2-3 years regimen with severe side effects such as death due to infections, kidney damage, heart problems and bone destruction. Hence better medicines are urgently needed and justifiably there is a lot of research being carried out in this area. Research into childhood cancer is urgent and important and this field will continue to expand in the immediate and distant future. Improved medicines can be developed only by researching the biology of cancer cells taken directly from patients. Such patient-derived cells faithfully replicate leukaemia biology and are indispensable in scrutinising leukaemia cell-characteristics. This in turn is essential in developing better medicines. Although leukaemia is a very aggressive disease such patient-derived cancer cells rapidly die outside the body. Hence currently these cells can be grown and studied only in mice-models. My aim is to develop a technology that will allow researchers and the pharmaceutical industry to study leukaemia cells and develop better medicines without having to use mice. I have developed a platform whereby patient-leukemia cells can now be grown in a petri-dish with the help of leukemia-supporting human bone-marrow cells. Given these bone-marrow cells do not survive long in the petri-dish they have to be constantly sourced from different individuals. Thus they behave differently across different laboratories resulting in high variability and inconsistent drug development data. To address this problem, I have developed a novel solution by which we can now use stem cells to generate such human bone marrow cells with uniform biology. These bone-marrow stem cells will provide an environment whereby patient-leukaemia cells can be grown and their biology can be studied without having to use mice. This means that dependence on animals in children's cancer research will reduce as fewer mice will be needed to develop better cancer medicines. In addition my non-animal solution is applicable in several other types of cancer affecting children and adults. I will establish an industrial standard biological test which will have a defined workflow pipeline and quality control programmes. I have established links with Cancer Research Technologies and working with a multidisciplinary team I will ensure that my test demonstrates high consistency at all times across different laboratories nationally and globally. In summary I will engineer a technology that will help scientists and pharmaceutical companies to test and formulate new medicines for cancer without having to heavily depend on animal-models. The defining characteristic of my platform will be setting it up at a standardised industrial level with validated protocols and authenticated quality control measures. The deliverables of this fellowship will replace and reduce animal procedures in cancer research and will also reduce drug failure rates which is currently a big problem in the pharmaceutical economy.