Good Genes Gone Bad: A Short History of: A Short History of Vaccines and Biological Drugs that Have Transformed Medicine, by the former head of R&D at ... | Penguin, Biotechnology, Medicine

In today’s day and age, the word “gene” has become a buzzword and gene therapy is drawing both fascination and fear from the public. “Good Genes Gone Bad” is a timely and informative work about the incredible opportunities and frightening challenges associated with developing safe and effective medical treatments based on the latest discoveries of how our bodies, cells and genes really work. The prologue sets the stage for the main chapters of the book, explaining how data transforms into information, then knowledge, and finally wisdom, as humans learn to answer the questions of “who/what/when/where”, then “how”, and finally “why?”. The scientists and organizations involved in drug development must progressively answer these questions in order to develop effective therapies by consolidating data into information and gaining meaningful knowledge that can then be used as the basis of innovation to design and test life-changing therapies and bring them to market.The central chapters of the book are a series of case studies of real-life drug development challenges in recent times. The author weaves together a well-curated set of examples that illustrate how drug development opportunities can have huge promise, but at the same time be wrought with pitfalls that can put a halt to even the most life-changing therapies. Rather than a dry reiteration of documented facts and history, the case studies include a personal touch, using real-life experiences of the author as a touchstone to allow the reader to develop a deep personal connection with the topic. For example, the first chapter is “The Story of Haemophilia”, and is told through the lens of Murali, a friend of the author who suffers from the life-threatening disease. The chapter describes how treatment for haemophilia progressed from whole blood transfusion to cryoprecipitate transfusion, before recombinant factor therapies were finally approved after many production and design challenges were overcome by drug development companies. Recombinant factors remain state-of-the-art today, but are cost-prohibitive to the general public in developing countries as neither the individual nor their insurance providers can bear the cost. The chapter ends on a bittersweet note, describing how the search for a permanent cure for Murali and others like him is still underway.Through the case studies, the author also endeavours to impart the wisdom that he has gained through his long years of experience in the biopharmaceutical industry. One key insight is that “success” in drug development is achieved when one has sufficient confidence that a drug can save patients’ lives without serious adverse effects. This is a very important understanding for the layperson, who might otherwise expect that a drug be 100% efficacious and have zero side effects, which is idealistic and impossible to really achieve. This is well-illustrated by the case study of the rotavirus vaccine, as the first vaccine Rotashield had to be recalled due to the occurrence of intussusception, a rare but dangerous side effect that was deemed too high-risk for a preventative vaccine, despite the fact that it would have been able to save the lives of millions of babies in developing countries. Thankfully, the story has a happy ending as another vaccine was able to gain approval after the developers successfully completed the largest clinical trial in history, carefully designed to demonstrate with statistical confidence that the chances of the rare ailment were not higher for those who had taken the vaccine versus the unvaccinated general population.Another key insight illustrated by the case studies is that a top-down approach can be dangerous in drug development. Trying to patch together a series of makeshift solutions has a high likelihood of failure, as even one weak link in the drug development step, whether it is a suboptimal modality, pharmacokinetic/pharmacodynamic profile, delivery mechanism, or formulation, can have catastrophic effects. Such problems are usually impossible to rectify at the clinical trial stage, dooming the drug to failure and causing huge personal and economic losses to everyone involved. In contrast, true success and life-changing impacts can be achieved by taking a bottoms-up approach and allowing new fundamental biological insights to drive the innovation of novel therapies. This is illustrated very well by the case studies showing the development of immunotherapy, cell therapy and gene therapy. Several fundamental discoveries related to the interaction between immune and cancerous cells led to the development of many critical therapies using agents such as interleukins and antibodies. However, lack of complete knowledge led to many dangers, as shown by the story of the monoclonal antibody drug Theralizumab developed by TeGenero, which passed preclinical trials with flying colours but induced Cytokine Release Syndrome in humans, a very strong adverse immune reaction that caused the company to shut down after the huge clinical trial failure. However, improved immunology knowledge led to many success stories as well, with a range of new monoclonal antibody therapies such as Keytruda successfully entering the market for the treatment of many types of cancer.However, most of these treatments were not a complete cure, leading researchers back to fundamental immunology research to develop novel therapies, including CAR-T cell therapy which was effective for certain cancers, and gene therapies which showed great promise. However, new challenges arose in the rush to bring these new therapies to market. Thus, another key insight offered by the case studies is the danger of attempting new treatments based on incomplete knowledge and insufficient wisdom. For example, there was a surge in clinical trials of adenoviral vector-based gene therapy after the treatment was initially successful at curing four-year-old Ashanti DeSilva of SCID, a previously incurable condition, leading to extensive media publicity. However, in one of the subsequent trials, a patient named Jesse Gelsinger died due to severe adverse immune reactions in another highly publicised case. This led researchers to switch to retroviral and adeno-associated vectors, but these also had problems such as the risk of insertional mutations, which induced cancers in many clinical trial patients. These adverse outcomes finally drove the scientists back to gain deeper knowledge about the vectors they were using, spurring the development of refined vectors which led to successful gene therapy treatments for retinitis pigmentosa and muscular atrophy.In conclusion, “Good Genes Gone Bad” de-mystifies the process of drug development, allowing the reader to take full stock of the challenges and dangers involved. Though some of the case studies in the book end in euphoric success, such as that of the rotavirus vaccine, others also end in failure, such as the sad story of the attempts to develop a cure for AIDS. In the latter cases, the author carefully explains the reasons behind the failure, such as why the interaction of different cell types during the pathogenesis of AIDS was an insurmountable obstacle for all attempts at developing an AIDS vaccine. Finally, the last few chapters of the book detail the story of India’s recent globally renowned successes with developing an indigenous Covid-19 vaccine and gaining US FDA approval for several biosimilars, and are a source of great hope. They provide inspiration to those of us working in the biopharmaceutical industry in India and other developing countries, as well as to all who hope for biological therapies to become more accessible and affordable across the globe. Overall, the author uses the knowledge and wisdom he has gained through decades of experience to present clear drug development case studies, including the difficult decisions and course-corrections involved, offering insights relevant to both beginners and experts in the biopharmaceutical field. Finally, the book also leaves the reader with a sense of awe at the vast scope of biological therapies, begging the question of whether humans can ever actually reach the stage of “wisdom” with regards to their own biology.

Recommended for every curious person out there!