Wouldn’t it be great to find a single cure for every disease? A ‘magic bullet’ medicine that can cure a disease quickly and completely,[1] without deleterious side effects.[2] But by focusing on selective toxicity and seeking ‘magic bullet’ cures at the expense of other promising treatments, are we overlooking other important innovations?
The first ‘magic bullet’ in medicine
The underlying principles of translational research and precision medicine originate from the work of scientists such as Paul Ehrlich, widely considered the father of modern chemotherapy. In 1897, Ehrlich proposed that certain cells expose a set of side chains on their surface, later termed ‘receptors’, which are associated with specific recognition.[3][4] Ehrlich and his team went on to develop the first pharmaceutical ‘magic bullet’, arsphenamine (Salvarsan®), which specifically targeted the bacterium Treponema pallidum, the causative organism of syphilis, without affecting normal host cells.[3]
However, the first ‘magic bullet’ was not a perfect drug. Resistance to treatment occurred, and combination therapy with mercury or bismuth treatment was often needed to eliminate all spirochetes (a group of spiral-shaped bacteria).[3] Patients required many injections over a long time period, and problems also arose from the galenic preparation of arsphenamide, which was insoluble in water.[3] While other targeted treatments for syphilis have since emerged, including neoarsphenamine (Neosalvarsan®) and oxophenarsine (Mapharsen®), other challenges remained (Figure 1).[3]
Figure 1: The Development of Targeted Treatments for Syphilis
Source: Valent P et al, 2016;[3] Strebhardt K et al, 2008.[4]
How realistic is the ‘magic bullet’ concept in pharmaceutical development?
Other transformational innovations in medicine have since been heralded as ‘magic bullets’ but have not provided a complete cure. The concept of ‘magic bullets’ gained popularity in the mid-twentieth century with the development of antibiotics and insulin, which were game-changing for medicine, but not infallible. The development of antimicrobial resistance to penicillin and the development of complications in patients with diabetes, despite treatment with insulin, proved major limitations.[5]
‘Magic bullets’ are more realistic in some disease areas than others. In many instances patients will have multiple, long-term conditions, that a single ‘magic bullet’ cannot fix.[5] What’s more, many diseases involve complex interactions between genetic, lifestyle and environmental factors, such as diabetes and heart disease. Patient to patient variability must also be considered, as individuals may respond differently to a treatment based on their underlying health conditions, age, or gender.
A ‘magic bullet’ approach would not be realistic for a condition where the cause of the disease is unclear or more complex, or where it is difficult to consistently determine which patients have the condition.[5] In the case of central nervous system disorders such as depression and schizophrenia, which are thought to be polygenic in origin, endeavors to develop effective treatments that are selective for single molecular targets have been largely unsuccessful. Here, the development of ‘magic shotguns’ – drugs that interact with several molecular targets – is a suggested approach.[6]
As many pathogenetic targets have multiple physiological functions, highly specific ‘magic bullets’ may impact multiple cellular pathways simultaneously, causing unintended side effects.[7] Target proteins may also have similar active domains to proteins involved in normal physiologic functions, which could be inadvertently affected.[7] Redundancy in critical biological pathways may limit the usefulness of a ‘magic bullet’ that targets a single, specific protein in a pathway; backup, or redundant, systems may emerge to compensate.[7]
Prioritizing the search for highly selective, curative ‘magic bullets’ that act on a single, specific disease pathway could also result in promiscuous drugs, which act upon multiple molecular targets, being overlooked. Promiscuous drugs may be perceived as posing a greater risk of side effects, yet can offer a broad range of therapeutic benefits. Aspirin (acetylsalicylic acid), for example, inhibits the cyclooxygenase (COX) isoenzymes COX-1 and COX-2, and targets any area where inflammation is present. Aspirin can also act as a blood thinner and reduce platelet aggregation to prevent cardiovascular disease and preeclampsia, and has an antiarthritic effect.[7] It is therefore important not to discount promising drugs simply because they do not act on a single target.
Are ‘magic bullets’ the way forward for cancer treatment?
Scientists have long been looking for ‘magic bullets’ for cancer. One success story is imatinib, a single agent that targets the molecular driver involved in the pathogenesis of chronic myeloid leukemia (CML). In CML, a reciprocal translocation involving chromosomes 9 and 22 results in a truncated chromosome 22, known as the Philadelphia chromosome.[8] The breakpoints of the translocation create a fusion gene, BCR-ABL1, which is not present in healthy cells. The BCR-ABL1 fusion gene produces an abnormal protein (BCR-ABL1) with persistently enhanced tyrosine kinase activity, which maintains proliferation, inhibits differentiation, and confers resistance to cell death.[8] Imatinib inhibits this protein.[8]
In 2017, the pivotal Phase III trial of imatinib for CML (the IRIS trial) found that the estimated overall survival rate at 10 years was 83.3% among patients who received first-line imatinib therapy, with 82.8% of patients having a complete cytogenetic response.[9] Due to the high rate of crossover among the patients who were randomly assigned to receive interferon alfa plus cytarabine early in the trial (65.6% of patients; median duration of therapy before crossover: 0.8 years), the final analysis of IRIS focused on patients who had been randomly assigned to receive imatinib. Before imatinib, only 30% of patients with CML survived for at least five years after being diagnosed.[10] Now, patients with Philadelphia chromosome-positive CML who are in remission after two years of treatment with imatinib have the same life expectancy as someone without cancer.[11][12]
However, not all cancers have well-defined molecular targets or driver mutations that can be targeted by a ‘magic bullet’. In cases where there is a suitable targeted treatment, accurate biomarkers are required to identify patients who are likely to benefit. Additionally, tumor heterogeneity provides a barrier; a single targeted ‘magic bullet’ may not effectively eradicate all cancer cells. In these cases, a combination of treatments may be required. Cancer cells may also develop resistance to targeted therapies over time via the mutation of drug targets, upregulation of drug efflux pumps, or activation of alternate signaling pathways, limiting duration of response to treatment. Despite the remarkable success of imatinib in CML, resistance can also emerge.[13] Indeed, approximately 17% of patients develop resistance to imatinib with 5 years.[14]
Pharmaceutical innovation: Where do we go from here?
While the concept of a ‘magic bullet’ is appealing, very few treatments, if any, truly act as curative ‘magic bullets’ without deleterious side effects. While ‘magic bullets’ have been transformational in the treatment of some diseases, the approach is not realistic for all. By acknowledging these limitations and recognizing that other treatments still hold value, we can avoid judging drugs solely on their ability to work as ‘magic bullets’ and seize exciting opportunities whenever they emerge.
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This post was written by Eleanor Ward, Medical Writer.
References:
[1]Collins. Definition of ‘magic bullet’. Accessed May 2024. Available online at: [https://www.collinsdictionary.com/dictionary/english/magic-bullet#:~:text=In%20medicine%2C%20a%20magic%20bullet,%5Binformal%5D].
[2]Merriam-Webster. Magic bullet dictionary entry. Accessed May 2024. Available online at: [https://www.merriam-webster.com/dictionary/magic%20bullet#dictionary-entry-1]. 2024.
[3]Valent P, Groner B, Schumacher U, Superti-Furga G, Busslinger M, Kralovics R, et al. Paul Ehrlich (1854-1915) and His Contributions to the Foundation and Birth of Translational Medicine. Journal of Innate Immunity. 2016;8(2):111-20.
[4]Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nature Reviews Cancer. 2008 2008/06/01;8(6):473-80.
[5]Richard Smith. The case for medical nihilism and “gentle medicine”. Accessed March 2024. Available online at: [https://blogs.bmj.com/bmj/2018/06/04/richard-smith-the-case-for-medical-nihilism-and-gentle-medicine/].
[6]Roth BL, Sheffler DJ, Kroeze WK. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery. 2004 2004/04/01;3(4):353-9.
[7]Mencher SK, Wang LG. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin Pharmacol. 2005 Apr 26;5:3.
[8]Kang ZJ, Liu YF, Xu LZ, Long ZJ, Huang D, Yang Y, et al. The Philadelphia chromosome in leukemogenesis. Chin J Cancer. 2016 May 27;35:48.
[9]Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017 Mar 9;376(10):917-27.
[10]Pray, L. (2008) Gleevec: the Breakthrough in Cancer Treatment. Nature Education 1(1):37.
[11]National Cancer Institute. How Imatinib Transformed Leukemia Treatment and Cancer Research. Accessed March 2024. Available online at: [https://www.cancer.gov/research/progress/discovery/gleevec]. 2018.
[12]Leukemia & Lymphoma Society. FDA Approves First Targeted Treatment for Newly Diagnosed Leukemia Subtype. Accessed April 2024. Available online at: [https://www.lls.org/news/fda-approves-first-targeted-treatment-newly-diagnosed-leukemia-subtype]. 2024.
[13]Bitencourt R, Zalcberg I, Louro ID. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia. Rev Bras Hematol Hemoter. 2011;33(6):470-5.
[14]Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006 Dec 7;355(23):2408-17.
