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Beyond Happy Accidents: Embracing the Complexity of Precision Medicine

February 24th, 2024 | Cell Therapy | Article

Source: Biorasi

Source: Robert S. Negrin, MD, Professor of Medicine and former Chief of the Division of Blood and Marrow Transplantation at Stanford University, Biorasi Scientific Advisory Board member.

The Precision Medicine Initiative was launched in 2015 in the United States. And while this new paradigm was quick to be accepted by the healthcare industry, the true definition of precision medicine’s role in treatment and diagnosis is still in progress.

Described by then President Obama as “the right treatments at the right time, every time, to the right person,” today’s precision medicine is most commonly referred to as the development of specific patient care plans through the leveraging of pharmacogenomics – combining pharmacology and genomics to create medications that are customized to an individual’s genetic makeup.1 Noted Hematologist, Dr. Robert S. Negrin, Professor of Medicine and former Chief of the Division of Blood and Marrow Transplantation at Stanford University, and Biorasi Scientific Advisory Board member, has a different take.

“While there are a lot of definitions out there, I define precision medicine as trying to understand the specific mechanisms of a disease process in a more fundamental way,” said Dr. Negrin. “And from there, we apply that knowledge to develop specific drugs, antibodies, or other types of treatment.”

“That being said, it is important to not make the concept sound too simplistic. We need to embrace both the serendipity and complexity of the process to understand it.”

How Serendipity, Leukemia, and a Chicken Virus Led to a Happy Accident

Chronic myelogenous leukemia (CML) is an uncommon cancer found in the bone marrow. CML begins when sections of two chromosomes (Chromosomes 9 and 22) switch places with one another, an event that creates an extra short chromosome 22 and an extra long chromosome 9, referred to as the Philadelphia chromosome. The result causes the buildup of abnormal blood cells and leads to cancer growth.2

Treatments for CML were originally limited to bone marrow transplants, immunotherapy, and chemotherapy. Fortunately, serendipitous events and excellent science led to a new therapy.

“It’s a fascinating story,” said Dr. Negrin. “The Philadelphia chromosome causes the formation of a new gene – an oncogene called BCR-ABL. That fusion results in an alteration in a tyrosine kinase, which triggers abnormal growth in cells. This same abnormality was identified in infectious tumors in chickens. This changed the entire course of the disease and led to the development of tyrosine kinase inhibitors as a treatment, replacing the risks of bone marrow transplants with a simple pill. That’s pretty dramatic.”

While this is a great example of how the basic science of defining the unique characteristics of a disease highlighted a specific pathway to treatment, it is important to keep in mind that this discovery was about 30 years in the making. It was a complex process that relied more on serendipity, diverse scientific studies, and “happy accidents” than precision medicine:

  • The discovery of a similar oncogene derived from the initial study of chicken viruses in 1911
  • Clinical researchers that were able to make a connection to the protein found in CML in humans
  • The availability of tyrosine kinase inhibitors that were originally listed as a “dead drug” discarded by a pharmaceutical company

Embracing Complexity in Precision Medicine

As mentioned previously, the healthcare industry offers a myriad of definitions for precision medicine. In another example, based on its designation, it could be interpreted as the development of an intentional design for treating cancer and other diseases. In actuality, it is a bit more unexpected.

“Precision medicine is not the design of a specific treatment based on the knowledge at hand that can be solved quickly,” said Dr. Negrin. “It is a multi-step process, equal parts hard work and serendipity. Human biology is very complex. Precision medicine highlights the value of basic research, of figuring things out without a specific goal in mind.”

Underneath the precision medicine umbrella, there are multiple challenges to the discovery of the right treatment for the right individual. Clinical research allows for the opportunity to gather knowledge from both successful and unsuccessful trials, leading to precision treatment through the better understanding of the following:

  • Metabolic Pathways – The human body encompasses multiple redundant and non-redundant metabolic pathways. Oncological and hematological disease utilize the same pathways for life and growth. Understanding these pathways is crucial to precision medicine as genomic changes made to a pathway to remove abnormal cells may lead to unexpected complications elsewhere in the body.
  • Specificity – Precision medicine can actually be too precise. Cancer cells, like normal cells in the body, can evolve to evade and bypass previously successful treatment. These changes often require further study into other metabolic pathways, sometimes multiple pathways, to find new therapeutic interventions.
  • Toxicity – Developing a patient safety profile is key to precision medicine findings, ensuring that the treatment results are not worse than the toxicity of the disease itself. For example, in on-target toxicity, clinicians must focus on the direct effect of intervention on a particular cancer cell. Off-target toxicity refers to side effects of the treatment itself. In both situations, understanding what patients can and cannot tolerate leads to a more robust patient safety profile.
  • ·nfrastructure – Precision medicine studies possess similarities to all clinical trials in that they are subject to the limitations of infrastructure. Specific and precise interventions for unique patients may lead to clinical trials with strict eligibility criteria. Poor enrollment and accrual is often the result. Additionally, validating ROI for the company and value for the patients enrolled in precision studies often stand in direct conflict with each other.

Knowledge is Powerful Medicine

Learning from failure is a necessary part of life and a crucial step in understanding oncological diseases. And, similar to the definition of precision medicine, it is not one that the clinical research community can agree upon. The sharing of this important trial data, whether the study is successful or not, will need a more widespread effort if precision medicine is to be established as a viable direction.

“The development of drugs by pharmaceutical companies remains in the private domain,” noted Dr. Negrin. “So it is up to the goodwill of these companies to publish their findings. Especially the negative results, as this data leads to further exploration of new diseases, the understanding of human biology, and the discovery of novel interventions.”

“For every successful trial, there could be five or more failed trials, and that’s normal. Learning from these experiences will bring us closer to a truer definition of precision medicine beyond serendipity and happy accidents. Every ounce of data culled from a clinical trial is an opportunity to be seized, not wasted.”


1 accessed on March 30, 2022.

2 accessed on March 30, 2022.

3 Cross, Simon S. “Metabolic Pathway.” Underwood’s Pathology, 2019