Andrew Pecora, MD
Chief Innovations Officer, Professor, and Vice President of Cancer Services
John Theurer Cancer Center at Hackensack University Medical Center
I am far from unique as a physician whose love for physics is limited only by my inability to “do the math.” I deeply enjoy reading the latest theories “of everything” that try to tie together all of nature’s forces with matter. Recently, significant attention has been focused on dark energy, despite our inability to directly detect it, because it represents 72% of everything in the universe, with regular matter representing only 5% and dark matter filling in the rest at 23%. Adam Riess, an astrophysicist from Johns Hopkins University, received the 2011 Einstein Medal for his confirmation of the effect of dark energy, which was deemed by Science Magazine as the “breakthrough discovery of the year” in 1998. Using the Hubble telescope, Riess and his team discovered that the expansion rate of the known universe is accelerating due to dark energy. Einstein himself thought the so-called cosmologic constant (now called dark energy) that pushed galaxies apart in the face of gravity was his greatest error in judgment. He would be happy today to know he was correct all along and probably amused that his biology colleagues are coming to an analogous conclusion regarding the inner workings of the human cell.
The symphony of life embodied in each cell of our body is finally coming into focus through systems biology. No longer are we limited to assessing cause and effect through a single pathway. Now, using systems biology, we are able to assess the effect of an external natural stimulus or drug on the entirety of the cellular pathways. Until recently, the understanding of the relationship between stimuli and effect at the cellular level was discernible only in small part, with most intracellular events occurring as a consequence of an amalgam of unknown pathways or “dark energy.” Biology remains an observational science due to the near limitless permutations of possible outcomes for any given stimulus. Nonetheless, there is probably a finite number of outcomes, albeit a large number, that defines a cellular phenotype, including malignant outcomes. Advances and synergies in computational sciences, genomics, epigenomics, transcriptomics, and metabolomics are beginning to enlighten biologists in discerning the pathways to and maintenance of the malignant cell phenotype.
It is common knowledge that our country and others are on an unsustainable path of increasing healthcare expenditures, particularly in oncology. The cost of drug discovery and ultimate FDA approval is staggering, exceeding $1 billion on average. Most of us realize that it will not be one drug but combinations of drugs that will significantly improve outcomes for our patients and hopefully reduce the overall cost of care. We can no longer support nor wait for the traditional approach of phase I-III in vivo clinical trials to get answers. Instead, using well-designed cellular models and systems biology readouts, drug combinations, sequencing, and dosing can be worked out for a fraction of the cost and time in vitro before time and money is wasted in vivo. In physics and biology, change is heralded by advances in technology. The time has come in biology to shine a bright light on intracellular “dark energy” and help to create a desirable cellular phenotype to improve outcomes for our patients living with cancer.