The personal side of cell biology
As with so many advances in the healthcare realm, the emergence of each exciting new breakthrough gets everyone's hopes up that a large swath of diseases will suddenly collapse at the hands of medical science and pharmaceuticals—followed by disappointment when no immediate results burst onto the scene. Perhaps the biggest example of that right now is "personalized medicine," which is the notion that therapies can be tailored specifically to individual patients, or patients better matched to the best drugs for their condition, or both. It's an area that has opened many possibilities in terms of diagnostics, drug discovery/development and companion diagnostics—made possible in part by genomic and proteomic leaps in recent years—but it remains a virtually unrealized dream. The key to making that dream a reality lies, in large part it seems, in cell biology.
That's not a simple road, though, and that even makes people within the healthcare community despair that they will see any progress in their lifetime. As Keeley Wray wrote in June 2010 on Vector, the science and clinical innovation blog of Children's Hospital Boston, "We're supposedly in the dawn of personalized medicine, where advances in molecular biology are providing doctors the opportunity to optimize each patient's care. As a technology marketing specialist in Children's Hospital Boston's Technology and Innovation Development Office, I should be enjoying the view. But I'm still waiting: how will it happen, when will it happen?"
However, while the "how" and "when" might be murky right now, the work has to start somewhere, and it largely began with the explosion in new sequencing technology and other genomics tools. But it is cell biology that will carry it home to clinical settings and useful patient outcomes, maintains Dr. Stephen Murphy, the managing partner and president of the Personalized Medicine Group in Greenwich, Conn., a clinical instructor of cell biology and anatomy at New York Medical College and a member of the Informed Cohort Oversight Board (ICOB) of the Coriell Personalized Medicine Collaborative.
"We can have all the sequences, SNPs or whatever else we want from genomic research, but until we understand what A and B are doing down the line in the cells themselves and how A and B might affect each other, we're shooting in the dark," Murphy says. "Cellular biology is a critical piece of personalized medicine."
Genomics is just the start
Personalized medicine, by and large, gets people thinking about genomics, notes Dr. Michael A. Mancini, director of the integrated microscopy core and an associate professor of molecular and cellular biology at Baylor College of Medicine.
"You get cells from the patient and you sequence the whole genome. That's been done a number of times and it's not far away from becoming affordable, with so many people working toward a $1,000 genome or even less expensive perhaps," he says. "But that's not personalized medicine, no matter how much the public thinks it is. Mapping a genome won't tell you the same kind of thing as if you take cells from patients and do the relevant physiology work and assays and say, 'Here's a tumor biopsy and let's try these 10 different anti-tumor drugs and pick the best one or the best combination of a few of them.' That's the type of personalized medicine that is truly personal—not only important but made practical."
That is something that has only recently come to be possible and achievable with available technology, he says, but it's a fact that researchers have known for quite some time.
As Andrea D. Weston and Leroy Hood of the Institute for Systems Biology in Seattle noted in a January 2004 Journal of Proteome Research article, "Systems Biology, Proteomics and the Future of Health Care: Toward Predictive, Preventative and Personalized Medicine," the ability to predict and prevent disease will always be dictated by how good researchers' and clinicians' fundamental knowledge is of the normal and diseased state of cells.
"Treating disease will require circumventing the limitations of specific genetic or protein defects. To do this, these defects, which include genetic mutations, inappropriate protein processing or folding, aberrant protein-protein or protein-DNA interactions and protein mislocalizations, must first be accurately placed within the context of disease," they wrote.
When genome-wide association studies started coming out, Murphy says, people got very excited about the possibilities that the causes of disease and their cures might come simply by finding the right candidate genes.
"But once you find those genes, you're still left with the need to say what else is going on. So it's more of a push-pull thing with genomics and cell biology in personalized medicine," he says. "Genome-wide association studies create new targets for molecular biologists to explore, and it becomes an accelerative process. Although cell biology is critical to bringing the genetic data into perspective, it's tough to really separate the genetic and cell biology parts into totally distinct units with personalized medicine, because they have to dance together for it all to work."
Still, personalized medicine will rely on some kind of therapeutic interventions, whether drugs or gene therapies or something else, and cellular and molecular biology are key to that because it is the cell that is the basic unit of life, Murphy emphasizes, not the genes.
"The great limiting step in any kind of medicine, personalized or not, is therapeutics and drug development," Murphy points out. "You can only describe and develop so many potential new medicines without new pathways. Cellular biology is what helps you really identify and characterize those pathways. So no matter how many genes you identify, you have to go back to cell biology to have it make sense."
"Genetics is critical, and it's a great tool, but genes are essentially two-dimensional, whereas cells are three-dimensional," adds Mancini. "They're much more complex stories themselves even at the single-cell level, much less the tissue level."
Boggled by biomarkers
That story becomes even more convoluted as genomics and proteomics advances keep revealing more twists and turns in the genome that further complicate the already challenging environment of the cell. Biomarkers, which are a huge part of the future of personalized medicine—as they can help clarify susceptibility to disease as well as disease vulnerability to various drugs—are a good example of this.
"Biomarkers are important for diagnostics, companion diagnostics and therapies that will make personalized medicine a reality. But because of shortcomings in cell biology knowledge, biomarkers can be just as confusing as the disease states themselves were before we even had the biomarkers for them," Murphy laments.
Part of the problem, as Mancini notes, is that researchers have barely even scratched the surface when it comes to biomarkers, noting that with some 20,000 genes present in the human genome, there are certainly far more than 20,000 biomarkers because genes make multiple proteins.
"We don't even know how many translational modifications exist in total," Mancini admits, "and we're probably going to need hundreds of thousands of biomarkers to get at the answers. Those will take some time to be made. This is an order of magnitude much larger than sequencing the genome."
Half of the genome is involved in transcriptional regulation, for example, he adds, and of those 11,000 or so genes producing proteins for transcriptional regulation, there are probably 10 or more versions of each protein.
"These permutations invite an enormous number of complexities, and we don't even have biomarkers for those 11,000 genes, so we're a long way away from true personalized medicine," Mancini says.
That transcriptional wrinkle alone would explain in part why the O'Shea Lab at Harvard University, for example, which has a heavy focus on cell biology, has as one of its three major project areas "The Logic and Evolution of Transcriptional Control."
Dr. Erin O'Shea, the lab's eponymous head, is the chair of the Coriell Personalized Medicine Collaborative ICOB on which Murphy serves.
"We seek to understand how regulatory regions of genes transform information about transcription factor input into quantitative gene expression output," notes O'Shea, director of the Faculty of Arts and Sciences Systems Biology Institute at Harvard University, as well as a professor of molecular and cell biology at Harvard and a Howard Hughes Investigator, on her lab's website. "Our goal is to develop a quantitative model that describes how promoter sequence influences the threshold for gene activation, maximum transcriptional output and the sensitivity of the response. To achieve this goal, we are using model promoters to analyze the relationship between transcription factor input and gene expression output in single cells."
Her lab also is looking into encoding and decoding information in transcription factor dynamics and investigating the evolution of transcriptional regulatory networks.
Beyond the cell
Given all the complexity involved with understanding the workings of the genes and cells to make personalized medicine a reality, cell biology and molecular biology aren't the end of the story either. What will likely be needed is a more comprehensive and cross-disciplinary systems biology approach that integrates engineering, physics and mathematical approaches with biologic and medical insights in what Dr. Ana Maria Gonzalez-Angulo, an associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center, and her colleagues described in a June 2010 Journal of Clinical Oncology article as "an iterative process to visualize the interconnected events within a cell that determines how inputs from the environment and the network rewiring that occurs due to the genomic aberrations acquired by patient tumors determines cellular behavior and patient outcomes."
A multidisciplinary approach like this is needed, she says, because the massive amount of data generated by high-throughput technologies has become too challenging to manage, visualize and convert to actionable knowledge otherwise.
As she notes in looking at her own oncology research, much of the data used to explore the structure of signaling networks are contextual and cannot be generalized to a cancer cell in its microenvironment. This problem is exacerbated, Gonzalez-Angulo says, by the fact that the development of high-throughput 'omics technologies has not been paralleled by equivalent improvements in cell biology technologies and approaches that can help researchers understand the consequences of these 'omics changes on cellular and organ-related outputs.
"Systems biology provides us with a common language for both describing and modeling the integrated action of regulatory networks at many levels of biological organization from the subcellular through cell, tissue and organ right up to the whole organism," according to Prof. Jeremy K. Nicholson, chair in biological chemistry and head of the Department of Surgery and Cancer at Imperial College London.
Mancini notes that as a researcher, "you need any and every way you can to connect the information, whether you're trying to kill cells or save them," and working at the systems biology level, while it may take much more time and effort than sequencing a genome, running a genome-wide association study or running assays, "will make things more relevant than what's been done up to now by focusing on the genes."
"Cell biology is hands-down in the top couple of things you need to have in play for personalized medicine to truly work, but it's not the only thing," Murphy adds. "To grasp all these genes, the proteins they create, the pathways at work and all the rest, the systems biology knowledge has to be firing on all cylinders. Because if you don't understand the biology, you don't have anything."
The tools to get you there
As noted in the main article by Dr. Ana Maria Gonzalez-Angulo of the University of Texas MD Anderson Cancer Center, cell biology tools haven't advanced at a speed parallel to those used in genomics research and some other 'omics areas. However, they have come a long way and are enabling achievements in recent years that were not previously possible. Here, two cell biology experts share with us some quick thoughts about enabling technologies in their field.
Dr. Michael A. Mancini, director of the integrated microscopy core, Baylor College of Medicine:
"Cell biology and microscopy are somewhat synonymous over history, and now, being able to truly do quantitative and automated multiparameter microscopy work in real time with drug screening and cells from different patients—well, that's a big leap that's only been available in the last five or six years. You combine current microscopy technology with the amazing wave of information you get from genomics, and it's like one plus one equals 10. I mean, you can pick out any multiple you like, but I can tell you it's much more than just a one-plus-one-equals-two effect."
Dr. Stephen Murphy, managing partner and president, the Personalized Medicine Group in Greenwich, Conn.:
"RNA expression arrays and new technologies for cell line storage have been a couple of the key advancements that have let cell biology really shine in recent years. Devices that have allowed for the real-time ability to see what's going on at the molecular level have been key as well. Also, the willingness and ability to share cell lines throughout the research community instead of holding on to them and keeping them within a single institution has been huge."