Basic Science vs Translational vs Clinical Research — A Primer
As an undergraduate student, I was naive about the different forms of scientific research one could pursue. People would throw around terms like basic science and translational research, and I was confused about how they differed. That confusion increased when I learned about clinical research. Can a PhD do clinical research? Can an MD do basic science? Where are the lines that distinguish these approaches, or does it represent a continuum?
In this post, I want to provide context and examples for how I’ve come to understand these research areas over time. I will share what forms of research make undergraduate students competitive for MD/PhD programs, and which forms MD/PhD students can pursue during their graduate training. My aim is to define and clarify these terms so that you can communicate about them more effectively.
Basic science: quantitative vs qualitative research
I divide basic science into 1) quantitative and 2) qualitative research, both of which you can pursue in graduate school as an MD/PhD. Quantitative research is the version you most likely think of when considering laboratory research.
In The Emperor of All Maladies, Siddhartha Mukherjee writes: “science begins with counting. To understand a phenomenon, a scientist must first describe it. To describe it objectively, they must first measure it.” Quantification is the first step to measure differences empirically among observations. This is how I began my research career in basic science. My undergraduate thesis work involved a genetic model of cell death in which the number of facets in the compound eye of Drosophila was reduced. There was variability in the amount of reduction across different genomic backgrounds and quantification enabled comparison. Through this approach, we could identify the gene(s) that correlated with activation or suppression of cell death. Next, I learned to count synapses at the neuromuscular junction of larval Drosophila after genetic knockdown (depletion) of various genes. This allowed the lab to screen for different genes involved with synaptic development (i.e., some knockdowns increased synaptic growth and others decreased it). It was tedious work and best achieved manually.
Quantitative approaches underpin basic science–the branch of research that aims to discover fundamental principles about natural phenomena. While I currently conduct basic science research in the fields of molecular neuroscience, genetics, and biophysics, it is also practiced across empirical sciences including chemistry, physics, and engineering. In MD/PhD admissions, basic science has been selected for traditionally. In part, this is because the technical skills you develop through basic science research are important for succeeding as a physician-scientist. Quantitative experiments, in particular, are prone to failure and require resiliency, rigor, and reproducibility. However, I believe this emphasis has shifted since computational methods have become more prominent. Students no longer need a “wet lab” background to conduct quantitative research; it can be done remotely and on a much larger scale. Regardless, I think undergraduate students should investigate questions focused on unraveling fundamental mechanisms.
For MD/PhD admissions, it is good practice to have pursued research that relates to biomedical science. I hold this view loosely, as this can be achieved through many different research experiences. As I’ve mentioned, my first research experience was studying the neuroscience of chemo- and mechanoreception in scorpions. At first glance, there is limited biomedical application. However, you might spin this to explain how people with sensory deficits might benefit from a technology that leverages lessons from the blind scorpion’s highly precise navigational ability. Storytelling is key, and you will likely be able to find connections between most fields of basic science with biomedicine.
In contrast, qualitative research aims to describe reality through more subjective evidence. Some people argue that this form of science is lesser — perhaps not true science, at all. Those people have a narrow view of scientific research, I believe, because in any domain working with and devised by humans, you must consider subjective experience and human error. Qualitative and quantitative research both have important roles in advancing science and are prone to variability and bias. For MD/PhDs, qualitative research is a tool commonly used in fields of psychology, medical anthropology, and population health. It is not the common research path for physician-scientists, though there are several programs that support MD/PhD students in pursuing this work. You can find a list of the MD/PhD programs that offer PhDs in social sciences here:
As you’ll see, MD/PhD students can pursue graduate training in medical anthropology, bioethics, epidemiology, health policy, philosophy, and more. For example, a friend in my MD/PhD program is completing their PhD in medical anthropology. They are interested in sexual and reproductive health in Latin America and are currently living in Guatemala applying ethnographic methodology and patient interviewing with the indigenous community. The possibilities are vast for MD/PhD students to find a niche and make important impacts in areas of interest. Therefore, if you conduct social science research as an undergraduate, you are eligible to apply for MD/PhD. To succeed in admissions, you should demonstrate commitment to rigorous qualitative research and provide a clear story for how you will apply it to advance your career as a physician-scientist.
Note, however, that you will likely be among the minority of applicants applying with this background. The NIH funding opportunities for qualitative research are fewer, which might explain why admissions committees are more likely to select for students with a quantitative background if pressed to choose. I believe you can use this minority position to your advantage to highlight important unexplored avenues. Overall, I think it’s a good idea to pursue a combination of quantitative and qualitative research in your undergraduate preparation to build a well-rounded foundation and keep doors open, and once you’re accepted, you can define your own training path.
Translational Research: a bidirectional endeavor
The chief aim of most physician-scientists is to translate findings from the laboratory to advance patient care clinically. Consider the advancements in cancer treatment achieved with immunotherapy. Scientists have been studying immune system regulation of cancer for decades to identify the markers that can be targeted for more precise therapeutic intervention. The results have been remarkable for patient outcomes. By identifying the surface receptor proteins on T-cells and tumor cells, scientists gained insight into how nefarious cancers can hide in plain sight. T-cells express a surface protein called PD-1 and some cancer cells have evolved to express its binding-partner ligand, PDL-1. When the T-cell and cancer cell interact, the binding of PD1-PDL1 sends a signal that effectively protects the cancer cell, allowing it to escape detection and proliferate. By studying this interaction through basic science methods, scientists were able to define this mechanism and devise inhibitors of the interaction. As a result, clinicians gained molecular tools to 1) detect the expression of PDL-1 in cancer cells, 2) combat immune escape, and 3) create more targeted and effective treatment options for patients (Akinleye and Rasool, 2019).
It’s important to appreciate that translational research is bidirectional: from the lab to the clinic, and from the clinic to the lab. For example, surgical oncologists will resect tumors from patients in the operating room and use tissue samples from the tumors to create cell lines for investigation in the lab. Think HeLa Cells, but ethical. In the lab, scientists analyze the cancer cells to define the genetic and immunologic characteristics of the tumor, which help define optimal treatment strategies. Cancer is heterogeneous, meaning it takes different molecular forms and evolves rapidly to change form. Translational research is critical for personalized medicine to identify the cancer characteristics for the individual and combat the cancer more precisely.
As an undergraduate, I desired to understand how to advance my basic science skills to practice translational research. After all, this is a driving force behind my decision to become MD/PhD: I want to improve the therapies of modern medicine. At first, I thought basic science and translational research were separate branches. Over time, I learned that translational research is basic science applied to clinical problems — they are not mutually exclusive; it is a continuum. In the case of immunotherapy, the therapeutic developments started with fundamental observations — indeed, counting — the response rates of cancer cell death to genetic and pharmacologic perturbations. Simple questions, such as “what happens if gene X is depleted from cell Y?” form the basis of modern immunotherapy.
While different labs work along various points of the continuum, physician-scientists typically aim their basic science to be translationally focused. As a wonderful example, I saw a talk at the Society for Neuroscience conference delivered by Dr. Michelle Monje, MD/PhD a neuro-oncologist who studies the neuroscience of brain cancer at Stanford School of Medicine. Her lab uses basic neuroscience approaches such as patch clamp electrophysiology to study the electrical interactions of networks involving glial cells and neurons to understand the drivers of gliomas — a common form of pediatric brain cancer. Their work illustrates that neural activity enhances the development of gliomas, and remarkably, that by silencing neural activity through visual deprivation, even in genetically predisposed models (Neurofibromatosis type 1), you can thwart development of optic nerve gliomas (Pan et al., 2021). These findings have been translated into the operating room where neurosurgeons are using electrocorticography to measure the electrical activity of brain regions infiltrated by gliomas pre- and post-resection. With the findings of neural hyperexcitability recapitulated in humans, the basic science work from the lab is validated further. It’s an exceptional display of the potential of physician-scientists to bridge the lab and clinic. The story goes further along the continuum to clinical research, where the basic science and translational research findings come to bear on advancing treatment paradigms.
Clinical research: from hedonometrics to FDA approval
Without getting into the complexity and definitions of the stages of clinical research trials, I want to explain how clinical research differs from basic science and translational research. There are 2 forms I want to address, which I will distinguish as: 1) clinical trials and 2) clinical research.
To understand clinical trials, consider the examples of Dr. Monje’s research, and the development of immunotherapy. For the glioma work, the neuroscience research has revealed molecular interactions between the neurons and glioma cells that activate cancer growth in an activity-dependent manner. Like I discussed for the PD1-PDL1 interaction in other cancers, inhibitors can be devised in the lab that disrupt this interaction to combat cancer. These inhibitors are tested in human patients through clinical trials — some more rigorously than others, admittedly — with the goal of gaining FDA approval for novel therapeutics. This is when we learn whether the in vitro cell culture and in vivo animal models have accurately represented human biology and if there are side-effects. It’s the dream of physician-scientists to go from benchwork to FDA approval, though the time course of this endeavor requires decades of work, and dare I say, politics.
In contrast, the other form of clinical research is quite different. I define this form as that which the physicians and medical students conduct to improve upon or inform others about clinical best practices. There is rigorous clinical research, but the culture of this field is seemingly orthogonal to the work you pursue as a PhD student. Let me provide examples:
I don’t mean to pick on plastic surgery, but I think you can appreciate how these works differ from the basic science research literature. Inherently, there is no problem with having both types. If this helps a physician make better decisions for their patients, I am all for it. Practically, however, students are compelled to conduct such research with a high output volume to stand out during medical school. The problem is that when medical students are applying for competitive residency positions, the quantity of publications is often valued higher than the quality of the work. While you can toil for years working on a single first-author publication for a high-power journal like Nature or Cell, clinical researchers can publish 10 papers in a year. This matters because residency programs see high publication output as a reflection of productivity relative to PhD researchers. The more you publish, the better it looks for the individual and institution, and the more funding comes to the institution as a result. It’s an unfortunate reality to consider, especially if you aim to apply for clinical residency programs, such as plastic surgery. Certain residency programs are biased more towards clinical than basic science research, and it’s important to keep this in mind as you determine where to apply as an MD/PhD.
As a personal example, I am motivated to apply for the Ophthalmology residency program at Bascom Palmer in Miami as my first choice. It’s a competitive one. This is a highly clinical residency program that will probably want to see more than my basic science research in the retina for evidence of program fitness. Therefore, to be a competitive applicant, I am keenly aware of the value of clinical research experiences. While I am focused on advancing my PhD research in the retina with the mantra “a mile deep, not a mile wide,” I also seek physician mentors to conduct clinical research projects. There’s a fine balance between spreading yourself too thin and exploring your interests during graduate training. Don’t neglect the latter in fear of the former. I am excited to be working on a telemedicine project to bring tele-retinal digital imaging with artificial intelligence diagnostics into the primary care setting to improve the screening and outcomes for patients with diabetic retinopathy. This work allows me to learn about advanced imaging technology and barriers to ophthalmic care, as well as provide much-needed solutions for people who are most at risk for blindness due to diabetes.
Conclusions
It can be overwhelming to jump into the world of scientific research. It’s a new language with many dialects and cultures that you should learn to navigate. By building your vocabulary and reaching for diverse research experiences, you will be able to better define where your interests align and passions emerge. Modern medicine and academia have many problems, which I plan to write about in more detail, yet these institutions have been fundamental for the incredible advancements in biomedical science and patient care. Critical evaluation of these institutions is necessary to ensure that the momentum increases positively and continues through the 21st century. I believe it takes a team of inspired and capable people from broad backgrounds and life experiences to make that happen.
The hardest part is getting started, and if you have questions or concerns about how to proceed, you can reach me anytime at info@jakekhoussine.com. I’m not saying I know the answers, but given my experiences navigating medicine and academia successfully as a first-generation student, I am confident that I can help you find the answers you seek and streamline the process.
