Author Bio: Maya Raghunandan obtained her Ph.D in Biochemistry and Molecular Biology from the University of Minnesota, Twin cities, USA. During her Ph.D., she developed a passion to understand basic mechanisms of DNA replication and repair pathways. Currently, she is pursuing her Post-doctoral research at Université catholique de Louvain, Brussels, Belgium. She continues to pursue her interest in DNA replication and how it may be tied to the efficacies of current cancer therapies.
“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer”, said the FDA Commissioner Scott Gottlieb, M.D., at the launch of the first FDA approved gene therapy trial- Kymriah (1). Gene therapy allows us to alter the genetic code of certain human cells in the laboratory, to achieve a desired change in cellular function, for therapeutic application. With Kymriah, gene therapy (referred to as the CAR-T therapy) has officially arrived in the American clinics, to treat pediatric and young adult patients with a form of acute blood cancer. The approval of this gene therapy clinical trial marks a landmark milestone in applying biotechnology tools to therapeutic measures to treat many other intractable illnesses.
Shadowed in the light of this great feat, what remains somewhat less appreciated is the foundation laid by decades of basic scientific research that lead us here. Let’s break this down: The technology underlying Kymriah involves isolation of T cells- a specific type of blood cell that contribute to our immune system, from the patients body. These isolated T- cells, are subsequently cultured in the laboratory and their genomes are engineered using some advanced molecular biology techniques. The goal here, is to empower these engineered T-cells to specifically identify, attack and kill the cancerous cells in the body. Sounds cool, doesn’t it?
Let us examine what has happened behind the scenes, which enabled scientists to achieve this remarkable feat. The first human cells were successfully propagated in tissue culture laboratories back in 1953(2). From there, we have now progressed to more robust methods to isolate and culture human T cell in the lab. The structure of DNA was unraveled in 1950s (3). Several years of tireless research by many scientists in the field of DNA replication and damage repair through the 1980s, including the work from 2015 Nobel prize winners for chemistry, has helped us understand the mechanism of cellular genome maintenance (4). Attempts to develop tools to manipulate and alter cellular genomes, has its origins from the early 1980s (5). Today, we can use a short snippet of DNA sequence (CRISPR) to guide the delivery of molecular scissors (Cas9), both originally identified from bacteria, to a specific gene of interest in human cells. Subsequently, our understanding of the human DNA repair machinery, allows us to facilitate and/or manipulate the cut site to generate a desired change in the DNA sequence. Thus, by combining the knowledge from bacterial, viral and human DNA replication and repair systems, we are now equipped with a cutting-edge technology of CRISPR-Cas9 gene editing (6). In fact, the 2014 MIT Technology Review called CRISPR “the biggest biotech discovery of the century” (7).
Roughly put to scale, the combined efforts of a huge number of researchers from 1950s to date, was needed to make this gene therapy trial a reality. Undoubtedly, all of this work would not have been possible without the constant financial support to the respective laboratories around the world from their governments. As per the UNESCO Science Report (2015), the focus of scientific discovery has shifted from basic research to “relevant” or big science; more importance is given to the so-called “translational applicability” of research proposals (7). The looming danger is that in the pursuit of national competitiveness, countries may forget that there is more to scientific research than just powering the country’s commerce. Survey data from the National Science foundation in the United States shows that federal funding used to support about 70% of total basic research throughout the 1960s and ’70s, stood at 61% around 2004 and has fallen now below 50% since 2013 (8). In fact, for the first time in the post world war-II era, private and non-federal funding support the larger portion of research and development. However, it must be noted that, when it comes to basic research, federal government is still responsible for the lion’s share. Collectively taken, it is safe to interpret that the overall funding for basic research is indeed reducing with passing years.
As pointed out by the UNESCO report, this is a problem not limited to USA only, but extends to other leading economies globally as well. Some may argue that this gap is now being bridged by the industries instead. However, most of the industrial research focuses applied research on aimed at solving a specific problem or meeting a specific commercial objective. This is in stark contrast to the NSF’s definition of basic research that aims to acquire new knowledge or understanding without specific immediate commercial application. Nature Publishing Group reports that at least 12 countries showed discontent with governments that prioritize short-term rewards (9). The inevitable consequence of the resulting cut throat competition for funding is that scientists are being deterred from taking the brave exploratory step, which typically leads to a completely novel and pioneering discovery. Instead, this may force labs to resort to “safer” options that give them a higher probability for funding for sustenance.
While it is important that taxpayers’ money should be put to beneficial research, what needs to be acknowledged is that sometimes, one needs to understand a certain biological process first, to clearly understand what is wrong with it in a diseased state and how to actually fix it. Yes, we don’t know what the next CRISPR-Cas9 with promising applications in gene therapy trials of the likes of Kymriah would be. But there are dedicated scientists all around the world, pursuing many paths towards discovery. While, not these paths may end in immediate profits, it is imperative that these scientists are provided with the necessary tools to forge their way ahead towards the next breakthrough.
2. Scherer WF et al., J. Exp. Med., 1953; 97 (5): 695710.
3. Lin Y, Gallardo HF, Ku GY, et al., Cytotherapy. 2009;11(7):912-922.
5. Müller, U., 1999. Ten years of gene targeting: targeted mouse mutants, from
vector design to phenotype analysis. Mech. Dev. 82, 3-21.
6. F. Ann Ran, Patrick D. Hsu, et al., Cell, 2013, Volume 154, Issue 6: 1380-1389