Innovations in Medicine

Imagine one day your doctor takes a swab from your buccal mucosa, and a few days later tells you that you have a pretty high chance of developing Alzheimer’s disease thirty years into the future. What would you do? Would you start living your life in a state of constant apprehension? Would you panic every time you experience a lapse of memory, ever fearful of the clutches of dementia closing in and turning you into a bumbling mass of drool and diapers, while the fog of forgetfulness washes off the entire world that you once knew? Or would you keep on living your life with nothing changed, determined to deal with the situation as it evolves far into the future?

The above scenario might sound like an exercise in science fiction. However, in reality it is actually a very possible situation that we might find ourselves in, thanks to the immense leaps forward taken by medicine, genomics in particular, in recent years. Next generation genome sequence has been there for some time, but finally we are close enough to making it available as a clinical diagnostic tool for the masses, ushering in the era of personalized medicine. The entire human genome is made up of around 3 billion DNA base pairs that code for roughly 30,000 genes. Until now, outside of the research sphere, genetic tests performed in a clinical setting only assess a single gene, or a small gene panel of interest, typically one that is relevant to a particular genetic condition in an individual. Next generation sequencing techniques, however, changes this approach quite drastically. It is comprised of three core approaches, namely whole genome sequencing, whole exome sequencing, and targeted sequencing. Whole exome sequencing only looks at the protein coding regions (exons) of a target genome, and targeted sequencing gathers information from a slice of the genome, usually one with high relevance to a specific disease. Next generation sequencing, when done on a cluster of genes, classifies them into one of five categories. They are a) likely pathogenic, b) pathogenic, c) unclassified, d) likely benign and e) benign.

This helps physicians and scientists determine whether that particular genetic variant will result in the development of a particular disease in the person or his descendants. On the other hand, whole genome sequencing enables us to know the exact position of every single nucleotide base pairs of a person’s genome. Comparing this to other genomes that have been sequenced, we can find out the genetic similarities as well as differences among different people. It will also shed some light over the mysteries of the non-coding segments of the genome. In fact, the technology of whole genome sequencing is already being used to determine the relationship of an endogenous population of people with other populations across the world, thus providing us with important information regarding the evolutionary history of mankind. The immense amount of information thus gained from next generation sequencing techniques gives us an in-depth understanding of a particular individual’s genetic make-up. This directly translates to better diagnostic, prognostic and therapeutic approaches regarding the patient, especially in light of his or her family history and genetic predisposition or resistance to particular diseases. This would thus enable a physician tailor a treatment plan to his patient’s particular needs.

The greatest value that the next generation sequencing adds, however, is where it enables physicians find out rare DNA variants that aresolely responsible for the presentation of certain rare diseases. This utility has led to astounding advancements in the diagnosis and treatments of numerous novel genetic conditions, reducing both the cost as well as burden of the disease on the person and society as a whole. Next generation sequencing has also changed the way we look at cancers, shedding new light into the hereditary aspects and various genetic and molecular factors involved in the development and progress of various tumors in the body. Looking at the whole genome of a person also provides us knowledge regarding recessive genes that would otherwise remain latent within the person, and would instead confer a carrier status to the person, leading to a potentially fatal manifestation of a disease or syndrome in his or her descendants. Whole genome sequencing can also be used to understand the relationships between different genes that lead to the expression of certain phenotypes in a particular person. This would lead to a better understanding of the multigenic nature of several diseases like hypertension or diabetes, and would also help physicians and scientists shed some light on to the roles that nature and nurture plays on the growth and development of a human being. One of the most important roles that next generation sequencing is poised to play in this context is in the field of genetic engineering, where it would enable us to see the different interactions that various genes would have amongst themselves and a modified gene inserted into the genome.

This would, in turn help us create new and improved treatment modalities to combat hereditary diseases like sickle cell anemia or hemophilia. In the past few years, the technology of next generation sequencing has left the realm of being exclusively used for scientific research to being a tool that can be used by physicians all around the world to diagnose various diseases in the common man. This is largely because of the fact that the cost of next generation sequencing has steadily reduced from millions of dollars per genome to only a around a thousand dollars in a very short span of time, and this cost is projected to fall even further in the coming years. Next generation sequencing can replace the multitude of single gene tests that are currently done on separate specimens with a singular standardized test required to be performed only on a single specimen. This would lead not only to increased efficacy in screening genetic disorders and correlating them with the patient’s family history, but also developing intervention strategies to mitigate, if not eradicate certain genetic disorders that have been plaguing civilization and mankind. Also, the increased accessibility of a technology such as next generation sequencing to the common public means that it can be employed in family planning programs, thus leading to early diagnosis and prevention of currently incurable genetic disorders. It can also establish itself as one of the gold standard diagnostic modalities to diagnose and combat several types of cancers. Having a database of genomes would also help us track how the different and constantly evolving environmental stressors are affecting humans on a genetic level, and whether these effects infer better or worse survival capabilities to the human species. The technology of next generation sequencing has finally made it possible for doctors to treat not the disease, but the patient; and is poised to play one of the most important roles in ushering in the era of truly personalized medicine. With all these benefits, however, there are still a number of hurdles that need to be crossed to translate this nigh revolutionary technology into clinical practice.

One of the most important challenges that need to be addressed is the requirement of expertise. Most of the Next Generation Sequencing technologies require complicated hardware and software, and therefore also requires a team of sophisticated experts well-versed with molecular and computational biology, bioinformatics, bioethics and medicine to interpret the test results accurately. Setting up such teams to would need changes in the existing curricula of medical sciences where the prospective physician would not only be taught medical disciplines but also the nitty-gritty of the interpretation of high dimensional data. Secondly, there is the question of theeconomic burden. While the cost of access to next generation sequencing has lowered drastically in the recent years, it is still a far cry from being universally accessible. Other diagnostic tests that are currently used can provide fairly accurate data at a mere fraction of the current costs of whole genome sequencing, without needing an expert in both medicine as well as computational biology to interpret the results of the test. Thirdly, there is the problem of data storage. Each whole genome that is sequenced generates hundreds of gigabytes of data, storing which is practically impossible in the current condition of the healthcare infrastructure that is in place. To make this technology a staple of medical diagnosis and treatment the entire healthcare infrastructure needs to be upgraded, enabling it to handle and sift through such large amounts of data, preferably through an interlinked set of computer clusters and advanced modes of cloud computation. Fourthly is the issue of too much information. The process of whole genome sequencing informs us of the location and status of each and every nucleotide base pair of a person’s genome, including all of the mutations that are present. This leads to the problem of misidentification of causative genes, where insignificant mutations are lumped together with significant mutations as the cause of a particular disease or syndrome.

Alternatively, significant, causative mutations are often lost in the maelstrom of incidental findings and non-significant mutations that often occur in genes and have no value in the development of a disease. This is especially a problem in case of multigenic disorders like diabetes mellitus or cancers, where seemingly important causative mutations often turn out to be false alarms. Also, sometimes, incidental findings mask much more important results, even though the chance of the person developing the rarer disease is often times much smaller than the more common mutations that are ignored for the sake of those incidental findings. Finally there is the problem of the ethics and mentality of the general public regarding the uses and implications of the next generation sequencing techniques. Knowing everything about one’s genome might not necessarily be a good thing, and situations like the one stated at the beginning of this essay might become a commonplace reality. The burden of knowing information about diseases that might not manifest might be a burden that many people would not want to bear. Also, living in a constant state of apprehension regarding a disease that might or might not manifest in their lifetime might also lead to an increase in mental health issues that has the potential to create many more health care problems that the technology might solve. Looking from the ethical perspective, the next generation sequencing techniques might be used to discriminate against genetically different individuals, and might lead to a surge in demand as well as popularity of designer babies. Balancing these with the right of a person to know about and have access to his or her genome might not be the most technically challenging of all the problems that next generation sequencing might face in its path towards translation into clinical practice, but it just might be the most important hurdle to cross. Next generation sequencing is a giant leap forward in medical sciences. It has fundamentally changed biomedical research for the better and is clearly poised to usher in a new era of fast, accurate and efficient diagnostic and treatment modalities in general clinical practice. It is still a technology that is relatively early in its development cycle, and though it is fairly optimized for clinical research, there are many problems and hurdles that need to be ironed out for it to be translated into the medical practice. Inherent complexities of the technology itself, the high skill cap needed to interpret and analyse results, and not to mention, and the ethical conundrum such a technology will bring are just some of the many problems that need to be addressed. And when they will be, the future of medicine would be waiting for us.