Genomics - What's next?

For a while now, newspapers and websites have been carrying at least one article every day on how a new gene has been discovered, how we might have potentially found a ‘cure’ for cancer or AIDS, why genetics is transforming medicine and healthcare, and that we perhaps inherit our intelligence from our mothers. Why does this field elicit so much interest, controversy, excitement and yet does not quite seem to usher in the advancements at the pace we have come about to expect from most fields in science given the computational power and the wealth of understanding at our disposal? The sequencing of the human genome was a hallmark in the history of the field of genetics. Nearly every major scientist (and politician) thought this would be the moment when the human race would finally unravel the secrets behind everything to do with looks, intelligence, physique, diseases etc. It has almost been 15 years since the project was declared a success (the complete human genome was sequenced) but how much have we learned about the genome itself to be able to address a gene’s many effects and perhaps, to be able to accurately predict one’s future based on his/her genotype (genetic constitution) and the environment he/she lives in? The answer is VERY LITTLE. Let that rather gloomy picture not discredit the extraordinary advancements that have been made in the short span of the last 3-4 decades, and especially in the last two decades with the tremendous innovations in the high-performance computing space. It is important, however to analyze and try to understand why we know so less and yet seem to believe that we know a lot about the fascinating world of genetics.

A field that has gained in prominence over the last three decades has been the interdisciplinary field of Behavioral Genetics – the intersection of psychology and genetics. The field tries to understand the genetics behind various behavioral traits which include psychiatric disorders such as schizophrenia and psychological measures such as the Intelligence Quotient (IQ). Studies on these topics have been around for a long time but the rise of the Eugenics movement in the late 20th century and the horrible practices it led to in the U.S and Europe led to the field of behavioral genetics suffering greatly after the Second World War. Eugenics (‘good genes’) was used as a tool by numerous scientists to advocate the importance of allowing only those who were healthy to procreate and thus ensure that the bad genes (traits/features) would be eliminated from the population. The biggest problem with the proponents of eugenics was that they lacked the understanding of heritability as the modern-day scientists do. Many major traits such as intelligence, height, skin colour etc. have been found to have a polygenic (multiple genes) origin. This logic applies to the majority of diseases too. Fortunately, the end of the Second World War brought the eugenics movement to an end too but left a terrible scar on the behavioral genetics field which had somewhat become synonymous with eugenics given that the field focused quite extensively on psychological traits such as intelligence.

After the discovery of the structure of DNA by Watson and Crick, the field of genetics witnessed significant advancements in the next two decades. While many of the earlier beliefs (including Crick’s Central Dogma principle) have been refuted by subsequent findings, the core ideas and discoveries remain vital for the field’s development. For years, the nature-nurture debate had raged on and on with each party believing that it had found a crucial piece of evidence to mark its victory. The most recent findings, however, confirm two facts. One - Every major physiological & psychological trait is heritable (has a genetic component) and two – genes work in close association with the environment and the environment can shape the expression of the gene. At the beginning of the human genome project, scientists and curious observers had grappled with a few questions. What would this project lead to? Would we then be able to use the knowledge of the genome sequence and combine it with highly-advanced genetic engineering technologies to perhaps edit and modify the genome? Would we be able to perhaps predict what was missing or what had changed in a person’s genome just by looking at it? Better still, would we actually be in a position to understand the individual function of each bit of the genome and thus, perhaps one day, be able to clone and create a new individual? The answer, in many cases, is both a yes and a no. One may be justified in asking why the response is paradoxical and inconclusive. To better understand this, we need to head back to twin studies – the study that resurrected the field of behavioral genetics.

Twins have always fascinated humans. Seemingly perfectly similar in identity, behavior, build, and sometimes, even in their idiosyncratic patterns, twins (especially the monozygotic variety) have emerged as a fantastic tool to study, understand, and comprehend the heritability of traits. Innumerable twin studies have been done by leading scientists and psychologists but the stand-out one in the last few decades has been the Minnesota Study of Twins Reared Apart (MISTRA). With monozygotic twins being perfectly identical genetically, any visible (quantifiable) change in a particular trait could be construed to be an environmental effect. By administering a range of tests to a number of twin pairs, psychologists found that a number of traits (features) were highly heritable with a correlation of 60% or more. Given that the correlation is never perfect (< 1), we can infer that the environment, especially the unique (non-shared) environment has a major role to play in determining the traits.

Not only have the twin studies been used to study traits such as IQ, they have also been instrumental in furthering our understanding of the genetics of psychiatric illnesses such as schizophrenia etc. As compared to the normal population, the risk of a co-twin developing the disorder (if the twin has it) is significantly higher. This finding undoubtedly demonstrates the existence of a genetic component. Finding the genetic component (or components, in this case) is a whole different ball game as scientists have found out. By comparing affected twins with a control group (unaffected population), scientists were able to identify candidate genes for multiple diseases. In quite a few cases, a single change in a nucleotide sequence (called Single nucleotide polymorphism or SNP) can determine whether a person was likely to develop a disease or not. For example, phenylketonuria (PKU) is a recessive disease (child inherits the disease only if both parents have the mutated copy of the gene) that can be traced to mutations in a specific section of Chromosome 12. A person with PKU is unable to metabolize phenylalanine and this causes significant problems and leads to mental retardation. If this can be discovered in pre-natal tests, then the child can be reared on a phenylalanine free diet thus ensuring a comfortable life. Similarly, such associations have been discovered for a host of other diseases but unfortunately, not every disease has a cure or preventive measure like PKU has. However, an early discovery in many cases can significantly help in altering one’s behavior, lifestyle choices and treatment approach. A great example would be the case of breast cancer. Early detection is the key in any form of cancer and death in many cases occurs simply because the diagnosis was done too late. However, with the discovery that the BRCA1 and BRCA2 mutations increase susceptibility to cancer, women can ensure that they screen themselves very regularly and thus, they will be able to tackle the disease highly effectively.

One might wonder why there quite a gloomy picture was portrayed in the beginning. The reason is simple – not every disease is caused by a single mutation. Almost every major disease (and trait) have polygenic origins and the effect seen (phenotype) is a result of interaction among multiple genes. The candidate gene approaches have proven to be quite disappointing since they do not show up to be statistically significant as the sample grows larger. The genome wide association studies (GWAS), which is a meta-study combining samples from multiple studies, has shown much more promise. Quite a few genes (loci) have been mapped to specific traits and diseases. For example, schizophrenia has had more than 100 such genes mapped to it. There is still a major problem though. Despite finding a number of associated genes, scientists are unable to explain more than 15-20% of the heritability with these genes. To recommend that people start testing themselves for a particular disease, at least 70% of the heritability needs to be explained. This implies that the sample size of the study needs to grow nearly 100 times. Does this mean that we should completely give up the approach? Not at all, according to many scientists.

As outlined in the breast cancer example, an early detection can be crucial in multiple contexts. A decision to have a child may be influenced by some finding. In certain other situations, lifestyle choices can be made based on the results of the tests. Personalized (and precision) medicine is also a major area of focus with most pharmaceutical companies subscribing to the view that the one-size-fits-all approach does not work anymore. Many biotechnology and genomic start-ups, including quite a few in India, are focusing their research on next-generation human genome sequencing and subsequent counselling and guidance.

Given that the computing power is only going to increase and that we are going to get better when it comes to our knowledge of the genome, there is a chance that people will start thinking that they can exercise their choice and control over how natural selection works. Eugenics is a grim reminder of how ugly things can get. Nature has also ensured that our understanding of the ways of the genome will always be limited. Curing diseases, preventing many others, ensuring lifestyle changes, and providing counselling & personalized treatment are all positive steps in the journey ahead. However, imagining that one can have designer babies, control transmission of traits, and clone human beings is a space to be avoided. As Jeff Goldblum outlined so beautifully in Jurassic Park “Genetic Power is the most awesome force the planet has ever seen but you wield it like a kid that’s found his dad’s gun.”