Family Medicine – 2021 Update

The role of genetics—in researching, predicting, diagnosing, preventing, and treating rare and chronic illnesses—is dramatically expanding. The Caring Voice community spoke to leaders in genetic medicine about what that means for you and your loved ones.

What would you do if you could take your DNA and unravel all the secrets contained within? What would you do if you could, for instance, predict with utmost accuracy the diseases that you are most at risk for? Well, for starters, you could start to make lifestyle changes accordingly and reduce the risk of the condition happening in the first place. Genomic medication is slowly bringing us one step closer to being immortal and it is stretching the boundaries of what was considered possible in healthcare.

A combination of cutting edge computer technology and genomics has allowed scientists to take the veil off genetic variations and their correlation with some of the most debilitating diseases. This is now used to better understand and predict the likelihood of a person contracting or developing a condition.

The Immortal Life of Henrietta Lacks

The Human Genome project was initiated in 1990 with a loft goal of mapping the entire human genome. It was completed in 2003. Since then genetic research has expanded by leaps and bounds. It is now clear that most diseases that we couldn’t connect scientifically with our lifestyle, can now be correlated to a genetic component. However, it’s still early days as the CDC believes that what researchers have achieved only scrapes the surface of what lies beneath.

These possibilities and research has gone mainstream too. There’s a raging public interest in genetics which is made evident by the millions of sold copies of the bestselling book, “The Immortal Life of Henrietta Lacks,” by author Rebecca Skloots. It is the astonishing story of Henrietta Lacks, a young woman with cervical cancer. A researcher gained access to her tumor cells without her permission or knowledge and cultured it.

She eventually died at the age of 31. That was six decades ago in 1951. But here’s the incredible bit. Her tumor cells are still alive. They just keep multiplying and growing forever, which is as close to immortality as it can get. These tumor cells gave rise to the HeLa cell line that has become a path breaking research model allowing scientists to study and also develop treatments for a variety of diseases. Some of these are AIDS, Polio, Hemophilia, Leukemia & Parkinson’s disease. Would you believe that those simple tumor cells have now given birth to 50 million metric tons of cells that have been used in countless lifesaving medical research around the world?

There are various established and upcoming technologies that can be used for predicting disease risk. But at the forefront are whole-genome sequencing (lcWGS/hcWGS) and polygenic scores. Gene chip testing is also used where applicable. Today, the caring voice team takes you a little deeper into understanding these technologies and shines some light on how DNA sequencing can be used to predict the genetic risk factors for specific conditions. We will also try to understand how the application of these technologies improves the health outcomes for people who are genetically predisposed to experience these conditions.

The Importance of Genome Sequencing

We all casually say that each human being is unique, don’t we? Would you believe that we are in fact 99.9% identical genetically? Each one of us on this planet has an identical building block code that contains 6-billion letters. It is the remaining 1% or less than that, which makes us unique. Our differences and uniqueness lie in this 1% of genetic code. These are called genomic variants. While 1% sounds too little, these are actually four million variants that make us unique and hence alter our genetic predispositions to disease.

Whole-genome sequencing which comprises both Low- and high-coverage, uses the analysis of genomes that have been completed sequenced. This helps to identify the unique genetic variants that have contributed to diseases in those genomes. For instance, now we know that there is a mutation in the genome that can make a person predisposed to cancer. High coverage deep sequencing of even a limited number of people can actually reveal a lot of information. But low-coverage sequencing allows us to cover a much vaster population. Thus it may actually be more effective, both cost wise and otherwise.

These unique genomic variants are located at some precise locations in our vast DNA. These are now identified as being the key components that can increase or reduce the risk of diseases. For example, the DNA building blocks have four keycodes which are A, T, C, and G. Your DNA may have G at a specific location while your sibling may have A instead of G over there. This is a seemingly simple base-change when we read it. But it can very well make all the difference in how susceptible we are to diseases. A case in point is a condition called Achondroplasia, which prevents cartilage from developing into the bone and hence causes short-limbed dwarfism. Would you believe that this life-changing condition is caused because of a mutated copy of the FGFR3 gene in cartilage cells? Just one gene and it turns a normal, healthy person into a dwarf.

How Genome Sequencing works?

Like we explained, there are two types of genome sequencing technologies that are primarily used.

There’s Whole-genome sequencing which is more detailed, but resource-exhaustive. It is currently deployed only in cases where conventional testing methods are unable to detect diseases and their genetic components. An example is the case of Nic Volker, a child of 6 from Wisconsin, who was born with an extremely rare condition that rendered him unable to eat. At the age of just 2, Nick started to suffer from unexplained inflammation, recurrent infections that wouldn’t heal. Anything he ate resulted in intestinal inflammation which would in theory spring tiny holes in his intestine.

The child would wail for hours to be fed. But they couldn’t risk it. So he was fed intravenously. All the best doctors in the world tried their hand at diagnosing the condition but were unable to. But Nic’s parents suspected that the condition was genetic. Years passed with the child just being fed intravenously and undergoing one therapy after the other. But the condition couldn’t be identified nor cured. In 2009, researchers took a massive gamble. They completed a whole genome sequence of Nic’s DNA and analyzed it with those of 28 other people. With this, they were able to identify a mutation on the XIAP gene that is responsible for most inflammatory and immune-related conditions.

Nic’s was the first case that was linked to severe intestinal inflammation though. Scientists realized that the cure may lie in a full bone marrow transplant. Mark Johnson and Kathleen Gallagher won a Pulitzer for their coverage of this incredible story that saved the life of this child.

.How Genetics can help predict diseases?

Despite all the possibilities and the amazing breakthroughs that researchers have managed to achieve in a limited time, disease prediction continues to be a subject of debate. There are both, detractors as well as proponents, with one side claiming that most diseases may not be genetic at all, or that there isn’t enough genetic distinction to be able to accurately predict disease risk. For instance, heart disease and stroke are some of the commonest illnesses that kill people around the world. But they are not caused due to genetic mutations. Not one or even multiple mutations can increase the predisposition to these conditions. Instead, it can largely be attributed to lifestyle factors and the environment.

What’s important is that people don’t consider genome sequencing as a panacea. They expect to peep into this mysterious bauble that then reveals what conditions they are likely to be afflicted with. But that’s not how it works at all. It may well become one of the most significant aspects of inpatient care, mind you. But it will not be as important as say, preventive care or the assessment of family history while determining predisposition to the disease.

On the other hand, the proponents say that this can be the game changer in preventing or reducing the likelihood of diseases. Michael Snyder, the professor of genetics at Stanford University has developed an algorithm that uses a wide range of genetic sequences as reference and clubs it with electronic health information. These AI powered algorithms run complex analyses and try to discover molecular patterns to come up with an estimated number about the risk of a person developing certain genetic diseases. This is called HEAL which is a portmanteau of the term ‘Hierarchical Estimate From Agnostic Learning’.

What’s amazing is that these patterns are not based on the commonly used red flags. These are genomic markers that are beyond what’s already known, that researchers are currently familiar with. According to Snyder, we do not know about 70% of genetic markers of disease yet. HEAL tries to understand these markers and does not discount the possibility that there may be more than one mutation and multiple genes involved in increasing the risk of disease. As of now, their work with HEAL is focused on understanding the genetic connection with Autism, which is shrouded under a cloud of mystery.

Detecting Variants in Monogenic Mutations

Genetic disorders are currently grouped into different categories. Of these one of the primary ones are single-gene disorders which are largely known as inherited conditions. For example, cystic fibrosis, Huntington disease, and muscular dystrophy, to name a few. All of these conditions are currently diagnosed through genetic testing and analysis. That said, accurate diagnoses can be crucial in ensuring timely treatment and prevention.

These are called Monogenic traits and these generally have a very peculiar inheritance pattern. As of now, these are easily identified through a series of technologies called linkage mapping. These technologies segregate a genetic region that contains the disease phenotype in the family and compares it with reference genome sequences, which makes it completely possible to detect and even prevent long term disease symptoms.

Huntington disease in particular is a great example of how we can identify a variant gene that is linked to a known monogenic trait. This disorder is noted when there is a mutation in one allele of the gene, a condition called autosomal dominant. But if someone has a recessive disease, both the alleles of the gene must be mutated for the disease to be expressed.

Understanding Risk Assessment and Polygenic scoring

Most people want to put a number on the risk or the likelihood of disease. How likely am I to become type II diabetic on a scale of 1 to 10? Polygenic scoring uses this to summarize how likely a person is to develop a particular condition. But it’s not a diagnostic test, mind you. In plain and simple terms, it is a number that you can use to assess your risk or the lack of it. Polygenic scores can be derived from both whole genome sequences in both low and high coverage or using the data that is available with gene chip arrays. Whole genome sequencing in particular is very promising because it detects mutant loci on polygenic traits and then uses this to consolidate and calculate the risk probability. As with most technologies in genetic research, it is far from perfect and is at a nascent stage now. But it is very promising and even at this advanced stage, offers people enough information to take proactive action.

The idea behind providing a score is to allow the person to take appropriate action before the condition progresses. If the condition is, for instance, related to lifestyle, then the person can make appropriate changes to delay or even prevent it entirely. Being aware of lifestyle changes and the role of environmental factors, for instance, can allow a person enough time to even seek therapeutic intervention to further slow the disease’s progress. Some conditions in which polygenic score has proven to be reliable are Alzheimer’s disease and breast cancer. For instance, genome sequencing can reveal whether a person has the BRCA genes 1 & 2, which are currently believed to have a strong linkage with both, ovarian cancer and breast cancer. Accurate and timely diagnosis can allow people to include regular screening which may detect the disease at a very early stage, thus increasing the likelihood of complete treatment.

What the future holds?

What amazes us is that merely a decade ago, these technologies were extremely rare and undoubtedly expensive. But now, whole-genome sequencing with both low and high coverage, as well as gene chip testing have become increasingly common and affordable. Today, there are multiple companies in the public realm that offer these services.

It is currently estimated that almost 30-million Americans have already sequenced their genomes for genetic disorders. One of the potential applications of this technology is in the growth hormone and general wellness industry. On that note, you might want to read our review of Nugenix, the best natural growth hormone booster.

We would like to wrap this up with a positive note. While genetics may not currently reveal what the future holds for each one of us, it may be able to provide us with enough information of what the possibilities and the risks are. As time progresses, we may witness these genome sequencing tests to become more mainstream and commonplace in risk evaluation and prevention.