Decoding Our DNA: Exploring the Future of Gene Sequencing at AACC 2023

This week I’m attending the American Association for Clinical Chemistry (AACC) now Association for Diagnostic & Laboratory Medicine (ADLM) 2023 Annual Scientific Meeting & Clinical Lab Expo, a five-day deep dive into the most disruptive technologies in the diagnostic space and the future of laboratories. 

On Sunday, the first day of the conference, I attended a half-day workshop on the current state of next generation DNA sequencing – and it really feels like the future has arrived! 

It was just over 20 years ago that the Human Genome Project completed its signature accomplishment: generating the first sequence of the human genome. It cost $2.7B. Thanks to the work of many talented researchers and scientists today the whole genome can be sequenced for as little as $200 in a matter of hours (though prices for patients are typically closer to a few thousand dollars once clinical interpretation and genetic counseling are factored in, especially since insurance doesn’t always cover it).

The workshop was led by three amazing professors – Christina Lockwood, Jillian Buchan, PhD FACMG, and Vera Paulson, MD PhD, coincidentally they were all from my alma mater, the University of Washington.

Here are my five key takeaways:

1. There are a lot of potential applications – some are already here and others are starting to open new frontiers.

Genome sequencing is the process of determining the sequence of an organism’s DNA, which is essentially a blueprint of one’s genetic code – an “instruction” guide for ourselves if you will. It serves as a valuable tool with a wide array of applications.

As Professor Lockwood points out, it’s become increasingly popular in prenatal tests, inherited disorders, and somatic analysis, which refers to the examination of genetic alterations that occur in “somatic” i.e. non-reproductive cells.

The advances in genome sequencing are giving rise to new frontiers. For example, the field of pharmacogenetics, which explores how an individual’s genetic makeup influences their response to specific drugs, and polygenic risk scores (PRS), which estimate an individual’s genetic predisposition or risk for developing a particular trait, disease, or condition.

2. There are different types of genome sequencing – and they each have their trade-off.

As Professor Buchan made clear, when you get your “genome sequenced”, you could get a 1) Whole Genome Sequence (WGS), 2) Exome Gene Sequence (EGS), or 3) a panel. The WGS looks at the complete DNA sequence. The EGS looks at the coding regions of the genome. The panel is a targeted sequence that contains a select set of genes or gene regions that have known or suspected associations with a disease or phenotype in question.

Imagine a genome sequence as a map. A WGS is like seeing the world map laid out with all the landmarks, including the ocean. An EGS is like getting a view of the continents only – you get the land where the majority of our human lives take place, but you’re still missing a huge chunk of what’s happening on earth. A panel is like getting one state, say “Texas” – it may provide more specific information for the one area but it doesn’t give the whole picture.

As you can imagine, the trade-off comes down to coverage and cost. A detailed WGS is the most expensive but it provides the most information. If you only need information on a few specific gene regions, a panel makes the most sense because you can get what you need more affordably.

There’s still so much we’re learning about our genome. If you get your whole genome sequenced, you’ll have all your genetic information ready to apply new insights to your own data as they become available. However, if you only get a specific region tested and new information arises, you may have to get another sequence in the future to apply the latest findings to yourself.

3. The real value in genetic sequencing isn’t just knowing; it’s actioning the insights to improve one’s health.

Initially, it was very exciting to observe variants in genetic make-up and associate said variants with disease states. However, getting genetic sequencing just to “know” your predisposition is relatively useless unless you have a way to improve any unfavorable variants. In other words, it is not very useful to know you have a genetic variant that indicates you’re extremely likely to develop breast cancer unless you can do something about it. 

As our understanding deepens, so too does our ability to use genetic insights to confirm diagnoses and estimate risk, then inform the best treatment and/or preventive action(s) for each patient. For example, we can now perform genetic screening on babies to determine if they have Hereditary Acrodermatitis Enteropathica or, in simpler terms, a genetically-induced zinc deficiency, which can be fatal if untreated. Once the condition is identified through genome sequencing, there’s an easy fix for the standard case: zinc supplementation.

4. Costs are going down but insurance coverage is still a barrier to widespread adoption.

On average, it costs around $1,000 per WGS, which many patients must cover out-of-pocket because insurance coverage is still spotty in the US. In an unfortunate and tedious chicken-and-egg situation, many insurance companies are waiting to see the clinical value of WGS but the hefty out-of-pocket cost deters many patients from getting their whole genome sequenced. When few patients are opting in for WGS, it makes it challenging to prove the value and so the cycle continues…

However, early studies have shown the value of genetic testing. Research from the 100,000 Genomes Project pilot study shows an increase in diagnostic yield across a range of rare diseases – and, more importantly for insurance companies, reduced costs in treating those patients!

What’s more, there’s a growing trend of “recreational genomics” (i.e. people getting their whole genomes sequenced to learn about themselves for fun), which is helping to move the needle forward!

5. Gene Testing has a very promising future ahead – but standardization and ethical dilemmas will be a huge challenge.

As costs continue to come down and insurance companies provide more coverage, DNA sequencing is likely to become a standard go-to in clinical care over the next 5-10 years. From a business lens, this is a huge opportunity: the potential market for gene sequencing is predicted to be at ~$23B by 2025.

However, as with all new technologies, there will be challenges. It will be important to establish accurate and appropriate reference ranges, to ensure a standardization framework for classification and reporting is in place, and to provide guidelines for net new scenarios. For example, what should clinicians do when they run a WGS for a patient and they discover information that may affect other family members? Is the clinician then obligated to inform those family members, even if they are not a patient? As Professor Buchan notes, one solution here is to have each patient decide whether they and their family would like to be informed of secondary findings in their consent waiver prior to completing the WGS. 

At the end of the day, the cat is out of the bag – or should I say, the DNA can no longer hide. We will have to do the best we can to move forward with these new technologies together as a society.