The Genome Pioneer

Reflecting on the 20th anniversary of the completion of the Human Genome Project (HGP) in 2023, what do you see as the most significant advancements or discoveries that have followed since this endeavor, particularly within the field of pathology and laboratory medicine?
 

The most impactful advance we have seen in genomics since the HGP’s completion has been the technical strides in genome sequencing. Back then, sequencing that first human genome cost about $1 billion. Now, less than two decades later, we can sequence a patient’s genome for diagnostic purposes for less than $1,000. Having inexpensive genome sequencing available also means you can do all sorts of research studies to gain a deeper understanding of how the human genome works and how variants in patients’ genome sequence influence their health. 

So, if I had to pick a single advance, it would be the greater than million-fold reduction in the cost of genome sequencing that we achieved in less than 20 years. 

What role has the NHGRI played in driving these advancements?
 

NHGRI was created by the US Congress to lead the National Institutes of Health’s effort in the HGP so it did not exist until 1989. [The HGP launched in 1990.] Since the project’s completion, the NHGRI has morphed quite significantly and is now responsible for leading basic and clinical human genome research in the United States. A big difference is that, 20 years ago, we were the only institute at NIH doing genomics; now, all institutes at NIH fund and conduct genomics research. At NHGRI, we aim to be at the forefront, driving advancements in the field and enabling others to use genomics in their studies. 

How has the landscape of genomics research and its applications in pathology evolved since the completion of the HGP? 
 

I became involved in genomics when I was a resident in clinical pathology. At that time, genomics was not very relevant in pathology. At most, we would do Southern blots to look at gene rearrangements for a handful of cancers – but no genomes were being sequenced back then, certainly not human genomes! Today, genomics is pervasive in pathology – especially in cancer diagnostics – but also in other areas, such as microbiology. It has become a fundamental tool for pathologists and other healthcare professionals, arriving faster on the scene than any of us anticipated. 

Looking ahead, what emerging technologies or methodologies in genomics do you anticipate will have the greatest impact on the practice of pathology and laboratory medicine?
 

I can think of several. If 20 years ago you told me that it would be routine within the next two decades to sequence the genome of a patient to diagnose a rare genetic disease, I would have said “Not a chance, but maybe in 40 or 50 years from now.” Yet today, this is routine, even in acute cases like severely ill newborns when genome sequencing can be performed in less than 24 hours. 

The speed at which we can generate data is remarkable and exceeds all expectations. However, we are just scratching the surface. Developing computational tools and new applications of artificial intelligence will certainly have a role to play in advancing the field. So, the next big frontier is not acquiring but rather analyzing the data – and we should expect to see significant progress in this space. 

Meanwhile, the area of “multiomics” – integrating genomics with other omic technologies, such as metabolomics and glycomics – will continue to evolve and give clues about people’s health, their disease state, its progression, and so on. Such advances may become mainstream in pathology and laboratory medicine in the coming years. 

In addition, we are just out of a pandemic, and genomics proved its relevance not only in the field of diagnostics but also in vaccine development, with the central role of RNA vaccines.

As genomics becomes increasingly integrated into routine clinical care, what challenges do you foresee – and how might they be addressed?
 

Genomics is encountering the exact same challenges that technical advances often experience in medicine. There are complex issues related to literacy, regulation, payment, and so on. And the additional problem is that genomics is moving fast. If genomics were a bit “sleepier”, then maybe the medical field could keep up. But think about this fact: the word “genomics” was coined in 1987. Which means, while I was in medical school, I never once heard the word because it did not exist. Now, genomics is becoming relevant in medicine and is moving fast, and the medical establishment (including pathology and laboratory medicine) is working hard to keep up with all the exciting developments. 

Meanwhile, genomics has permeated into many different medical specialties, without any  grand plan as to which discipline would be the major provider of genomics expertise. In that way, there is a real opportunity for pathologists to play a crucial role. 

Separately, there has been considerable private sector involvement in genomics because of the opportunities that it brings. For example, noninvasive prenatal genetic testing is now the most common genomic test worldwide, and it is performed almost exclusively in the private sector. 

Your institute recently published the 2020 NHGRI Strategic Vision. Could you give us a little insight?
 

The main difference between our 2020 Strategic Vision that is guiding human genomics this decade, and the two earlier iterations (in 2004 and 2011) is the overt acknowledgement that we can no longer strategically plan for everything going on in genomics – the field has become too expansive. And NHGRI is now just one of many funding organizations investing heavily in genomics research. However, as I said earlier, we are the leaders even though the institute is relatively small. We now consider ourselves “at the forefront of genomics” (our organizational mantra), and in our 2020 NHGRI Strategic Vision we describe how that means we are providing responsible stewardship for the field across four major domains:

1. Articulating the values and principles that undergird the field of genomics, such as data sharing, diversity and inclusion, health disparities, training, and more. We aim to help uphold and enhance these values, and also study the ethical, legal and social implications of genomics advances.
2. Maintaining the foundation for genomics that everyone relies on, like data resources, data standards, and software tools.
3. Identifying and overcoming barriers to progress in genomics. Twenty years ago, it was the cost of genome sequencing. I was a co-author of the NHGRI 2003 Strategic Vision that called for the “$1,000 genome.” As the only pathologist involved in writing that paper, I pushed for making genome sequencing something that could be done as a routine diagnostic test, and that required its cost getting down to $1,000 or less. 
4. Tackling big and audacious projects in genomics. One of them, for example, is around the multiomics integration effort that I mentioned earlier. 

What advice would you offer to pathologists and laboratory medicine professionals who are navigating the evolving landscape of genomics?
 

First, I’d remind them that they should not rely on what they have learned to date to guide their future area of expertise. If I had done that, I would have never been in genomics because I did not have any formal training in the field. In that sense, I’m a good example of a life-long learner. By doing so, it is allowing me to be part of a transformation in medicine that is changing the medical landscape, whereby all boats are being raised – including those associated with the field of pathology.

Second, if I was going to go into pathology now – and I think it is a great field to go into – I would commit to becoming agile, literate, and competent in genomics and data science so that I could help teach others. That would allow me to establish great partnerships with oncologists, ophthalmologists, and others across many different domains. Such multidisciplinary teams will come together and the more comfortable you are in genomics and data science, the more you will be able to contribute to advancing medicine as part of the team. 

I think the coming decade is going to be really exciting, especially at the interface between genomics and pathology.