David Altshuler, MD, PhD, Executive Vice President and Chief Scientific Officer, Vertex Pharmaceuticals

Since joining Vertex Pharmaceuticals in 2015 as Executive Vice President and Chief Scientific Officer, David Altshuler, MD, PhD, has been instrumental in bringing several new medicines to patients living with serious genetic diseases, most notably cystic fibrosis (CF), including ORKAMBI®, SYMDEKO® and TRIKAFTA®. Altshuler’s strategic directions are focused on developing therapeutics for CF, alpha-1 antitrypsin deficiency, APOL1-mediated kidney diseases, pain, sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes.

Before joining Vertex, Altshuler was Deputy Director and Chief Academic Officer at the Broad Institute, professor of Genetics and Medicine at Harvard Medical School, Adjunct Professor of Biology at MIT, and a physician at Massachusetts General Hospital (MGH). Following the completion of the Human Genome Project two decades ago, Altshuler led major international programs that more fully characterized human genetic variation — the SNP Consortium, HapMap and 1,000 Genome Projects — and pioneered the methods and practice of genetic analysis of common human diseases.

In a recent interview for GEN Edge, Altshuler discussed the development of the field of genomics and its therapeutic impact since the publication of the human genome twenty years ago. (This interview has been lightly edited for length and clarity.)

GEN Edge: David, how far have we come in the application of genomics to clinical therapeutics and what are the current obstacles that we face?

Altshuler: There are three domains in which we should measure the success of genomics in clinical medicine. First is the tools and technologies and data used to perform all of biomedical research. Second is the use genetic testing to better understand people’s risk. And third is insights into human biology that inspire therapeutics.

People have often talked as if clinical genomics meant genetic testing. I think it’s the first and the third that are most important — not the genetic testing — because testing a patient is only a value if there’s something you can do about it. And the way we’re able do something about it is through better understanding tools, technologies, and data, or developing new therapeutics.

Let me give some examples of tools, technologies, and data. One is simply, it is as impossible to imagine doing biomedical research today without the human genome as it is impossible for us to imagine doing this interview and you taking notes without computers and the internet. Imagine what you and I would be doing right now. If we didn’t have that, we wouldn’t know each other. We wouldn’t be looking at each other and we wouldn’t be able to read the internet and look things up. That’s what genomics is to biomedical data.

It’s so taken for granted. My son, who is working in a biotech company now, having just graduated from college, could not imagine doing biomedical science without that data and information, where when you want to know what a gene is, you just look it up. You want to know where [a gene is located], what other genes look like it, or want to measure the expression of every gene or what have you.

The second thing that’s critically important is the example of COVID. When HIV was first described, it was three years between the description of the clinical syndrome and the discovery that HIV was the cause. How long did it take with COVID? I believe it was two weeks. How did that happen? Why was it three years before and two weeks afterwards..?

The reason is because the tools of genomics made it possible to sequence bodily fluids, and also to then subtract out computationally in a computer everything else that wasn’t COVID and what’s left is the new thing, which is COVID. But you had to sequence the human genome to do that. If you hadn’t sequenced all those viruses and bacteria, you wouldn’t do that. If you didn’t have the technology for sequencing at high-depth and high-quality you wouldn’t have that.

The other thing is: how did we end up with mRNA vaccines nine months later? They’re based on mRNA technology, which is a technology that took the sequence and turned it into a candidate therapeutic: genomics. I don’t think people necessarily connected the dots. Why is it that nine months after the description of COVID we have a vaccine? That is the fruit of the human genome project.

Genetic testing for Mendelian diseases is now widespread and routine. At the onset of the Human Genome Project (HGP), around 1986, there were few genes cloned even for Mendelian diseases. Today we know the genes for thousands of Mendelian diseases because of the HGP and the tools that were developed because of it — SNP and haplotype maps, genotyping, and later exome sequencing and whole genome sequencing. We now know the root causes of essentially all Mendelian diseases, and we know tens of thousands of genetic risk factors for common diseases and they are routinely tested.

What is the most surprising thing that came out of genomics? If you had said to me, 15 years ago, that I would watch football on TV and many of the commercials would be for consumer genomic testing for personalized risk and ancestry, I would never have believed that. It was such a basic science activity. The idea that tens of millions of people would be tested didn’t occur to us.

To the extent genetic testing facilitates risk stratification that helps identify individuals who might choose different paths and to the extent people find understanding their recent ancestry to be helpful—those are fine things. But that’s not where I think the greatest value to medicine lies. The greatest value to medicine is the elucidation of the root causes of human diseases that then inform the basis of therapeutics…

We recently published a paper in the New England Journal of Medicine on the treatment of sickle cell disease and beta thalassemia in two patients using CRISPR [genome editing]. The target we went after, BCL11A, was discovered through genome-wide association studies. It never would have been possible without the human genome that led to the novel discovery by Stuart Orkin and others of this BCL11A enhancer, which we were able to target. We could never have designed that therapy without the HGP. You need to know the sequence of the whole genome to know where not to bind.

PCSK9 and many therapies have come straight from genetic studies to the clinic. We will see many more in the coming years. That’s what the human genome has brought forth.

GEN Edge: Is our understanding of basic biology on par with our efforts to apply genomic insights for clinical therapeutics, or do you think basic biology still needs to play catch up? And what can be done if this needs to be the case?

Altshuler: One of the goals of the HGP was to reveal and study a full range of genetic inheritance that all of us have—all genes, not just looking under the light at the genes that we knew about previously. All of our DNA, all of our inheritance, not just what people had studied. And it was successful beyond our wildest dreams, in so far as we now know all the genes and people can study them. What you discover when you turn on the light in a previously dark room where there was a little candle burning, is you don’t understand most of what you see. It’s all new.

To give an example: When I was going through school, we were taught that 99% of the human genome was junk DNA and that only 1% was functional. Today, we know that of the functional DNA in the human genome, the vast majority is non-coding—25% of the human genome is functional based on evolutionary conservation, protein binding, transcription, and only 1% is coding.

We were completely blind to most of that. And in fact {laughing} there’s an article published in Nature that I love, from 1986, called The Proper Study of Mankind that argues against sequencing the human genome. One of the lines in it says, ‘some would argue that the non-coding, the junk DNA, has function, but that’s not clear, and even if it does, it’s highly unlikely that you would figure it out by sequencing it’. In fact, the way it was figured out was by sequencing it, doing comparative genomics and then studying what you had found.

To answer your question, the first thing to say is, 20 years after first turning on that light, we’ve learned a tremendous amount about genes, functions and roles of genes we didn’t know about. As a field, we’ve learned a tremendous amount about non-coding DNA and if these [regions] play a role in gene regulation—which is critical. We’ve learned a tremendous amount about population genetics and evolution. We’ve learned about the role of RNA genes, about epigenetics, a tremendous number of things.

Now, clinical genomics application almost always follows knowledge and understanding. It usually doesn’t precede it. We still need to understand, much better than we do, the roles of human genes, the complex interplay of different genes and pathways that cause disease. And that growing knowledge will inspire additional therapeutics and make the predictive tests more valuable. It’s not really a question of playing catch up. It’s not like there’s a race and there’s an end. It’s more like a spiral upwards. The more we identify about the science of human biology, the more therapeutic applications we find. The more therapeutic applications we can achieve, the more other insights can be actioned upon. I don’t think it’s a matter of all or none. It’s more a virtuous cycle.

GEN Edge: Could you comment on the advent of next-gen sequencing on personalized or precision medicine, not genetic testing?

Altshuler: The key to precision medicine is to discover medicines that are aimed at underlying cause of disease, and that are transformative medicines because they get at that root cause. So again, that is in contrast to the idea that genetic testing will somehow personalize the use of previous medicines. I don’t actually think that’s the value of genomics…

I think actual precision medicines are when you understand the root cause of a human disease, whether it’s in cancer, where there’s the discovery of a certain mutations in melanomas that then lead to B-raf inhibitors that then treat those patients, or whether it’s the CF gene being cloned and then medicines being developed that address the underlying mutations. That to me is precision and personalized medicine…

I wouldn’t interpret the term clinical genomics to mean genome sequencing and returning sequence information to individuals. That’s an extraordinarily narrow definition of what genomics has meant to medicine.

GEN Edge: What have been some of the obstacles in applying the knowledge of genomics to understanding basic biology? And could you also comment on the newfound complexity of the human genome [since the HGP] is now being considered in basic biological research?

Altshuler: Those are great questions. First, our biology is complicated as it is. Our confronting the problem by knowing all the genes and the interplay of genetic factors with the environment to cause disease, is not making it complex. It is actually making it tractable, because now we understand the complexity.

One of the biggest barriers in the application of genomics has been a cultural and generational barrier. Prior to the advent of genomics as a comprehensive knowledge base about the biology of humans and model systems, there was an unquestioned reductionism where a gene or a model system would be well understood and studied by hundreds of people and it would be thought of as the answer, the biology. People weren’t as curious about that which they could not see.

So when the genome was first sequenced and the tools and methods were made available, it was our experience at the Broad Institute and my experience in this industry that it’s often the young people who weren’t indoctrinated in a previous view who simply wake up and look around — I was one of those young people at the time — and say, hey there’s a new continent to explore. Let’s figure it out. I’ve often used the analogy of a map. People came to America. America needed to be explored, mapped out and understood. The genome was new territory.

Of course, then you discover many things you don’t know, but they are important. How do we know they’re important? Evolutionary conservation. We know that 25% of the human genome is functional and important, but we only know the functions of a little bit of it. That was true, whether we knew it or not. And that was important stuff.

Now we know it. And the next generation is working. They take that as the facts on the ground — that there is a lot of the human genome that is functional and regulatory, let’s go figure out what it does. My generation coming up was blind to it. We didn’t ask questions about things we didn’t know. I think that the barriers are obviously just of knowledge. If you don’t know how something works, you have to do experiments and figure out how it works. I think the tools and technologies have come along remarkably quickly, much faster than any of us could have known. If it wasn’t for computers and the internet, we would have been unable to. None of this information could have been managed. That was very fortuitous. If the genome had been sequenced by computers, and the internet hadn’t been there, it would be in a big book somewhere, useless. That’s an important consideration.

But what’s the biggest barrier? I actually think it’s just being interested in things we don’t know as opposed to things we do. There are many genes for common diseases that have been identified by GWAS, but the number of people who work on them as opposed to the ones that have been studied for many years, is few. The reason is you have to make all the tools yourself. You have to generate the interest. It’s harder to get a grant. Since I believe the future of medicine is causal human biology of disease and understanding that — as we have worked to do at Vertex in cystic fibrosis, sickle cell and other diseases — the more the community embraces the challenge of understanding the complexity of human disease rather than turning away from it, because it’s not reductionist, the sooner we will be able to help the people who suffer from diseases caused by that complexity.

GEN Edge: Are you suggesting that the success of genomics allows for a more systems biology approach rather than a reductionist gene model-based approach in current and future biology?

Altshuler: I would say two things. For the goal of helping people living with disease, understanding human biology of disease is critical. It is a complicated thing. It is not going to be simply reductionist, but it is the challenge if we want to help our fellow human beings.

And yes, one of the challenges conceptually for the future is for us to understand how complex gene networks and multiple genetic risk factors and environment lead to human disease, because that is evidently what’s happening in common diseases. If we choose to only understand those things that we can make simple, we probably won’t ever fully understand all the diseases we need to cure. That is the challenge now in front of us…

At Vertex, we’re working hard on a set of diseases where we think that prism has led to deep insight into a target we can go after. I think it is also important for basic scientists to work to understand all the myriad risk factors and causes of human diseases. When we click in to understand that there’s something to be done therapeutically or for diagnostics, then they can be taken and brought forward for patients.

GEN Edge: What advances do you expect in the future for genomics?

Altshuler: Three. In the coming decade we will understand much more about the role of human genes and conserved non-coding elements, and their role in biology than we know today, which will fuel a whole new world of biology.

Second, genome sequencing and testing is becoming routine and for certain diseases and certain people, it will prove very valuable, but not necessarily for everyone.

And I think we will see more examples of precision medicines that target underlying causes of human disease, and that provide transformative benefit to patients because rather than basing their hypothesis on an overly reductionist model or a model system, they will be based on causal human biology.

David Altshuler talked to Anjali Sarkar, science editor at GEN. Excerpts from this interview were first published in Clinical OMICs.

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