The very first woman to make a breakthrough that has influenced precision medicine was Rosalind Franklin via the famous Photo 51, an x-ray defraction image taken under her direction by one of her graduate students that showed the exquisite structure of DNA. Shown to James Watson without her knowledge, the image was an instrumental piece of evidence used to develop the chemical model of the DNA molecule.
Sadly, Franklin died before Watson and Crick published their findings, so she never knew the significant contribution Photo 51 made in this breakthrough discovery.
Fast forward to today, and women are making more contributions to the advancement of precision medicine—both at the bench and in the boardroom—than ever before. In this issue we publish the first of two installments highlighting some of the women helping to significantly advance the field: Lisa Alderson, CEO, of precision genomics and population health company Genome Medical, and geneticist Heidi Rehm of the Broad Institute and chief genomics officer in the Department of Medicine, the Center for Genomic Medicine at Massachusetts General Hospital.
How did you get involved in life sciences and what was it that drew you to precision medicine?
I have a varied background. I was introduced into the field of precision medicine around 2000 and at the time we were sequencing the first human genome. I was introduced to Randy Scott, who is a visionary and pioneer in precision medicine, when he was just starting up Genomic Health. I saw firsthand the importance of genomics to improve the quality of care for cancer patients. At the same time, I had a lens through which I was looking as I had friends or family members diagnosed with cancer, and took a more active role in trying to help support them and their care decisions. It became so clear to me how with the promise of precision medicine—which at that time was still about the promise—we could vastly accelerate getting the right patient to the right care. Obviously, with something like cancer time is not always on your side.
So I made this my life’s work and my passion. Even though I’ve been trained in business and came out of consumer- and technology-based businesses, it was the science of genetics and genomics I fell in love with, and the realization that medicine at times is more of an art, and having more informative tools to guide medical decision making felt critically important to me. Over the past two decades it has been amazing to see the progress in the field.
You talked about the promise of precision medicine drawing you to the field. Fast forward 19 or 20 years to where we sit today, what is the continued promise of precision medicine?
A lot of the inherent promise has remained anchored under the notion that we can deliver more efficacious medicine—and ultimately at a lower cost. That means at a population level, if we can detect disease earlier, intervene earlier, navigate patients to the right treatment faster, and reduce adverse drug response, we will improve health. Holistically, that means we will reduce some of the waste—or inappropriate utilization—by guiding those to the appropriate clinical care faster.
I’m equally excited about the use of precision medicine for prevention as well as for diagnosis and treatment. At Genome Medical, we operate in all three of those areas. Meaning, how do we understand predisposition risk and start to put individuals on more active surveillance earlier? How do we get those with rare genetic conditions to an accurate diagnosis, and do so faster? And how do we use genomics to inform treatment?
I’m also focused on the continuum of care. I think about genomics as a lifelong journey and how it can inform your care at different life milestones. Today, more and more drug development has a biomarker that will determine efficacy within a given cohort of the population, so I’m excited about so many different areas; it would be challenging to drill down on just one.
Prior to launching Genome Medical you were well situated at Invitae, what was the opportunity you saw that led you to launch the company?
I saw an incredible amount of investment going to improve molecular diagnostics, which is so important. But we now have many, many high-quality labs delivering exceptional testing in the market and there continues to be innovation in early cancer detection, liquid biopsy, etc.
My epiphany, if you will, was I saw that the field was gated and would continue to be gated by many service delivery challenges and that is all across the country. There are simply too few clinicians knowledgeable in the field to know which patients would benefit, what test to order, and how to interpret the information to inform clinical treatment decisions.
It has been my mission to democratize access to genetic care, and in so doing, lead to better disease detection, better selection of the right course of care and, ultimately, I hope, to saving lives.
We have the medicine, we have the science, we have the technology, we just can’t get it into the hands of every patient. Even today, we are 20 years after the discovery of the BRCA gene, we have had medical management guidelines in place, and we have had reimbursement coverage in place, and yet the vast majority of patients—assuming NCCN guidelines for BRCA genetic testing—are not receiving it. It is this that drives me, and not just for one specific gene. It is this notion that you have to build the clinical utility, of course, of molecular diagnostics, of great medicine, and great science, that eventually you drive the medical management guidelines, which drives to reimbursement coverage, and that eventually drives to physician and patient adoption
It is such a long cycle, and my vision for Genome Medical is, when we have utility, how do we bring forward appropriate adoption of innovation, of new technology, of new tests, faster?
When you say democratization of cancer care, I usually think of bringing it to the community setting. Is that what you mean?
Yes it is. It is how do we bring genetics and genomics to every patient all around the country and how do we do so in collaboration with providers that have so many different areas of medicine? So this affects primary care; it affects all specialties.
We do work with leading academic centers that is centered more around innovation and driving adoption of precision medicine and building the strategy and the workflows and appropriate patient consent to solve many of the barriers around just the care pathways. We do work with both the innovators, if you will, and more so today we do work with community health system.
In a community health system, we may be the genetics program. We bring a complete clinical care team across six specialty areas in all 50 states. We are transforming access effectively via telehealth, creating faster and more affordable access to clinical genetics specialists—primarily geneticists and genetic counselors, but it also includes PharmDs and other specialists.
I think of this as turning it on its head. You know patients today in need of genetic specialists are typically navigated to one of the leading academic centers and that could entail plane travel, or a long drive, and a long wait. We say why don’t we bring that knowledge and expertise, which is in such high demand and such short supply, and bring it to more providers and more patients by making it accessible to patients directly.
It is important to note that patients do self-refer to Genome Medical and we see patients directly, but our predominant model is working very closely with hospitals, and health systems, and providers, as well as payers. We want to prop up genomics more broadly and support the appropriate adoption of genomics-based precision medicine.
It seems the application of genomic medicine has started to hit its stride in the past five years. What do you think we can expect in the next five?
The biggest thing I would point to is it seems the pace of scientific discovery is rapidly advancing. The more we know about what is causative of disease and the role our genes play in cell function and overall health, the more the pace of discovery seems to accelerate.
It is that combination of the rapid decline in the cost of sequencing profoundly expanding clinical utility. The way I think of it is, if you have a declining costs curve and you have an expanding or increasing clinical utility curve, there is a point at which those two intersect and that is the point at which it becomes truly cost-effective to bring these technologies to more and more of the population.
That builds the case for population genomics. You are doing sequencing on larger portions of the population. You are doing genomic sequencing on what is identified as a high-risk cancer cohort and what is identified as a high-risk cardiovascular cohort, and what is identified as individuals thinking about family planning, and what we identify as risk or vulnerability to certain drugs, or understanding pharmacogenomics, and understanding gene to drug interactions. That is where it gets exciting and is where we are reshaping the face of healthcare.
To me, moving from translating clinical results to the provision of care and then using the result of that care is the feedback loop of accelerating new discovery and care models.
That is exactly right. It is that investment in a technology platform that we are building to drive innovation in service delivery that we see as part of our solution to bring genomics forward, to the masses. Partly that is clinical decisions support and partly that is the combination of focusing on the interpretation from the molecular diagnostic lab, which determines pathogenicity of a particular variant, and clinical care.
Knowing you have a variant doesn’t tell you what to do. So how do you turn the information of a pathogenic variant into recommended clinical care for that patient informed by their personal health history, their family health history, and that molecular diagnostic testing result? It is that combination that we are putting a lot of emphasis on to bring support to non-genetics professionals and to providers who will need to bolster their knowledge in the field of genomics and genetics. They will need tools that integrate into workflows to help identify folks where there is actionability and to bring forward medical guidelines, which are everchanging.
As our pace of discovery accelerates, medical management guidelines change, and the patient’s health history changes. That is a very dynamic set of information at play for their ongoing management. And it is that informational challenge that we are tackling in addition to the service delivery challenge.
Chief Genomics Officer, Massachusetts General Hospital
co-leader the Broad Center for Mendelian Genomics
Where did your interest in the life sciences, in precision medicine, and rare diseases spring from?
I’ve always been interested in math and science, but it was probably in high school when I first learned about genetics and became fascinated by it. I think some of it was the precise structure and the predictability—to go from this DNA sequence, to RNA, to protein, to function. And then the ability to discover—which came a bit later—how a gene can be disruptive and lead to a predictable mendelian disease.
It was the ability to understand at such an exquisite level and then offer the opportunity to inform an understanding of why people have these diseases that was really satisfying to me. You could sequence a gene, or eventually a genome, and find the cause and give that explanation to someone. Then, because you understood it—the hope for treatment is also something that I saw—that we could actually do something for those patients.
From my standpoint, two of the things that fascinate me the most is to diagnose and then begin to treat, based on the underlying cause. That is mostly in the mendelian diseases side of things, although we are beginning to understand more complex diseases in a way that will allow better prediction for which treatment, pharmacologic, and surgical interventions might make more sense in a person’s disease—be they genetic or not genetic. The other element is the better ability to predict disease, which is something we’ve often not been able to do well in medicine. But genetics and genomics offer a greater promise in that area so that we could anticipate the onset of disease and intervene to prevent that outcome.
That is certainly true of rare diseases, especially diseases like hypertrophic cardiomyopathy and other rare diseases that have a later onset. This allows the ability to screen and intervene, but also—as we start to understand complex disease and better make use of polygenic risk scores—to stratify the population into those that might warrant more aggressive standard approaches to preempt even more subtle disease.
Most of things we do to treat patients that are amenable to calculating polygenic risk scores are not that different between those at risk and not at risk. But how aggressively do we treat these patients in terms of screening and when we provide pharmacological treatment for lipid lowering drugs and other (treatments)? We can’t afford to treat everyone, healthcare just costs too much, but being able to stratify people by risk holds hope that we can place our healthcare dollars in those at most need.
Based on what you have witnessed in your current roles with the Broad and Mass General, and the trajectory of advancements in knowledge and technology, what do you think the next three to five years hold?
Three to five years is not that far away. We still have a lot of barriers to overcome to getting routine genomic medicine in the hands of patients. Right now, our approaches are still focused on diseased individuals, for the most part, and ensuring that they have genetic or genomic testing to be able to diagnose existing disease and ensure that we understand and treat it appropriately.
It was shocking to me, when I took this role (at Mass General), to see that there were many clinics and areas that just weren’t getting routine genetic testing offered to them. Some were, and we have very robust hereditary cancer testing that is ongoing, but we had other areas that weren’t as long standing and people were figuring out just how to get these patients tested. So we have been standardizing and developing best practices across the hospital. In three to five years, I believe we will make sure everybody has access to genetic testing when they have symptoms that warrant it.
I think in five plus years is when we really want to ask if should everybody have their genome sequenced and have access to preventative medicine. Carrier screening; polygenic risk score calculation; rare diseases that could onset all could take a little longer, but in the five- to 10-year range, I hope that is where we are headed.
I’ve spoken with people who are pessimistic about being able to get there based on our fragmented healthcare system.
I think there are major challenges there. The interesting thing is that research sequencing is taking off. The number of biobanks and cohort programs that are developing where people are getting sequenced are growing enormously. Obviously, in the U.S. we have the All of Us program. There is a lot going on where people can get access to their sequence and there is so much we have to learn from that data, that it does beg the question whether people are more likely to get their genomic sequence from a research program than they are from clinical care.
The interesting thing is because people can get access to results—we are going to be returning actionable findings from the All of Us research program from the genomes that we sequence—people may essentially get some of the clinical information back from research programs that they would have ideally gotten in the clinical setting. All of Us is starting with hereditary disease risk and pharmacogenomic risk, but is likely to move on to carrier screening and polygenic risk scores and other information.
So it begs the question of where people will get this first—through well-organized research programs or through clinical care. And to be honest, I don’t know, but my money is on the research side.
In your role at Mass General, what mark are you hoping to make?
At Mass General it is about establishing best practices, integrating genomic medicine into medical practice. That is everything from getting patients the genetic testing they need and supplying genetic counselors. Some clinics have full-time staffing needs for genetic counselors and others need just part-time genetic counselors. We can help supply genetic counseling, as needed, for these smaller clinics, but it is really getting best practices, and consent, and ordering, and return of results, and all of those things, back to patients. We have also launched a preventive genomics clinic to think about the preventive side and not just address existing symptoms.
We are trying to roll this out in a systematic way that includes when we have genetic testing done, that those results are entered into the electronic health record in a way that is not just a scanned pdf, but actual data that can be accessed over time and can be updated as genomic knowledge changes so these patients are getting the most accurate and up-to-date results.
As we move to exomes or genomes and we learn information from these exomes or genomes that might have been ordered for a different reason, we can access that data and use if for other indications. So that is where I’m hoping on the clinical care side I can really make a difference.
And how about at the Broad?
Some of my work is gene discovery. We have a large effort in that area to discover new causes of genetic disease. The other really important areas are the work in ClinGen and gnomAD where we are trying to support global knowledge sharing and global data sharing—trying to provide resources to enable everybody out there to offer (genomic medicine), not just the most prestigious academic medical centers.
We are encouraging approaches to share data, to collectively interpret variation and its role in disease. Making the results of that work accessible to the entire community is a critical thing.
And my role in the Global Alliance for Genomic Health is about standards, so that we can interoperate across the world and everybody’s data can be a part of gnomAD and everyone’s knowledge can be a part of ClinGen and ClinVar. It is going to take that because genomics is so enormous and so complex and understanding the role genetics plays in disease will require enormous data sets to do that. It requires standardization of genomic data, in clinical data/phenotyping, as well as knowledge curation.
It strikes me that serving in both research and clinical roles that you have a comprehensive view of the genomics landscape, how important is that to inform the work you do?
I would say it is really important to have people who understand both worlds because they deal with very different issues. In research, everyone gets consented into a research study and you can put in that consent that we are going to share your data with X, Y, and Z. It is established as a requirement. Now interoperability of these data is a different thing, and we have a lot of work to do there. At least there is a standard.
In clinical care, physicians are so strapped and healthcare dollars are so limited, that adding extra time to allow patients to (consent to) share their data is very difficult. So thinking this through, how do we take an environment that is poorly optimized for what it needs to do and add labor and add requirements. That is really challenging. But we’ve seen the ClinVar data sharing model was really about working to define what could be shared without consent and defining the ability to do that, why it was acceptable, and what could be shared, so labs could just dump their databases into the public domain without concern. Coming up with those standards and the guidance was hugely important.
And now the over one million unique variants and our unique interpretations that are in ClinVar have provided massive changes to the accuracy and quality of genetic test interpretation.