How genomics can benefit us all

TRISH BROWN: (00:00:00)

So what we're capable of now in terms of isolating, finding DNA and what we can do with it at different stages is just incredible.

Dr. DANIEL KRAFT: (00:00:11)

Welcome to Healthy Conversations, an original podcast from CVS Health. I'm Dr. Daniel Kraft. Today we're talking genomics. What's the latest in the field? How can we translate genomics into access to care and what's the human impact? We have two guests to help us really dive into this topic. First, Trish Brown, the [00:00:30] Genomics and Precision Medicine Program Director for CVS Health. So Trish, you've been involved in genomics as a genetic counselor and beyond, and you've seen a lot of changes in the field. Maybe let's just dial back to how did you get into this space and what's happened since you first started studying genetics that you think is eye opening?

TRISH BROWN: (00:00:46)

So I got my master's degree in genetic counseling over 30 years ago. I have always loved genetics and biology, first in high school and then later in college. And at that [00:01:00] point in time, DNA was so expensive to manipulate that even though my degree was in genetics, I only got to touch DNA once. But I was really passionate about the intersection of how this new technology was going to change healthcare and impact people. When I first started, there were only two types of genetic tests that were relatively common. One was a biochemical test that you did during pregnancy to see whether or not the baby had spina bifida. And then we also had [00:01:30] chromosome analysis, and we were just starting to discover individual genes. So I've had a front row seat to this huge evolution where we've gone from looking at things single gene by single gene to being able to sequence the entire genome. And it's been a really exciting ride.

Dr. DANIEL KRAFT: (00:01:50)

Yeah, it's been definitely an exponential ride. I'm in the same era where I was undergrad, taking genetics or medical school, cutting out chromosomes and lining them up and no [00:02:00] ability to really sequence at all. So let's just zoom way back out and start with the basics. Can you kind of talk about the three key kinds of genetic tests, cytogenetic or chromosomal studies, molecular and DNA studies, and the ones you mentioned earlier, biochemical.

TRISH BROWN: (00:02:15)

There are three big buckets. The first is looking at how our genes or DNA are packaged, and those are the chromosomes, the basic units of inheritance that we get from our mom and dad and our eggs and sperm, and [00:02:30] they carry all of the genes. So some common examples of some chromosome things gone awry is where you may have a missing or an extra chromosome. And one of the more common of these disorders that people are most familiar with are Down syndrome, which is also called trisomy 21, where you have an extra chromosome. This type of chromosome test is also really important in cancer, particularly blood cancers because as we develop leukemias and other myelodysplasias, [00:03:00] the chromosomes can get rearranged. But we can also look at chromosomes at a molecular or DNA level. Through different sequencing techniques, we can also have what we call a molecular karyotype, where we can see not only the big changes like Down syndrome where you have a whole extra chromosome, but we can also look at submicroscopic changes, but are still at that chromosome level. And as you remember, genes make protein. [00:03:30] And so we can also look at the protein, the biochemical expression to see whether or not we actually are making a particular protein. So very common disorder that happens in people of Ashkenazi Jewish, for example, called Tay-Sachs disease, they're missing an enzyme called hexosaminidase A. So we can identify people who are carriers or who have that condition by either looking at their DNA, but we don't know all of the DNA [00:04:00] mutations that might cause the hexosaminidase A to be missing. The intermediate step is genes make messenger RNA that then tell us what proteins to make. And that messenger RNA is something that we can now measure and see how genes are being expressed. And looking at this gene expression through mRNA is becoming an important part of identifying precision medicine for cancer.

Dr. DANIEL KRAFT: (00:04:26)

So we've seen again, as you mentioned over the last 30 [00:04:30] years, a huge seed change in what's testable and then in some cases what you can even do about that on the genetic level. Sickle cell is sort of on the edge of being cured with gene therapies, bone marrow transplantation with hematopoietic stem cell, but many diseases are polygenic. What's the state of the art now about what of the 77 or so thousand genetic tests are related to a single disease and how do we kind of connect the dots between multiple genes, particularly around genes and diseases that have multiple variables?

TRISH BROWN: (00:04:58)

Genetics [00:05:00] is really primed and is best right now at identifying those single gene disorders or how a change in a single gene can impact disease. We are slowly moving into looking at things that are still classically considered Mendelian, meaning you can see a clear inheritance pattern in a family. So for example, in cardiomyopathies that are inherited, we can see two different [00:05:30] genes that independently may be associated with a cardiomyopathy.

And then as we move further down into polygenic risk scores where we're trying to understand what are the accumulation of mutations in different genes that are associated with a particular cancer pathway, and then combine that with risk factors such as smoking or drinking a lot of alcohol, where you live, simply can have an impact on your cancer risk. [00:06:00] So that's our new frontier and new challenge is how to take all of this information and we're starting to apply artificial intelligence to it as well. How do we validate that this is going to work from a public health or population perspective, whose algorithm is right? And then how do we democratize that to make sure that everybody has access to it? So those are the new questions that we're wrangling in the genomic space.

Dr. DANIEL KRAFT: (00:06:25) 

I love the sort of concept of polygenic risk course. The way I sort of think about it is [00:06:30] soon every child, even before birth, will be sequenced. We're almost entering the Gattaca age and we'll have a bit of a roadmap of their genetic risks, whether it's from diabetes or heart disease or dementias. And not everyone needs a mammography at age 40 or colonoscopy age 45 or 50, but there's a lot of things probably in between to much better guide prevention and early detection and obviously personalized therapies, when these really enter the workflow.

TRISH BROWN: (00:06:54)

Your genetics only tell you so much. They tell you what you were born with, but they don't tell you [00:07:00] what gets turned on and turned off in regards to how you're exercising, what you're eating, where you're living, what kind of environmental things you're exposed to. There's nothing available on the market yet for those types of interventions like your Fitbit or your Apple Watch with your genetic information and routine lab information that's kind of telling you what your glucose level is today, but it's something that we're really excited about at CVS Health. What can we [00:07:30] help people really personalize and bring to life in the future?

Dr. DANIEL KRAFT: (00:07:33)

Right. Yeah, the art of the possible now is getting really incredible. There's certainly been an uptake in the volume of genetic testing and now testing in utero and it what's sort of driving all this and what are some of the pluses and the pitfalls from your perspective?

TRISH BROWN: (00:07:47)

Early genetic technologies were very labor intensive and you had to know exactly what gene you wanted to test. Now we have next generation sequencing testing platforms where [00:08:00] if you wanted to, you could sequence the entire human genome and then you use bioinformatic filters to just pull out of that what you think is relevant. And so those sorts of technological advances have really dropped the cost and has really allowed for a broader set of testing. During pregnancy, there is fetal DNA that will cross the placental barrier into the mother's blood. Collaborating with other sorts of disciplines like nanofluidics [00:08:30] with physicists, we are now able to extract cell-free DNA out of human plasma. The tests that have the best evidence and are validated and in clinical use right now are the non-invasive prenatal testing, NIPT.

And that does look for chromosome problems like Down syndrome, trisomy 18, trisomy 13. So those are things that are commonly in use. But we see that with cancer as well. As cancer [00:09:00] grows and develops in your body, those cells break apart. Your body's attacking it, trying to get rid of it. So there is DNA that has come from tumor cells in the body that are in the blood, and we can also extract those circulating tumor DNA and do testing to find out what kinds of genetic changes have happened in that tumor. Is there a specific precision medicine therapy for that tumor? So what we're capable of now in terms [00:09:30] of isolating, finding DNA and what we can do with it at different stages is just incredible.

Dr. DANIEL KRAFT: (00:09:37)

And from my perspective, I think what's exciting just in the last year, you can now order, still mostly in a bucket, a blood-based biopsy for early cancer detection, using essentially the same technology. And that's going to be a big game changer, particularly for things like ovarian and pancreatic.

TRISH BROWN: (00:09:53)

We still have some evidence to collect on those particular early cancer screening tests, but they've been [00:10:00] really well demonstrated that it works well for colorectal cancer. As you might imagine, something like pancreatic cancer, ovarian cancer, takes a longer period of time because they are just such hard cancers to find at an early stage. So the evidence is going to take a while to come about for those particular tests, but I feel certain that it will.

Dr. DANIEL KRAFT: (00:10:24)

It kind of feels like we're entering this golden age of omics and multi omics and being able to connect the dots-

TRISH BROWN:

Definitely.

Dr. DANIEL KRAFT: (00:10:29)

From data [00:10:30] to insights to action, it's a complicated moving field. What do you see as the human impact of all this when you need to communicate with parents to be or someone diagnosed with a new genetic disorder? Or how do you as a genetic counselor think about that conduit?

TRISH BROWN: (00:10:44)

There's definitely a lot of conversation to be had with people that are considering genetic testing. You need to think about all of the implications of inherited cancer screening when you undergo it. When you test [00:11:00] yourself, you're also getting information about your biological family members, and you may want to share information about what your own test results were, and they may not want to hear it. People have very complicated reactions to learning about their own inherited cancer risk. Even if a test is negative where no inherited variant was found, if you come from a family history where there's a lot of people in the family with cancer, [00:11:30] you might have survival guilt.

It may make you feel isolated. And so those are the things that genetic counselors help people think through. It's also important to know what kind of lab that you're dealing with. Because this technology has gotten so inexpensive, there's a lot of people who are not specialists in this area that are basically out there to take your money and give you back information that may not be useful for you, if they do any testing at all. It's really important to make sure [00:12:00] that they are credible, they've got good reviews, they've got a customer service support, they have the ability for you to contact an expert and a genetic counselor so that you know that they really are a legitimate entity.

Dr. DANIEL KRAFT: (00:12:14)

Yeah, there's certainly been an explosion in consumer genetic testing, whether it's the early days of 23andMe to ancestry.com. But even something as relatively low cost as pharmacogenetics really hasn't yet translated to clinical care. How would you see the challenge and opportunity to go from [00:12:30] all these new massive forms of data into the workflow of the physician, the pharmacist, and the patient?

TRISH BROWN: (00:12:35)

One of the problems with pharmacogenetics, and it's something that I've been working on since well before 2000 when pharmacogenetic tests were first starting to be developed, is that how to determine the genotype and how to assess how someone per medication is actually reacting to it, has only been standardized in the last [00:13:00] couple years. For example, the most prominent gene for pharmacogenetics is the cytochrome P450 2D6 gene, which metabolizes 30 to 50% of all medications that people might take, particularly the common ones. But there were not standards in how many variants you needed to use in order to be able to call whether a gene is a poor metabolizer or not, until 2021.

There was a study that came out of University [00:13:30] of Michigan just last summer that showed that when they looked at different pharmacogenetic reports, there was disagreement between 30% of the reports on whether a person was truly a poor metabolizer, an intermediate metabolizer or not. You need that information at the point of care before you prescribe a drug. And also, if the pharmacogenetic information has an impact, you need to get that back in front of the prescriber in order for them to make the right [00:14:00] sorts of decisions about it. Physicians have alert fatigue from all of the little messaging that they get from the EMR, and so we can now put pharmacogenetic information there at the point of care, but I feel more confident than ever that we're inching toward the right solutions.

Dr. DANIEL KRAFT: (00:14:16)

There's an overwhelm with alert fatigue, but also sort of data fatigue. Very few clinicians are genomic experts, so you need to sort of synthesize that down. Meaning there's a common set of pharmacogenetics around statins, for example, or aspirin resistance, [00:14:30] or the trick is the insights made applicable and not requiring a PhD to implement them.

TRISH BROWN: (00:14:36)

Sometimes the reports that come back from the laboratories are so complicated, you do need that PhD in order to read them. Regulatory requirements to do good may have gone a little too far. So one of the most important growing areas of genomic testing is somatic tumor profiling. What are the genetic variables that are [00:15:00] driving this cancer for this patient? And it's a requirement for the laboratories to report back what are the possibilities that are associated with what they found in the tumor. Well, that's a pretty overwhelming task to keep up with all of the potential clinical trials that are out there. And so often a healthcare provider might get a 14 to 20 page PDF about their patient's tumor, and it's all written in [00:15:30] genomics language. And I know that some treating physicians are loath to use some of these technologies because they may get something back that's not actionable for them.

Dr. DANIEL KRAFT: (00:15:41)

Right. I'm an oncologist, and those reports can definitely be overwhelming. We're a few months into the chat GPT explosion, and there's a lot of potential to use some of these integration tools to create that digital twin or the synthesis of what might be the most actionable next step. So we're in a really exciting time. We've talked about the pace of [00:16:00] change. The first human genome was arguably three, four billion dollars in early two thousands. Now it's arguably down to about 200 US dollars. Probably in a decade we'll be down to $10 or less than certainly a complete blood count or a chest x-ray. Where do you see the field going in terms of the speed of sequencing, the ability to make a rapid, genetically based diagnostic and how that's going to impact precision medicine?

TRISH BROWN: (00:16:23)

You had mentioned newborn screening earlier. Well, there is now a new project of doing [00:16:30] whole genome sequencing as newborn screening. And so that's something that we've talked about in this field forever, where you're born and you get your genome done and it travels with you throughout your life as part of your medical record. And you query it as needed based on the sorts of health issues that you want to manage or you might develop.

Now, the intent is to just return results of that newborn genome for just [00:17:00] about 400 disorders that are considered actionable in the newborn period. That if we do something in the newborn period, it will prevent negative downstream consequences, such as diagnosing epilepsy very early and making sure that if there's a novel therapy that will help control or prevent seizures, that we get it to that infant right away. In the newborn period, it's really difficult to diagnose those things. Between 30 to 50% of babies in the NICU [00:17:30] do have what appears to be a genetic condition. And by doing rapid whole genome sequencing of those babies, you can really change what happens to them in the NICU. We have seen a record now of from the point blood was taken to the time result was given back to the doctor, 13 hours.

Dr. DANIEL KRAFT: (00:17:50)

Yeah. I think last year at Stanford actually, they broke the record to six hours from blood to full sequence. I remember as a resident in the NICU, a couple tragic cases, twins that had a [00:18:00] urea acid cycle rare genetic issue. It took a couple weeks to get the results back, but maybe having that within hours would change the intervention and the outcome dramatically.

TRISH BROWN: (00:18:08)

Especially for those metabolic disorders, hours, minutes, absolutely matter.

Dr. DANIEL KRAFT: (00:18:15)

But it does come with a whole Pandora's box of ethical challenges. We're obviously entering an era where if you know you have a potential recessive trait, you could do IVF and select your embryos. What do you see when you're counseling or beyond that all the way to [00:18:30] the potential discrimination that might occur from underlying genetic risks?

TRISH BROWN: (00:18:35)

There are definitely a lot of ethical, social, legal issues to consider. And there's some just really simple ones that often get overlooked. Children have gone through some significant hardships because their parents did not understand some results that they got from newborn screening or from family testing. So there was one family that shared with the school [00:19:00] that their child was a carrier of cystic fibrosis. It was information that they had gotten from newborn screening. Well, the school didn't understand what that meant and said, so sorry, we already have a child here with cystic fibrosis. You cannot attend. There was a misunderstanding of you're not supposed to have a lot of children with cystic fibrosis in one place because of the risk of spread of pseudomonas and other infections that they're most prone to.

So that's the first place, that we educate the families that receive [00:19:30] this information what is actionable, what is useful, and what is not. That raises the ethical question of at what age would you reveal to someone that they're a carrier of a BRCA variant, for example, that puts you at increased risk of breast cancer? We do see teenagers with a BRCA mutation that can develop breast cancer. Usually people develop it in their thirties, but it's a spectrum. It can happen younger, it can happen older. At what point do you share [00:20:00] those adult onset disorders? Most IVF clinics offer aneuploidy screening to see if there's extra or missing chromosomes for an embryo prior to transfer. But if they've done broad carrier screening or even a whole exome or whole genome on the parents, then they will also start trying to select traits just to prioritize which embryos they might transfer. So is it ethical to screen an embryo for an adult onset [00:20:30] condition that might be readily treatable in the future?

And I think it's also important to talk to this from a community perspective as well. The vast majority of our genetic insights are on people of Northern European ancestry. Definitely the Black population is underrepresented. Native American is underrepresented. And projects like all of us are attempting to remedy that. But the way that different communities [00:21:00] go about consent issues and thinking through those ethics are very different. The Native American community, for example, thinks of consent at the community level, not the individual level. As these technologies are becoming more widespread and more accessible, we have to think about the complexities for all people that might be participating.

Dr. DANIEL KRAFT: (00:21:26)

Tell us a bit about some of the innovative programs that CVS Health is doing. [00:21:30] For instance, Aetna's guided genetic health product, how does that work? And maybe a bit about the gene-based cellular and other innovative therapies network program.

TRISH BROWN: (00:21:37)

Guided genetic health is available to members that are a part of our Transform Oncology, enhanced maternity, as well as some other products that employers can participate in on behalf of their employees. Healthcare providers are not always able to identify familial risks because either they haven't [00:22:00] been trained in it, they don't have time in it, or quite frankly, it's a family secret and people don't want to talk about it. So we reach out to the member and we offer them the ability to talk to a genetic counselor, and then they can participate in screening. For inherited cancer screening, we have 67 genes that they can utilize to understand their inherited cancer risk.

We have an expanded carrier screening profile so they can understand any potential inherited recessive disorders that they [00:22:30] might want to know about during their family planning process. And then we also have a proactive screen that includes inherited cancer, inherited cardiac disease, as well as a few other adult onset disorders. We also have another program through CVS around somatic tumor profiling to get to precision medicine for a particular individual's cancer. The pipeline for gene therapy is growing rapidly. We have a network of over [00:23:00] 80 centers of excellence where gene therapy can be administered. Right now we include about 14 conditions in our gene therapy network, spinal muscular atrophy, retinal dystrophy, Duchenne Muscular Dystrophy, and CAR-T therapies for cancer, hereditary amyloidosis. And we expect things like sickle cell disease, hemophilia, beta thalassemia to be on the market relatively soon.

Dr. DANIEL KRAFT: (00:23:31)

The whole spectrum is moving quickly to the point where we might treat genetic diseases before they manifest, right? You have a child born with sickle cell or thalassemia, you may correct their genetic defect soon in vivo. Will CVS Health and Aetna cover a complete human sequence for each of its members? Do you think that'll become part of our medical record?

TRISH BROWN: (00:23:48)

Definitely something that we contemplate. It really will help inform people to take control of their life. One of the things that's really important for us is [00:24:00] ensuring the privacy of that information and that the member whose DNA sequence it is, that they get a say in who looks at it and when and for what purpose. We do have laws on the books, the Genetic Information Non-Discrimination Act, GINA, that helps prevent misuse of genetic information. But at the end of the day, when you're thinking about having somebody's genome sequence that follows them throughout their life, one of the top considerations is ensuring that [00:24:30] it's used for the right purpose at the right moment as dictated by the person who owns it.

Dr. DANIEL KRAFT: (00:24:

And it gives the opportunity for many folks to get engaged in their health at a different level, understanding their base genetics.

TRISH BROWN: (00:24:41)

Definitely. And genetic information can be motivating. Does it change how a person adheres to a diet when they know that information about themselves, when they see it on a piece of paper? And the answer is yes.

Dr. DANIEL KRAFT: (00:24:56)

So as we finish up, anything that we left out or that you want to cover that we haven't touched on?

TRISH BROWN: (00:24:58)

Our seventh [00:25:00] graders are manipulating DNA in the classroom, in middle school. Everybody is much more comfortable with genetic testing, how it might impact them, how they might feel about it. So we're seeing an evolution of how genetic counselors are interacting in the healthcare system. We're no longer at a point where every single genetic test has to have genetic counseling in front of it. But there are some tests that do. And so my message to healthcare practitioners is that [00:25:30] if you're uncomfortable with genetic testing, reach out to a local genetic counselor in your area that will help you figure out the right plan for you to incorporate genetic testing appropriately into your practice.

Dr. DANIEL KRAFT: (00:25:42)

Well, thanks so much, Trish, for being with us on Healthy Conversations. It's been fascinating to hear your experience and your perspective as we enter this sort of interesting golden age of genetics and genomics. I'm Dr. Daniel Kraft. You've been listening to Healthy Conversations, the podcast. [00:26:00] Subscribe to stay up to date with our latest episodes.