Democratizing the power of DNA sequencing
Some of you may be old enough to remember a time when we had magazine subscriptions. Every week a new magazine issue would be delivered right to your mailbox. My family is a family of avid readers and we loved reading magazines. For some reason, when we were finished with them, we wouldn’t toss them away. We would stack them up in the basement for some future purpose.
When I was in high school, cleaning up the basement, I came across an old issue of Life Magazine. It described DNA as the secret to life. I knew about genes and I knew about inheritance, but to read this article about how a molecule can control cell differentiation and gene regulation was really amazing to me. Thus, began my fascination with DNA. I knew right then that I wanted to be a scientist.
It’s no surprise that after high school I went to college, where I pursued a degree in biology. I still had that love for science but wasn’t quite sure how to apply it to real life. I decided to go to graduate school and pursue an advanced degree, and because of my fascination with DNA, I decided to study molecular biology.
It was in graduate school that I learned more about gene regulation, how genes get turned on and get turned off, and also about tools that we could use to understand DNA at its most fundamental level, the actual DNA sequence. In fact, it was during graduate school that I learned how to sequence DNA.
Back then, everything was completely manual. We used radioactively labeled chemicals to tag DNA fragments so that we could visualize them on a piece of x-ray film. Each column on that x-ray film represented one of the DNA bases or the building blocks of DNA. We would put that piece of x-ray film on a lightbox, and use a ruler to keep track of where we were, and go line by line and write down each base by hand. It was very tedious work.
On a good day, we could determine maybe 400 bases of DNA sequence. Remember, the human genome has three billion bases of DNA. It was kind of like trying to dig a ditch with a teaspoon.
As a postdoc, I learned about the biotechnology industry and how biotech companies were working hard to take cutting-edge technology from the discovery space into practical use. I spent the next 15 years, in fact, working to take the polymerase chain reaction technology, or PCR, into the clinical space.
PCR is a very sensitive chemical technology. It allows us to look for small fragments of DNA and then to make copies of that DNA so that we have enough material to analyze. We used to refer to this as looking for a needle in a haystack and then making a haystack out of those needles.
When this technology was first described, we had to use test tubes and water bats and pipettes in order to set up these chemical reactions. At Roche, where I was working at the time, we were able to simplify this technology and take what was a very laborious and delicate technique and turn it into something that was automated, reliable, and reproducible. Today, in fact, PCR is used in every molecular diagnostic lab around the world to look for things like the HIV virus, or the hepatitis virus, or other infectious diseases in human samples.
Today I’m doing much the same thing. I’m pursuing my passion for bringing technology closer to patients at Illumina, a local company that develops advanced DNA sequencing technology.
Well, what’s the big deal about DNA sequencing? DNA is the blueprint for life. The reason we call it that is that our DNA contains all the information that’s needed for us to grow, develop, survive, and reproduce. Sequencing our DNA can help us understand our individualized blueprint.
I once heard Eric Topol describe the importance of individualized genomic medicine from pre-womb to tomb. Pre-womb is that time when a couple has decided to start a family. We can use genetic screening to test one or both of the parents to see whether they might carry any genetic variants that could be passed on to their children and result in an inherited genetic disease.
If a couple is having trouble getting pregnant and has to use invitro fertilization, we can use DNA sequencing of the embryo prior to implantation to screen for a healthy embryo and ensure a more successful pregnancy.
During pregnancy we use DNA sequencing of DNA that is circulating in a pregnant woman’s blood to assess the genetic health of her unborn child. For women over the age of 35, it is standard of care to be tested early during the pregnancy to see whether her baby might have any genetic abnormalities, like Trisomy 21 for example, which causes Down syndrome.
Traditionally, this is done by a test called amniocentesis where a very long needle is inserted directly into the womb to take a sample of amniotic fluid that is then tested genetically. Today, using DNA sequencing, we can do that same genetic analysis from a simple tube of blood.
In newborns, genetic testing is used to test infants in the neonatal intensive care unit who are suffering from undiagnosed causes of genetic disease. In fact, right here at Rady Children’s Hospital genetic testing is being used routinely to speed up that time to diagnosis.
Earlier this year, Dr. Stephen Kingsmore and his colleagues at Rady were awarded the Guinness World Record for the fastest human genome ever sequenced, just 19 and a half hours. A few years ago, it would have taken weeks or even months to sequence an entire human genome.
To date, the team at Rady has done DNA sequencing on over 300 children. They’ve also expanded their outreach to children’s hospitals in Orange County, in Colorado, in Florida, and in Minnesota. To date, they’ve determined a diagnostic result for over 111 of those kids whose genomes were sequenced. In over 69% of them, Dr. Kingsmore said that that diagnosis has changed the way the patient was treated.
Now, some of these cases are even an emergency type of situation. For example, one baby who was admitted to Rady was suffering from severe seizures that were flatlining the brain activity in the eight-day-old infant. Using DNA sequencing the team was able to trace the cause of those seizures to a pair of genetic mutations that cause a condition called pyridoxine-dependent deficiency, epilepsy, which is treatable with a form of vitamin B6. Within 36 hours of treating the infant, the seizures stopped.
Without this genomic information, it would have likely taken the doctors weeks of trial and error, testing one antiseizure medication after another, and waiting to see whether it worked, before they found the right treatment. Getting to the right diagnosis more quickly, Dr. Kingsmore said, likely saved this baby’s life.
Throughout adolescence and into our adulthood, we use DNA sequencing to screen for infectious diseases, to track disease outbreaks, to test for predisposition for disease, and even get a better understanding of cancer.
The study of cancer has been around for hundreds of years, but it wasn’t until scientists understood that carcinogens, or cancer-causing agents, were causing damage to DNA. This genetic understanding of the nature of cancer has even led to differences in the way we treat cancer.
We started with treating with surgery alone, and then moved to radiation and chemotherapy. Now, quite frequently, cancer is treated with targeted molecular therapies, which are therapies that are directed at specific unique variants in the genes that cause cancer. In fact, today, cancer is even thought of in the molecular terminology of cancer, not just lung cancer or breast cancer, but EGFR cancer or ALK cancer, described by the genes that caused the cancer.
More recently, newer therapies have evolved that harness the power of the patient’s own immune system to fight the cancer. Cancer cells are not normal and DNA damage doesn’t kill cancer cells. In fact, cancer cells often change or mutate in order to hide from our immune system.
These new immunotherapy drugs alert the immune system to these mutated cells so that it can locate and destroy those cancer cells. You’ve probably seen ads on TV for drugs like Opdivo, Yervoy, or maybe Keytruda. In fact, Keytruda was the drug that was used to treat former President Jimmy Carter.
The next revolution is already underway. We’re moving from treatment to prevention. Several companies are using DNA sequencing to look for cancer DNA that circulates in the blood in order to detect cancer earlier and earlier, even before symptoms appear or before a tumor can be seen on a scan. All from a simple tube of blood.
That all sounds great, but these technologies can’t help patients if they don’t have access to them. It turns out that the top cancer centers in the U.S. only treat about 10% of all cancer patients. That means 90% are in local hospitals and medical centers where this technology may not be available.
My goal and my drive is to enable labs all around the world to have access to this kind of technology so that patients can be closer to the technology that they need to get the best treatment. We’re working every day to make this technology simpler, faster, and more affordable in order to bring it closer to patients.
We are truly unlocking the power of the genome. From screening prior to and during pregnancy to testing for genetic diseases in newborns to screening for predisposition to molecular profiling of cancer, we’re using DNA sequencing to understand our individualized blueprint and use that information to inform better treatment decisions and improve quality of life.
We’re just getting started, though. There is much more to learn and much more to discover. Just like the internet or our smartphones, one day genomics will be a routine part of each one of our lives.