Cracking the Genetic Code: Why Gene Sequencing May Hold the Key to Intercepting Diseases Before They Start

What if there was a way to figure out exactly who is likely to develop a certain disease, and what drives the development of it, before the disease even manifests? And then, what if we could target treatments to prevent it from ever happening?

It may sound like a far-off goal, but this kind of research is in the works right now at Janssen Research & Development, part of the Janssen Pharmaceutical Companies of Johnson & Johnson.

And it's all centered around studying a person's genes and DNA—the components that make up what we know as a human genome.

Through a few key partnerships—including, most recently, the UK Biobank Whole Genome Sequencing project, the largest human genome sequencing project in the world—Janssen scientists are developing genomics to not only help spur new treatment options but also increase understanding and awareness around certain diseases. They're doing it by first sequencing the DNA of many people's genomes—that is, using technology to identify every single component that makes up each individual's genome.

“By analyzing people's DNA, we can discover specific gene variants that may predispose them to specific conditions, or make it more or less likely that they will respond to a specific treatment,” explains Guna Rajagopal, Ph.D., Head, Computational Science, Discovery Sciences, Janssen Research & Development.

As a promising new year of innovation kicks off, we spoke to these scientific pioneers to see how their work harnessing the human genome has the potential to change how we approach disease prevention—and help shed light on why some people may develop certain diseases but others may not.

Tapping Into an Unprecedented Gold Mine of Genetic Information

So how does a scientist even begin to embark on such a lofty undertaking?

For starters, you need access to a significant volume of genetic samples, which is why last September, Johnson & Johnson became part of a groundbreaking moment in history when it joined forces with the UK Government, a private charity, the Wellcome Trust and three other healthcare companies to sequence the genomes of half a million people participating in the UK Biobank Whole Genome Sequencing project (UKB WGS), a collaboration that was facilitated through a partnership with the Johnson & Johnson Innovation team based in London.

The 500,000 volunteers participating in the project had previously donated their blood, as well as access to their medical records, to the UK Biobank, a vast and comprehensive longitudinal health resource dedicated to improving the prevention, diagnosis and treatment of a variety of illnesses.

“Being part of the world’s largest Whole Genome Sequencing project gives Janssen a rare opportunity to use a large volume of human genetic data to gain meaningful insights about the causes and consequences of diseases, such as cardiovascular disease and Alzheimer’s,” explains Rajagopal, who is Janssen’s principal investigator for the UKB WGS. “We’re hoping it allows us to use this rich bank of human data to help us innovate new treatments.”

What makes this collaboration particularly unique? In short, the UK Biobank's high-quality sample collection. “It’s always difficult to analyze data sets, because some samples may be meticulously collected, while others may not be,” Rajagopal explains. “But the UK Biobank is best in class.”

And then there's its size and scope.

Unlike any other similar project, not only is the UK Biobank very large but it is also very detailed. “It contains an absolute wealth of medical information on half a million people. It's completely unprecedented," says Sir Rory Collins, FMedSci, FRS, Principal Investigator of the UK Biobank. "We have all kinds of information about the participants' lifestyles and medical histories, plus blood samples in which we’ve measured lots of known risk factors, such as cholesterol levels, as well as genotype and, now, genetic sequence. And for about 100,000 people we are obtaining brain, heart and abdominal MRI images. This data can then be linked with health outcomes that occur during follow-ups in order to better understand the causes of many different diseases and ways to prevent and treat them.”

Sequencing, which is being conducted at the Wellcome Sanger Institute in the UK and deCODE genetics in Iceland, began in mid-September. "We’re already ahead of schedule,” says Rajagopal, adding that data on the first 125,000 genomes should be available by the middle of 2021. Each company involved in the collaboration will then receive nine months of exclusive access to the genomic data for their own research, before the data becomes publicly available. The expectation is that data for all 500,000 Biobank patients will be accessible to anyone by 2023.

Uncovering Clues to Help Drive New Treatments for Diseases Like Alzheimer's

The total amount of genetic data that the project expects to yield is huge—around 600 billion pages of text—and Janssen’s main focus, says Rajagopal, is to try to discover “driver” genes that, if mutated, raise the risk of a person developing a disease like cancer or Alzheimer’s.

“Once we’ve identified these 'drivers,' we can begin to develop treatments with the potential to modulate their effects,” he explains. This can be particularly important for diseases such as Alzheimer’s, as researchers still don’t completely understand how this condition progresses and thus have yet to develop effective medications.

What’s innovative about this approach, adds Mary Helen Black, Ph.D., M.S., Director, Human Genetics and Head of Population Analytics, Computational Sciences, Janssen Research & Development, is that using human genomics to identify novel targets represents a significant shift in the approach to developing drugs.

“Currently, we use various methods to screen thousands of compounds, and then follow up on promising experimental results,” she notes. "But now, Janssen is strategically using human genomic data to pinpoint specific targets that we can then build treatments around.”

Indeed, a study published earlier this year found that when a treatment has genomic evidence behind it, it’s more than twice as likely to make it through clinical trials and the FDA approval process than one that doesn’t. It’s also another way for researchers to identify tools they already have in their arsenal that may be effective. For example, "it may be that we have a drug in development that didn’t work on Alzheimer’s, but genetic information may tell us that it could be a possibility for a certain immunological disease or cancer,” Rajagopal explains.

The first step, adds Black, will be for scientists to mine the UKB WGS data to find genetic variations associated with a particular disease, like heart failure. Once these variations are found, researchers could then investigate biomarkers that might be associated with heart failure.

"If it looks like we’ve identified a gene variant involved in this disease development," Black says, "then the next step is to understand how we can modulate the target with a new therapy."

Diving Into the Study of the DNA of Related Populations

While the vast amount of genetic data in the UKB WGS certainly holds promise, so does a more targeted set of information.

The University of Utah Health has been collecting data on local residents for more than 50 years and has compiled it in the Utah Population Database (UPDB), which provides access to information on more than 11 million people. It is one of the world’s richest sources of in-depth information that supports research on genetics, epidemiology, demography and public health—and is the only database of its kind in the U.S.

“Utah is a very interesting population because it's comprised of people who tend to live in the same areas for many, many years, so it's a great way to track family genetics through the generations,” Rajagopal says. As a result, it has become a rich trove of research on people and families with higher than normal incidence of familial cancer and other rare diseases because of the ability to trace these illnesses through robust family trees. In fact, it has contributed to important gene discoveries, including those for colon cancer, breast cancer, melanoma and cardiac arrhythmia.

In 2017, Janssen announced a collaboration with the university to study the genomics of three diseases and conditions, including juvenile idiopathic arthritis. “There may be rare gene variants that cause some people to develop this disease in childhood,” Rajagopal explains. “We’re rapidly sequencing samples collected by University of Utah Health researchers to pinpoint potential genetic markers among patients and their family members.”

Another focus area in this partnership: identifying genetic variants associated with an increased risk of suicide. “While some mental illnesses do raise the risk of suicide, most people who struggle with mental illness don’t die by suicide, which suggests that it may actually be a heritable trait,” Rajagopal explains. “If we can identify certain genetic factors, this may help us predict who might be most at risk, and possibly offer up unique treatments for them.”

And that's really what's at the heart of all this work in the lab: impacting lives out in the world. While these projects are all diverse, Rajagopal stresses that they’re united by one common thread of using the human genome as a tool to unlock potentially lifesaving new therapies.

As he puts it: “We’re hoping the research and insights we gain from this work will help us revolutionize medicine as we know it in the 21st century.”