By Priya Kalia, PhD
Human genomes are nearly identical from person to person, but the small degree to which our genomes differ, about 0.1%, is medically significant. It contributes to the variability in our susceptibilities to particular diseases, as well as in our responses to particular medical treatments, including treatments such as cancer immunotherapy. (We might add that in cancer immunotherapy, two genomes may be relevant: the genome of the patient and the genome of the tumor.)
Differences at the genomic level and their consequences are becoming better understood, leading to a new medical paradigm: precision medicine. Precision medicine follows a patient-specific tailored approach. In its consideration of genomic details, precision medicine goes beyond traditional medicine’s “one size fits all” approach.
Advances in precision medicine were covered at the International Precision Medicine Conference, a virtual event that was held April 19–21. Some of the experts who participated in the event (or had been scheduled to do so) also contributed commentary to this article. Here, the experts discuss precision medicine applications that involve low-cost sequencing, metabolomics, regenerative medicine, or the secure use of patient information.
Plummeting sequencing costs
Genome sequencing and mass spectrometry technologies are easing the adoption of “omics” approaches, or even more holistic systems biology approaches, in medical research. These technologies are also facilitating the development of precision medicine applications while hastening the translation of precision medicine to the clinic.
“In the 1980s, even sequencing a small plasmid was a major undertaking,” said David I. Smith, PhD, professor emeritus at the Mayo Clinic. “Advances in Sanger sequencing brought down sequencing costs dramatically. In 1999, a draft sequence of the human genome cost about $3 billion. Soon, sequencing will cost as little as $100 per genome. It’s absolutely phenomenal.”
Smith’s research into human papillomavirus (HPV) has used whole genome sequencing to study different mechanisms of HPV-linked cancers. He has also demonstrated how the sequencing of clinical specimens from cancer patients can expand treatment options.
Smith credited massively parallel sequencing with bringing down the cost of whole genome sequencing to an affordable range. This method has increased sequencing output by multiple orders of magnitude. Today, one can generate enough sequencing for a single genome on Illumina NextSeq instruments for just $375. However, this is just the sequencing cost.
“Technology is developing faster than ever,” Smith added. “Last year, BGI in China stated that soon it will cost only $100 to sequence a complete human genome! The reality is that a personalized medicine approach, based upon genomics and whole genome sequencing, is going to change the world.”
Applications in degenerative disease
In disease areas such as cancer, precision medicine applications already exist. Examples include precision diagnostics and checkpoint immunotherapy. However, in other disease areas, precision medicine applications are still emerging. For example, in the degenerative disease osteoarthritis (OA), researchers are still trying to identify specific biomarkers, that is, biomarkers that could allow OA to be easily and cost-effectively diagnosed.
OA affects patients’ joints and causes symptomatic patients to experience pain while walking. It is the most common joint disease in the United States with a prevalence of 10% in men and 13% in women over 60 years old.
A variety of clinical assessments are used for diagnosis, including radiographs, MRI scans, and pain scores. End-stage treatment is joint replacement with a metal implant, which is a successful yet expensive and invasive procedure that might not be necessary for all patients. To better gauge the need for joint replacement, precision medicine approaches are being developed.
“OA is a very heterogenous disease, in terms of how it develops and how it progresses,” said Guangju Zhai, PhD, professor of genetics at the Memorial University of Newfoundland. “The biggest challenges for classifying OA include predicting disease progression and developing effective therapeutics.”
Over a number of years, many research groups around the world have tried to identify biomarkers for the early diagnosis or prediction of OA. Zhai’s group has taken a metabolomics approach to trying to accurately diagnose OA, measuring phosphatidylcholines (PCs) and the lysophosphatidylcholines (lysoPCs, also called lysolecithins) that are derived from PCs via partial biological hydrolysis, where water reacts to remove one fatty acid group using an enzyme called phospholipase A2. PCs and lysoPCs are phospholipids that are a key component of cell membranes.
By calculating the lysoPC to PC ratio, Zhai found evidence suggesting that the conversion of PC to lysoPC was overactivated in OA patients, and that the plasma/serum lysoPC to PC ratio indicated OA risk. Interestingly, the group also found that having high levels of phenylalanine in the blood was also associated with knee OA progression over five years, indicating that at-risk patients should try to avoid aspartame, which contains a small amount of phenylalanine. Arginine meanwhile has been found to be deficient in OA patients.
These results indicate that a metabolomics approach to precision medicine could even help scientists and clinicians develop and adopt a personalized nutritional approach to clinical treatment. “I use metabolomics because it is cost effective,” Zhai noted. “It can also indicate genetic factors that might be in play, causing subtle changes in metabolism that could contribute to degenerative diseases such as OA.”
Zhai’s goal is to use his group’s findings to develop precision medicine tools that could facilitate improved patient stratification for clinical trials. “In this way, we can start to change the perception that OA is a single disease,” Zhai explained. “OA is a group of conditions with different causes that present similar or the same symptoms in patients. Therefore, patients should be treated on an individual level [and not] in the same way.” Predictive methods could be used to identify patients more at risk for developing OA, allowing treatment strategies to be deployed before symptoms appear.
Once disease endotypes have been established, a precision medicine approach can be taken; that is, treatments can be personalized to patient subgroups. In the case of OA, precision medicine could facilitate the use of regenerative medicine in certain patient groups. This approach is being pursued by Ashish Anand, MD, a staff orthopedic surgeon at the Veterans Affairs Medical Center in Jackson, MS.
In terms of surgical treatment strategies, there is one particularly challenging group of orthopedic patients that are currently benefitting from a precision medicine approach. “These are patients that are either too young to be considered for conventional joint replacement surgery or are not keen to have a procedure done,” Anand points out. “And yet they not responding to first-stage conservative treatment.”
At the first stage, if exercise and weight loss and/or painkillers do not help, then injections with glucocorticoids are often given directly into the knee to help reduce inflammation and swelling. Anand, looking for a solution for this challenging group, found that amniotic tissue, derived from human placentas, could help with the mitigation of pain.
In a clinical study of 40 patients treated with AmnioFix, Anand found that 65% of patients reported an over 60% improvement in pain as measured by a pain score, which is considered to be a significant improvement. The majority of patients treated with amniotic tissue were also able to increase their walking distance.
Precision medicine is opening up a raft of new ways of thinking and new ways of diagnosing and treating disease and maintaining health longer. However, as precision medicine becomes more accessible, affordable, and “the norm” in clinical practice, significant amounts of data will be created and stored containing vulnerable, private patient information. It will be critical for this data-driven approach to be safe, secure, and accessible to individuals in any society. Could the key to data security lie in the same blockchain technology that is used for popular cryptocurrencies such as Bitcoin and Ethereum?
Data democratization and blockchain
Distributed ledger technologies such as blockchain have the potential to support precision medicine in a number of ways, promoting enhanced privacy and security while also democratizing it, said Ingrid Vasiliu-Feltes, MD, president of Detect Genomix, chief quality and innovation officer at Mednax, and chief ethics and innovation officer at the Government Blockchain Association. In her discussion with GEN, Vailiu-Feltes emphasized that she was sharing her personal professional opinions, not representing the views of any of the organizations with which she is affiliated.
Blockchain stores information in “blocks” and relies on a consensus model, rather than a centralized authority, to permit the real-time addition and updating of data. However, data that has been added to the ledger cannot be removed or edited. Doing so is prevented by the “chain” in blockchain, which refers to how blocks accumulate. New blocks are continually added, in chain-like fashion, to the originating block, such that any change in previously entered data, in any given block, would also have to occur in every subsequent block—an exceptionally difficult task, given that data is secured cryptographically when it is replicated from block to block.
According to Vasiliu-Feltes, blockchain is advantageous in several respects. “Blockchain presents the opportunity to decide what we are going to put ‘on the chain’ versus what can be kept off,” she explained. “That allows us to segregate and utilize data in a very meaningful way that is not currently possible with any other database formats, ensuring optimized privacy and self-sovereignty. It also allows all other key stakeholders to use only data that is necessary for their particular operations, including healthcare plans, healthcare providers, pharmaceutical companies, research institutes, and clinical professionals.”
Vasiliu-Feltes continued: “Blockchain also allows enhanced access and decentralization, allowing as many international parties as possible to benefit—as opposed to the siloed way of working we have now. As has been proven throughout the COVID-19 pandemic, when everyone worldwide has been able to collaborate on a vast scale never seen before in history, they have been able to expedite the development of critical treatments such as antiviral vaccines in record time.”
She concluded by citing yet another advantage: “Blockchain allows a high degree of auditability and traceability, and data cannot be easily tampered with due to its inherent immutability. A number of pain points in healthcare today could be addressed by putting very sensitive data, such as genetic and other precision medicine and life sciences data, into this type of digital technology platform. It provides a higher degree of autonomy while at the same time facilitating compliance and auditing processes, preventing waste, fraud, and abuse.”
Prediction, prevention, and a global data exchange
“In the future,” Smith predicted, “we’re going to have a much better understanding of which nutrients are best for individuals based upon their own genotypes.” He suggested that genome sequencing could become a routine part of clinical care within at least the next five years. “With this approach, before people even get sick, we will know which ones to monitor more than others for particular conditions.”
Smith also emphasized the potential of pharmacogenetics, or pharmaceutical strategies based upon patients’ genetics. For example, with insights from whole genome sequencing, clinicians could adopt a pharmacogenomics approach, selecting and monitoring treatments in accordance with patients’ individual needs.
Vasiliu-Feltes envisions a major role for a blockchain-enabled global precision medicine “data exchange.” In such an exchange, everyone could share relevant data without losing intellectual property or benefits gained from their own research and development. When combined with an artificial intelligence portfolio of tools, this type of exchange could also help accelerate the development of innovative precision medicine–based solutions that address current unmet medical needs.
“In the life sciences and healthcare industries, we have definitely seen an uptick in the use of blockchain technology over the past 12 months,” she observed. “A global exchange could contain all relevant information, including information pertaining to prevention, diagnosis, clinical decision-making, support, and treatment. It could enable us to overcome stubborn challenges such as acute or chronic diseases, and it could help us maintain wellness and extend longevity.”