Fueling Precision Medicine

The 20th century saw an explosion of technological advances that completely reshaped modern life. Transport shot from the earth’s surface to the skies, and then into space. Scattered telegraph lines reconfigured to form a global, multimedia internet. Glass-lensed microscopes gave way to a host of sophisticated analytical modalities that reveal the world around us in astonishing detail. More than any other in history, the 20th century was the Century of Technology.

Today, the surge of discoveries and development continues, particularly in biology. And it’s very possible that our counterparts in the future may look back on the 21st century as the Century of Biology (1).

The key to planning for – even shaping – the future lies in our ability to identify patterns in social and technological change. Individual trends may come and go, but megatrends – which reflect movement on a global scale – are essential for us to recognize and understand.

The era of DNA sequence

One megatrend of distinct promise is the emergence of enormous volumes of DNA sequence information as a driving force in biological discovery; precision medicine and cellular manufacturing are poised to transform DNA sequence information into a tool of remarkable power.

Precision medicine is the ability to understand and treat disease at a molecular level. It has already begun to effect revolutionary change in oncology, where cancer subtype classification and treatment is transitioning from organ (for example, lung, breast, colon) to biomarker (for example, EGFR, HR+/HER2, BRAF). Cellular manufacturing – the ability to reprogram cells for practical, useful purposes – is also capturing and transforming industrial biotechnology. Many chemicals and materials traditionally produced through petrochemical processes are now harvested as products of engineered biological cells. In addition to sequence information, cellular manufacturing requires deep understanding of cellular metabolism and pathway interdependencies. The expansion of this understanding is being accelerated in turn by the vast amount of metabolomic information now becoming increasingly available through advances in mass spectrometry.

Compared with traditional chemical synthesis, cell-based manufacturing is generally more sustainable and can often produce new, better-performing materials. A leading early example is Dupont’s Sorona biopolymer (2), an alternative to nylon partially produced through the reprogramming of E. coli. When used in consumer products, such as footwear, not only does Sorona biopolymer produce less greenhouse gas emissions but it also has better stain resistance and is rated as more comfortable than the alternative by customers. 

Both of these waves of change share a common driver; the past 20 years have seen a marked shift away from biology as a primarily qualitative science toward a biology that is increasingly quantitative. This shift carries the promise of one day allowing us to understand, model, and predict biology in much the same way that we are now able to do in the physical sciences – an exceptionally complex proposition that lies beyond our current capabilities. 

At a fundamental level, as the current rapid growth in our capacity to understand and control biology at the molecular level both deepens our understanding of disease and fuels parallel advances in industrial biotechnology, these life science technology waves  reciprocally open new areas of discovery, amounting to a self-accelerating continuum of understanding in the life sciences.

The hidden power of the code

Even beyond the knowledge gained from individual sequence milestones – say, focused analysis of this species or that disease state – the sheer volume of sequence information available to researchers today is, itself, transformative. Since their relatively recent introduction, sequencing tools have undergone rapid generations of improvement in speed, accuracy, affordability, and accessibility. The cumulative body of sequence knowledge these tools have uncovered has also driven similar improvements in the bioinformatics tools needed to help researchers make sense of it all.

In the process of sifting through this rapidly accumulating mountain of data, certain actionable knowledge has begun to surface. We are now seeing concentrated efforts to develop methods and technologies that take advantage of this knowledge; for example, enabling us to edit and engineer the sequence to further the goals of precision medicine and cellular manufacturing.

In addition, the abundance of sequence information has opened fields of study such as metagenetics and the microbiome – fields whose enormous complexity had until now rendered them largely inscrutable. We are already beginning to understand the many ways the microbiome contributes to a growing list of complex health conditions – and academic, venture, and industrial resources are now searching for ways to manipulate the microbiome to improve health outcomes relating to digestive disorders, cancer, mental health, immune deficiencies, and more. 

Precision medicine aims to improve therapeutic outcomes by adding a previously missing but critical factor to the treatment equation: the unique biology of the patient, as revealed through examination of their relevant molecular information. 

Three examples…

Focusing on genetic sequence as a driver of precision medicine, I’d like to offer a few examples of how precision therapies might benefit millions, thousands, or just a single patient. In each case, the new therapeutic is an oligonucleotide – a short sequence (less than 100 base pairs) of RNA or DNA that can interact with its target through a variety of functional mechanisms.

Firstly, inroads are being made in the treatment of cardiovascular disease through sequencing of the PCSK9 gene. It was discovered that various mutations of this gene are associated with high low-density lipoprotein (LDL) cholesterol levels, which are a factor in multiple diseases. The knowledge that this gene played a role (and that high LDL levels weren’t simply a matter of poor diet) has contributed to the development of inclisiran (Novartis/Alnylam) – a short interfering RNA (siRNA) therapeutic that acts to silence the PCSK9 gene and effect clinically significant reductions in LDL cholesterol levels. In principle, such sequence-based insight could change the lives of millions of patients. The resulting drug is already approved in Europe, and pending approval in the US. Sequencing remains a critical tool in such treatment scenarios because it is essential to know which patients have mutations in the PCSK9 gene to identify candidates for inclisiran therapy.

Secondly, similar progress has been made in the treatment of a debilitating condition known as hereditary transthyretin-mediated amyloidosis. Sequencing of the transthyretin (TTR) gene revealed mutations that were an essential contributory factor, opening the possibility of a gene-targeted therapeutic strategy. Treatment with Alnylam’s Onpattro (patisiran) – the first siRNA drug approved by the FDA – was found to effectively silence this gene, reversing the progression of polyneuropathy in a majority of patients, and improving the quality of life for its thousands of sufferers (3).

Thirdly, and perhaps the most personalized of all precision medicine outcomes, we have the development of milasen – a one-of-a-kind drug created in less than one year by Timothy Yu’s team at Boston Children’s Hospital to treat a disease caused by a mutation affecting a single patient (4). In 2017, sequence information from the DNA of that desperately ill child, Mila Makovec, revealed a genetic alteration disabling her CLN7 gene, resulting in Batten disease – a very serious and ultimately fatal malady of the nervous system. The customized antisense oligonucleotide therapeutic that was developed for her on the basis of this alteration was given the name milasen. After the FDA gave permission, Mila received the medication just nine months after her one-of-a-kind mutation was identified. The treatment substantially improved Mila’s condition, reducing the number and length of her seizures and adding years of improved quality of life prior to her sad passing in 2021. 

Milasen is a case study in our ability to achieve positive clinical outcomes based on an intimate understanding of pathogenic mutations. Such “n of 1” therapies, as they have come to be called, truly illustrate the potential of sequence information to enable treatment previously thought impossible for diseases with a genetic component.

The emergence and early success of these precision medicine efforts is triggering significant changes in the way the pharmaceutical industry approaches therapeutic development. One benefit is that clinical trials aimed at smaller and well-defined patient populations can be far more streamline, lowering a key hurdle in bringing a drug to market.

A newly developed drug that works in only 20 percent of the general population may have a much higher efficacy rate – and much greater odds of gaining FDA approval – for a smaller and more narrowly defined target patient population. This “rescue of therapeutics” approach – itself a direct result of deeper molecular insight into the therapeutic approach – offers pharma companies an avenue for monetizing R&D investments that might otherwise have been abandoned.

Century of biology; decades of precision medicine

Looking forward, oligonucleotides will continue to advance precision medicine and the molecular treatment of disease. Beyond antisense and siRNA, several new mechanisms of oligonucleotide therapeutic action are being demonstrated, including small activating RNA, regulatory RNA, and CRISPR genome editing.

CRISPR derives its sequence specificity through the use of application-specific guide RNAs that specify the site-to-be-edited. And it is quickly establishing itself as a superior enabler for both ex vivo gene modified cell therapy and in vivo gene therapy. Cell and gene therapy are the fastest growing segment of biopharma and a potentially transformative frontier for precision medicine, because they  not only treat disease – they can cure it. To enable such breakthroughs requires a functional understanding of genetics and an ability to target genetic edits – both of which are greatly enabled by widespread access to sequence information.

DNA sequence is already a keystone of biology, and we look forward to discovering the full impact of this megatrend – not only on precision medicine and cellular manufacturing but also on the technology waves yet to be defined as we continue our journey into the Century of Biology.

Acknowledgement
I would like to thank Gary Carter for his valued conversations and expertise in oligonucleotide therapeutics, Jay Gregory and Catherine Kaye for their inputs in preparing this article, and Agilent Technologies for the opportunity to lead technology innovation important to advancing quality of life.