“Fifty Years In Biotech”

The coronavirus pandemic has already shown the world the importance yet fragility of our healthcare system. At the same time, we have seen the tremendous strength of modern biotech infrastructure. While a century ago, a disease as devastating as Covid-19 might have no recourse, in 2020, our nation’s top scientists will have advanced vaccine candidates to Phase III trials at an unprecedented pace. What explains this and where did the modern biotech stack come from?

Humble Beginnings

The ‘birth’ of biotech is commonly cited as the founding of Genentech in 1976 by Herb Boyer and Bob Swanson. Genentech’s core innovation centered around manufacturing, the ability to produce and manufacture human growth hormone (hGH) using microbes and recombinant DNA. With the ability to genetically engineer microbes to produce biological molecules of interest, biology suddenly became an efficient means of production, usurping the traditional and crude methods of harvesting biomolecules from animals. By 1979, Genentech was able to produce the first human version of insulin using their microbial based genetic engineering technique. Genentech (named from Genetic Engineering Technology) was not the only company founded on the breakthroughs of molecular genetic engineering.

Thus, the key tenant of the biotechnology industry has been engineering and application. While basic science research has existed for centuries, modern development in the biotech industry has been about manufacturing, scale, efficiency, and distribution. A heavily involved engineering approach to harness biological insights and address problems in human health.

The Rise of Molecular Engineering

The 1980s built strongly upon the strides in genetic engineering made in the 1970s. Core tools in today’s molecular biology stack including polymerase chain reaction (PCR) and DNA fingerprinting were invented to refine the study of molecular engineering. Accelerated by the commercialization of biology from patenting genes and the growing need for targeted therapeutics led to a rise in biologics and recombinant proteins. By 1988, five proteins from genetically engineered microbes were approved by the FDA: insulin, hGH, hepatitis B vaccine, alpha-interferon, and tissue plasminogen activator (TPa); all of which are still in use today. By the end of the 1990s, however, a flood of 125 more therapies enabled by genetic engineering would be approved by the FDA. These include monoclonal antibodies, vaccines, enzymes, growth factors, hormones, and peptides across 70+ different indications. Regeneron, a company built on the promise of antibody based treatments, was founded in 1988 and Vertex, one of the first biotech firms to champion rational drug design, was founded in 1989.

With the rise of molecular level engineering came a desire to further understand the human genetic source code. In 1990, the human genome project was started. The $3 billion international research project pushed the physical and computational boundaries of genomics and sequence analysis, providing identification of cancer mutations, discovery of genes responsible for diseases like Cystic Fibrosis, and allowed the design of medication and more accurate prediction of their effects. The 1990s were a significant leap forward in developing data driven approaches to exploring biology, providing bioinformaticians a democratized and open source medium for exploration.

Biopharma Breakthroughs

These resources allowed in the 2000s an explosion of hypotheses downstream of computational analysis; targeted therapies, vaccines, and rational drug design. The 2000s were a decade in which some of the largest blockbuster therapies were developed. Imatinib for CML, sitagliptin for diabetes, erlotinib for solid tumors, and Gardasil, the first HPV cervical cancer vaccine were all targeted therapies developed based on a robust understanding of genetic mechanisms of disease and enabled by testing for ‘cancer genes’. Imatinib specifically which boasts an unprecedented 90% 5 year survival rate, was developed after the Philadelphia chromosome mutation and hyperactive BCR-ABL protein were discovered wherein drug developers screened chemical libraries to find a drug that would inhibit that protein.

Nearing the end of the 2000s came several milestones that expanded the commercialization of biology past molecular biology and genetics. In 2007, scientists in Japan provided first evidence of iPSCs, demonstrating the potential scalability of stem cell therapies. Just two years later, President Barack Obama signed an executive order freeing up federal funding for broader research on embryonic stem cells. In 2008, chemists in Japan also created the first synthetic DNA molecule, the first piece of progress toward not only reading biological source code, but also writing it. In 2008 came the first big papers describing RNA-Seq, a breakthrough technology enabling the large-scale study of the transcriptome in coordination with the genome.

The Modern Biotech Stack

While the 2000s gave the world and specifically cancer the first wave of biotech enabled therapeutics, the 2010s began the period where the industry truly took off as one of the fastest growing sectors of the economy. On a macro scale, this was partly enabled by large biopharma’s new found willingness to make large scale acquisitions based on scientific data alone. A new wave of commercialization was allowed to develop with a more focused aim of developing breakthrough technologies and therapies in a variety of indications, spanning oncology, virology and rare diseases.

Several major areas within biotechnology took off as their own fields in the past decade, most principally cell & gene therapies, synthetic biology, and computational bio. A major landmark and breakthrough in gene therapy came in 2012 with the commercialization of CRISPR, allowing the democratization of simple and cheap gene editing to bench scientists in any domain. Leaders on the CRISPR therapeutics front including CRISPR Tx, Editas, Intellia, and Beam were founded in 2013, 2013, 2014, and 2017 respectively. Though a CRISPR based therapy has not yet been approved, other gene therapies including Luxturna for leber congenital amaurosis, Spinraza and Zolgensma for spinal muscular atrophy, and at least 6 others have been approved starting from 2017.

On the cell therapy front, the FDA approved the first CAR-T cell therapy Kymriah for the treatment of ALL in 2017. An entire arsenal of cell therapy companies were founded in the past decade from the promise of using the body’s own cellular machinery to cure disease including the notable founding of Tmunity Tx in 2015 by pioneer CAR-T researchers at the University of Pennsylvania. While stem cell based therapies have comparably lagged behind, advances on the scientific frontier have demonstrated potential use in a variety of indications including neurological disease, diabetes, bone repair and regeneration, and blood based diseases.

Perhaps most in line with the origins of the biotech industry was scientific and commercial advancement of synthetic biology in the 2010s. Giants including Zymergen, Ginkgo Bioworks, and Twist Biosciences have pioneered new methods of manufacturing designer proteins, DNA, microbes, and organisms. These have been enabled by rapidly decreasing costs of DNA sequencing, new techniques such as molecular protein evolution, and microfluidics. The synthetic biology stack will provide a new generation of scientists the unique toolbox to manipulate biology not only on the DNA and RNA levels, like in the 80s, but also on the protein and cellular levels.

The final major advance of the 2010s has been the rise of computational and data science approaches to exploring and developing biological assets. Companies like Atomwise, Recursion, and BenevolentAI have applied advances in the computer software industry such as machine learning, computer vision, and natural language processing to process vast quantities of biological data ranging from drug target interactions to images of cell culture to scientific research journals. Comprehending these data sources at much higher dimensions than those understandable by human scientists, algorithms can develop novel insights and guide scientists towards promising hypotheses. As biology continues to transform towards an engineering discipline, data driven approaches will be key to speeding up design — test — learn cycles to iteratively improve therapeutics, novel materials, and beyond.

This brings us to 2020, and we are quickly coming up on 50 years in biotech. What is coming up next? Given the tremendous progress made in the 2000s and 2010s, we should expect similarly large steps forwards. Key areas for development will include better delivery mechanisms to more efficiently bring medications to where they need to be within the body, a suite of engineered tools to accelerate R&D such as microfluidics and robotic lab automation, diagnostics and other earlier detection tools to cure disease when most vulnerable, and finally, organoid and tissue on a chip technologies to improve our ability to model biological phenomena. Thematically however, the 2020s will be about intersection. Companies like Dyno Tx who use a suite of machine learning and synthetic biology tools and apply it to gene therapy delivery or LabGenius who has developed another closed loop engineering system using machine learning and high throughput in vitro experiments will become major players in the modern biotech stack.

We’ve come a long way from Herb Boyer and Bob Swanson but we still have a long way to go. The 21st century will be defined by biological revolution, and the modern biotech stack is just getting started!