“Biotech to TechBio”

Nearly a century ago, the world had no recourse for the 1918 influenza (Spanish Flu) pandemic, a pandemic comparable to Covid-19 that infected over 500 million people and killed over 10 million people. Fast forward to 2021, the world’s top scientists & pharmaceutical companies have become household names that have advanced and deployed Covid-19 vaccines to over 4.4 billion people around the world. So where did our modern biotechnology toolbox come from? And where could it be going?

The Dawn of Biotech

The ‘birth’ of the biotechnology industry is frequently recognized as the founding of Genentech in 1976 by Herb Boyer & Robert Swanson. Genentech’s core innovation centered around manufacturing; specifically, the ability to produce and manufacture human growth hormone (hGH) using microbes & recombinant DNA. By genetically engineering microbes to produce biological molecules of interest, biology suddenly unlocked an efficient means of production for biomolecules, usurping the traditional and crude methods of harvesting biomolecules like epinephrine & insulin 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. Biogen (formerly Biotechnology Geneva) and Amgen (formerly Applied Molecular Genetics), were founded in 1978 & 1980 respectively to harness and engineer recombinant microbes to manufacture treatments and cures for diseases.

Thus, the key tenant of the biotechnology industry has been engineering and application. While basic science research has existed for centuries, modern developments in the biotech industry have been about applying science to manufacturing, scale, efficiency, and distribution. In other words, modern biotechnology harnesses biological insights and addresses problems in human health through engineering.

Biotech Leaps Through the 80s, 90s, & 00s

The 1980s built strongly upon the strides in genetic engineering made in the 1970s. Core tools in today’s molecular biology toolbox, including polymerase chain reaction (PCR) and DNA fingerprinting, were invented to refine the study of molecular engineering. Accelerated by the ongoing 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.

Within the next decade, a flood of 125 more therapies enabled by genetic engineering would be approved by the FDA. These new therapies included monoclonal antibodies, vaccines, enzymes, growth factors, hormones, and peptides across 70+ different indications. And the growth in new therapies coincided with a new wave of biotech companies. Two standout companies founded in the 1980s include Regeneron, a company built on the promise of antibody based treatments, in 1988 and Vertex, one of the first biotech firms to champion rational drug design, 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 began under the leadership of Dr. Francis Collins (who eventually served as the 16th Director of the NIH). The nearly $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 Age-related Macular Degeneration, Spinal Muscular Atrophy, and Multiple Sclerosis), and allowed the design of therapies 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.

These resources allowed an explosion of ideas driven by computational analysis in the 2000s; targeted therapies, vaccines, and rational drug design. And this first wave of rational drug design therapies resulted in many blockbuster therapies. 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. Take the case of Imatinib, which boasts an unprecedented 90% 5-year survival rate. Ciba-Geigy (which merged with Sandoz in 1996 to become Novartis) developed Imatinib in collaboration with Dr. Brian Druker of Oregon Health & Science University after the Philadelphia chromosome mutation and hyperactive BCR-ABL protein were discovered, leading drug developers to screen 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 biochemistry, molecular biology, and genetics. In 2007, Shinya Yamanaka and colleagues in Japan provided the first evidence of induction of pluripotent stem cells (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. Also during the 2000s came a flood of big papers describing RNA sequencing (RNA-Seq), a breakthrough technology enabling the large-scale study of the transcriptome in coordination with the genome.

The Meteoric Rise of Biotech in the 2010’s

As the 2000s gave us the first wave of rational drug design-enabled therapeutics (many being biologics for cancer therapy), the 2010s began the period where the industry truly took off as one of the fastest growing sectors of the economy (see figure). 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. This latest wave of commercialization developed with a more focused aim of cultivating 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 gene and cell therapies, synthetic biology, and computational biology methods.

A long-running dream for biotechnologists has been the development of gene editing therapies. A major breakthrough in gene therapy came in 2012 with the development (and subsequent commercialization) of CRISPR-Cas9 through the discovery of trans-activating CRISPR RNAs (tracrRNA) that guide site-specific DNA cleavage. This breakthrough allowed for the democratization of simple and cheap gene editing to bench scientists in any domain. Leaders on the CRISPR therapeutics front include CRISPR Therapeutics (CRSP), Editas Medicine (EDIT), Intellia Therapeutics(NTLA), and Beam Therapeutics (BEAM) were founded in 2013, 2013, 2014, and 2017 respectively. Though a CRISPR-based therapy has yet to be FDA approved, other gene therapies — including Luxturna for leber congenital amaurosis and Spinraza and Zolgensma for spinal muscular atrophy — have been approved since 2017.

On the cell therapy front, the FDA approved the first CAR-T cell therapy Kymriah for the treatment of acute lymphoblastic leukemia (ALL) in 2017. An entire arsenal of engineered immune cell therapy companies were founded in the past decade on the promise of using the body’s own cellular machinery to cure disease; like Kite Pharma (acq. by Gilead), Juno Therapeutics (aqu. by Celgene), and Celgene (aqc. by Bristol-Myers). One other notable cell therapy venture includes Tmunity Therapeutics — launched in 2015 by pioneer CAR-T researchers Carl June, Bruce Levine, Yangbing Zhao, Anne Chew, & James L. Riley at the University of Pennsylvania. While stem cell based therapies have comparably lagged behind, advances on the scientific frontier have demonstrated potential 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 the scientific and commercial advancement of synthetic biology in the 2010s. Giants including Zymergen, Ginkgo Bioworks, & 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, improved molecular evolution techniques, and advancements in microfluidics. The modern synthetic biology toolbox 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 trend of the 2010s has been the rise of computational and data science approaches to exploring and developing biological assets. Companies like Atomwise, Recursion, & 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.

What about the next 50 years in Biotech?

2026 will mark the 50th anniversary of the birth of biotech. And what comes next? Given the tremendous pace of progress over the past two decades, we should expect similarly large leaps forward. Key areas for development will include better drug delivery mechanisms to more efficiently bring medicines to where they are need to be in the body, a suite of engineered tools to accelerate R&D such as robotic lab automation, diagnostics and other earlier detection tools to treat and cure diseases when they are most susceptible, and organoid and tissue on a chip technologies to improve our ability to model biological phenomena. Ultimately, the 2020s will be about the intersection of technology & biology (TechBio). Examples of this intersection include companies like 64x Bio (computational feedback in high throughput discovery and screening platform of viral vectors), Xilis (enabling precision medicine through patient derived micro-organoids & computational analysis), or Mythic (re-engineering cellular trafficking of antibody drug conjugates to increases therapeutic potency) will become major players in the modern biotech ecosystem.

We’ve come a long way from Herb Boyer & Rob Swanson, but we still have a long way to go. The 21st century will be defined by the biological revolution & biotech leaders are just getting started. Welcome to the era of TechBio🚀