Written by: Franco Tavella

Editors: Jennifer Baker, Kristen Loesel, Christian Greenhill, and Madeline Barron

As an Argentinian, I’ve shared a wish with my country for 16 years: to see our nation’s soccer team win a major tournament with Lionel Messi as team captain. Even Argentinians uninterested in soccer felt the frustration of having one of the world’s best players on the national team, yet never winning a tournament. Finally, this summer we watched with joy as Messi received the trophy after defeating our greatest soccer rival, Brazil, in the 2021 Copa América finals. A large crowd celebrated in the iconic Obelisco, and despite being abroad in the U.S., I felt closer to home. However, this moment of national pride and celebration may have never happened without biomanufacturing. 

At 11 years old, Lionel Messi was diagnosed with growth hormone deficiency. Without treatment, he could have stopped growing, which would have compromised his budding career. Thanks to daily injections of the protein he lacked—human growth hormone (hGF)—he overcame his disease and reached the top of his profession. Unfortunately, producing hGF is not simple. Hormones, or more generally, biological medicines, can’t be manufactured with the same techniques used for chemically-based drugs like Advil or Claritin. The only way to obtain biological medicines is by using living cells as factories. 

Using cells as factories, or biomanufacturing, consists of harnessing the capabilities of cells to our advantage. Cells contain machinery to produce the proteins necessary for their growth, which scientists can redirect to manufacture proteins of medical interest, such as hGF. To do this, researchers provide cells with DNA, which contains instructions for building the desired protein. As cells grow, they also produce the protein of interest from the provided DNA. 

While the cellular factories are microscopic in size, scientists need highly-specialized facilities to manufacture proteins on a large scale. These facilities resemble breweries, with metal containers much taller than their operators and hanging labyrinths of steel tubes. Workers place cells in these containers, called bioreactors, to ensure optimal conditions for cellular growth. Usually, cells start in vessels as little as a soda can, and, as they divide, end in containers as large as a tanker truck! After weeks in the bioreactor, workers separate the protein of interest from the cells in a process called purification. Ultimately, this purified protein is used in different products, such as hormone treatments (e.g., hGF and insulin), therapies for cancer and rheumatoid arthritis, vaccines, and enzymes that reduce the environmental footprint of stone-washing jeans

Illustration by Katie Bonefas

Unfortunately, cell-based biomanufacturing has limitations that affect both the production and accessibility of biological drugs. For example, cells can’t produce the cancer therapeutic onconase, since its toxic properties kill cancer cells and cellular “factories” alike. Additionally, the inefficiency of cell-based manufacturing restricts accessibility to drugs made with these methods. A recent study pointed out that the production capabilities of even the most developed economies cannot provide biological medicines worldwide. Scientists estimate that the first biological medicine to slow Alzheimer’s (recently approved by the FDA) could only reach less than 20% of the U.S. patient population using the current biomanufacturing methods. Even with improvements to cell-based methods, it is unlikely that these efforts alone will suffice to meet the increasing global demand for biological drugs.

Thankfully, new approaches using cell-free systems hold promise for addressing such issues, tackling a central problem of cell-based biomanufacturing in a simple yet powerful way. In cell-based approaches, the molecular machinery that cells use to make proteins coexists with many other unrelated cellular components, impeding efficient protein production. On the other hand, in cell-free approaches, scientists extract the specific cellular machinery for synthesizing proteins and discard any unrelated cellular parts. The extraction results in a liquid that contains the core protein manufacturing machinery. Since cell-free extracts don’t have a membrane boundary, nor do they need to grow—they are a collection of molecules in a tube—protein production is more efficient and versatile. 

The flexibility of cell-free systems has kickstarted new biotech applications in recent years, especially in the field of biosensors. Biosensors are detection devices (e.g., pregnancy and blood glucose tests) that use biological molecules to identify the presence of specific compounds. While traditional biosensors use enzymes or antibodies to spot compounds, cell-free-based biosensors use their protein-building capability for detection. For example, in virus detection, the presence of the viral genetic material triggers a cell-free reaction that produces a colored protein, indicating a positive test. Using this approach, researchers have built biosensors to detect human viruses like Ebola, Zika, and norovirus, as well as deadly plant pathogens that affect agricultural products. Beyond biosensors, scientists have also used cell-free systems to expand the production of biomedicines, including a therapeutic to treat skin disorders, an influenza vaccine candidate, and the anti-tumor agents interferon-⍺ and onconase. Additionally, scientists have used cell-free systems to optimize the production of antimicrobial compounds, a much-needed tool in the current fight against antibiotic-resistant bacteria. 

Despite their promise, cell-free applications are generally developed in small-scale labs before they are fully scaled for mass production. Industrial-level scaling of cell-free systems is challenged by high costs and poor performance of these systems in large bioreactors. Encouragingly, some companies—including Liberium, Synthelis, Sutro Biopharma, and Greenlight Biosciences—have demonstrated the feasibility of large-scale, cell-free applications to manufacture products such as RNA vaccines, therapeutic proteins, and antibody treatments. 

While technological and accessibility challenges remain, biomanufacturing is already helping us address big and small problems alike. Years after Lionel Messi’s soccer career was enabled by hGF injections, the Copa América had to be postponed in 2020 due to the COVID-19 pandemic. Without the key role of biomanufacturing in vaccine development, the Copa América would not have been able to safely resume in 2021. In fact, the Pfizer-BioNTech vaccine against SARS-CoV-2 is made with cell-based methods (to produce DNA instructions for the vaccine’s core mRNA component) and cell-free systems (to synthesize the vaccine’s mRNA). Thus, without biomanufacturing, Messi never would have led the Argentinian team to victory, bringing joy and relief to a nation in the midst of a global crisis. 

Just as it shaped the story of one soccer star, a nation’s long-hoped-for victory, and the trajectory of the current pandemic, biomanufacturing will continue to help solve new challenges in unexpected yet beautiful ways. This past summer, through a series of events made possible by biomanufacturing, soccer brought me joy during these dire times. In the future, I look forward to seeing how biomanufacturing might spark similar emotions in others and create more unexpected connections along the way.

Franco Tavella is a Biophysics Ph.D. candidate in Qiong Yang’s lab at the University of Michigan. He studies cell cycle oscillations using cell-free systems, microfluidics, and simulations. If you can’t find him in the lab, he’s probably in one of Ann Arbor’s bookstores browsing for his next read. Franco writes because he believes that biotechnology will benefit society even more if it’s accessible to everyone. Find him on Twitter to chat.

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