Automation has a long history of driving enhanced production. During the Industrial Revolution, manufacturers first harnessed automated machines to increase yields for materials like cotton and paper. Decades later, the rapid expansion of the automobile industry in the early 20th century saw automotive companies streamline assembly lines, reducing assembly time from 12 hours to about 1.5 hours per car.

Today, robotic process automation plays a pivotal role in the life sciences industry. AI-powered technologies like machine learning have rejuvenated automation, enabling data-driven machines to control and interact with each other autonomously. Many industries are moving towards this goal. While these benefits are something for which they strive, greater quality and consistency are even more critical in the strictly regulated biopharma sector. So why has biopharma and the wider pharmaceutical industry been slower to adopt fully automated technologies?

Complex and variable

The complexity and variability of bioprocessing are often cited as the main reason for the lag in uptake. However, success stories such as Moderna, which utilized automation and AI to develop an mRNA SARS-CoV-2 vaccine within a year, show it is achievable, without risking the quality and consistency that is so important to therapeutic manufacturing. Even with this compelling story, some firms opt for less-integrated options because they are simpler to deploy initially and align better to their current timelines, workforce, and budget.

The limited duration of patent protection is also a factor. Making major changes to a licensed facility can be challenging and time consuming. Once a facility is licensed to manufacture a biologics product, there likely won’t be multiple changes, and overhauling an entire factory can be cost prohibitive.

Additionally, there are different pressures on the biologics industry. For example, technology advancements are pivotal in reducing costs in the automotive industry. In the biopharmaceutical sector, the priority is on delivering products that maintain high quality, consistency, and reasonable pricing.

Because of the risk in changing a facility, automation is often considered in the design of new facilities. Modern biopharma facilities are constructed to be multipurpose, handling different products or production campaigns. Automation enables flexibility, allowing seamless transitions between different product lines without extensive manual reconfiguration. Automated systems can adapt quickly to different process parameters, making facilities more agile and future-proofing their operations.

Despite the advantages of automation, there are potential challenges to consider. Implementing fully automated systems can take time. Changeover times may present issues depending on how flexibly you’ve designed your systems and the facility to handle changes and multiple products. Legacy systems must be considered as many biopharma companies still rely on outdated, manual systems and integrating automation with these legacy systems can be expensive and technically challenging.

The data that automated systems generate needs to be integrated into existing data management and quality control systems. The transition from paper-based or manual tracking to automated digital systems can be slow and met with resistance.

Manufacturers may encounter difficulties when they adopt technology without clear objectives. However, aiming for continuous improvement of manufacturing processes is a clear and achievable objective. By consistently using technology to enhance processes and optimizing human and capital resources, manufacturers can achieve remarkable success.

Nearly a century ago, Alexander Fleming discovered a penicillin-producing mold. Over the following decades, various microbes were used to make a range of therapeutics, from insulin to vaccines. Although gene-editing and other techniques can improve the production of microbe-based biologics, artificial intelligence (AI) could push these drugs even further.

“Artificial intelligence and machine learning play a crucial role as transformative tools in pharmaceutical research and microbial engineering,” according to Ayaz Belkozhayev, PhD, associate professor in the department of chemical and biochemical engineering at Satbayev University in Kazakhstan, and his colleagues. “These technologies enable the analysis of large datasets, the optimization of metabolic pathways, and the development of predictive models.”

Plus, Belkozhayev’s team points out that AI-based technologies can be used to develop efficient microbes that provide sustainable production of biotherapeutics. These biotherapeutics include ones that battle largely drug-resistant microbes, such as Acinetobacter baumannii, which can infect a person’s blood, lungs, wounds, and more.

AI-based tools could also be applied to microbes that produce lipophilic compounds, such as modified antibodies or peptides. Nonetheless, Zhang Dawei, PhD, an investigator in synthetic biology and microbial manufacturing engineering at the Tianjin Institute of Industrial Biotechnology in China, and his colleagues explain that lipophilic compounds can accumulate in cell membranes during fermentation, which can decrease production or even kill the cells producing the biotherapeutic.

To address this membrane-capturing problem, scientists explore what Dawei’s group called “membrane engineering techniques to construct highly flexible cell membranes … to break through the upper limit of lipophilic compound production.” AI could play a key role in this process. As Dawei’s group notes: “With the continuous advancement of artificial intelligence technology in the field of biomedicine, computer-assisted scientific research will provide a more comprehensive blueprint for the construction process of highly flexible cell membranes.”

Nonetheless, AI alone will not make better microbes for producing biologics. As Belkozhayev’s team emphasizes, “Innovations in genetic engineering, synthetic biology, adaptive evolution, [machine learning], and high-throughput screening have led to substantial progress in optimizing microorganisms for the efficient production of complex biological and chemical compounds.”

So, as is often the case, no one thing is the solution to all of the challenges in making biotherapeutics from microbes. Still, AI will probably enhance this area of bioprocessing.

Research, headed by teams at Trinity College Dublin and University College Dublin, has uncovered how lipid-rich fluid in the abdomen, known as ascites, plays a central role in weakening the body’s immune response in advanced ovarian cancer.

The scientists explored how ascites disrupt immune cell function, with a particular focus on natural killer (NK) cells and T cells, which are key players in the body’s ability to eliminate tumors. By analyzing the contents of ascites fluid from ovarian cancer patients, they identified a group of fat molecules called phospholipids as key drivers of this immune dysfunction, suggesting that the lipids suppress the tumor-killing properties of natural killer (NK) cells.

The findings offer new insights into immune suppression in ovarian cancer and open promising avenues for future immunotherapy strategies. “We found that these lipids interfere with NK cell metabolism and suppress their ability to kill cancer cells,” said Karen Slattery, PhD, Research Fellow at the Trinity Translational Medicine Institute. “Crucially, we also discovered that blocking the uptake of these phospholipids into NK cells using a specific receptor blocker can restore their anti-tumor activity, which offers a compelling new target for therapeutic intervention.”

Slattery is first author of the team’s published paper in Science Immunology, titled “Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer.” In their paper the team reported, “… we identify polar lipids as central mediators of lymphocyte immunosuppression in ascites …These lipids caused dysregulation of NK cell lipid metabolism homeostasis and impaired cytotoxic function.”

“High-grade serous ovarian cancer (HGSOC) is an unmet clinical need, with limited treatment options and a 5-year survival rate of just 28%,” the authors wrote. “More than 70% of patients already have metastatic disease at diagnosis.”

Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. This ascites fluid not only supports the spread of cancer throughout the abdominal cavity but also significantly impairs the body’s immune defenses, although the underlying mechanisms remain poorly understood, the team continued. “Understanding the impact of ascites on the immune system is critical for developing effective immunotherapies for patients with metastatic ovarian cancer.”

Natural killer cells are antitumor lymphocytes that have several advantages as targets for immunotherapy, Slattery and colleagues suggested. “Unlike T cells, they are not tumor antigen specific and pose lower risks of graft versus-host disease or cytokine storms in cell therapy … Critically, NK cells defend against metastasis, and their infiltration into tumors correlates with a better prognosis in metastatic cancers.”

However, NK cells can become dysfunctional in patients with cancer, the authors commented. “Despite the potential of NK cells as prospective immunotherapy targets, a better understanding of the mechanisms driving NK cell dysfunction in cancer is needed to overcome immunosuppressive factors.”

For their newly reported study the scientists examined blood, tumor, and ascites samples from patients with advanced HGSOC. They found that immune cell function was suppressed across cancer sites within individual patients, and in particular, the ascites microenvironment inhibited NK cells’ tumor killing abilities.
The team found that removing NK cells from ascites rescued their antitumor function, while depleting lipids from ascites lifted immune suppression. “Removing lipids from ascites abrogated the suppression of the immune system by ascites,” they further reported. Their studies showed that NK cells took up large amounts of lipids from ascites, which caused a lipid overload that disrupted plasma membrane remodeling. The investigators speculated that disruptions to the plasma membrane could impair NK cells’ tumor cell targeting abilities, thus restricting their antitumor activity.

The experiments in addition demonstrated that NK cells in ascites upregulated the lipid transporter receptor SCARB1/SR-B1. Inhibiting lipid uptake through SR-B1 restored NK cells’ tumor killing abilities in vitro. “Blocking the uptake of lipids through SR-B1 restored the activation and antitumor functions of NK cell in ascites, highlighting SR-B1 as a potential NK cell immunotherapy target,” they stated.

The studies also pointed to the polar lipid PC(36:1) as a contributor to NK cell dysfunction in ovarian cancer, with data suggesting “… that uptake of PC(36:1), and likely other certain lipid species from ascites, results in perturbed plasma membrane order, which could disrupt their capacity to polarize toward target cells, resulting in reduced tumor killing.” The team concluded that, collectively, “… these data show that uptake of polar lipids such as PC(36:1) through SR-B1 restricts NK cell functions in ascites and that SR-B1 represents a potential immunotherapy target for boosting NK cell antitumor responses in advanced ovarian cancer.”

Slattery commented, “This work adds a critical piece to the puzzle of why ovarian cancer is so aggressive and has such poor outcomes. While the immune system is naturally equipped to detect and destroy cancer cells, this function is switched off in many individuals with ovarian cancer, and we now know that this is in part due to the fat-rich environment created by ascites.”

Prof. Lydia Lynch, PhD, formerly based in Trinity and now in Princeton University, is the senior author of the research article. She further commented, “This study marks a significant advancement in ovarian cancer research, identifying a new mechanism underpinning immune failure and laying the foundation for new therapies that could restore immune function in these patients. By targeting the fat-induced suppression of immune cells, future treatments could empower the body’s own immune defenses to fight back and in doing so, improve outcomes for ovarian cancer patients.”

The marine bacterium Alcanivorax borkumensis feeds on oil, multiplying rapidly in the wake of oil spills and thereby accelerating the elimination of the pollution, in many cases. It does this by producing an “organic dishwashing liquid,” which it uses to attach itself to oil droplets.

Researchers in Germany have discovered the mechanism by which this organic liquid is synthesized. Published in Nature Chemical Biology, the research findings, “Biosurfactant biosynthesis by Alcanivorax borkumensis and its role in oil biodegradation” could allow the breeding of more efficient strains of oil-degrading bacteria, according to the scientists.

Loosely translated into English, the Latin name of the bacterium is “alkane eaters from Borkum” as alkanes are chains of hydrocarbons that exist in petroleum in large quantities. A. borkumensis feeds on energy-rich chains which occur naturally in the sea—and on non-naturally-occurring chains like those dispersed in oil spills. In many cases the bacteria multiply rapidly, thereby accelerating the pollution-clearing process.

Oil and water don’t mix

Because oil and water don’t mix, in order to eat its favorite food, the A. borkumensis requires a chemical aid. It makes it for itself, producing a kind of natural dishwashing liquid. This “detergent” is a compound consisting of the amino acid glycine and a sugar-fatty acid compound.

“The molecules have a water-soluble part and a fat-soluble part,” explains Peter Dörmann, PhD, who is a biochemist at the University of Bonn’s IMBIO institute (Institute of Molecular Physiology and Biotechnology of Plants). “The bacteria settle on the surface of the oil droplets, where they form a biofilm.”

The mechanism by which the alkane eater synthesizes this detergent was not understood until a working group led by Karl-Erich Jaeger, PhD, of Forschungszentrum Jülich and the Heinrich Heine University Düsseldorf, studied the bacterium’s genome.

“In our research we identified a gene cluster which we believed could play a role in production of the molecule,” says Jaeger. In fact, when the genes of this cluster were switched off, the bacteria were impaired in their ability to attach to oil droplets. “As a result they absorbed less oil, and grew much more slowly,” adds Lars Blank, PhD, of RWTH Aachen University.

Potential biotech applications

One of Dörmann’s doctoral students, Jiaxin Cui, succeeded in elaborating the synthetic pathway by which A. borkumensis produces the detergent. Three enzymes are involved in this process, in which the molecule is assembled step by step. The three genes contain the instructions for building these biocatalysts, without which the bonding process cannot efficiently proceed.

“We successfully transferred the genes involved to a different bacterium, which then produced the detergent as well,” Cui explains.

Bacteria like A. borkumensis are important for degrading oil pollution, so these findings are of significant interest, possibly leading to the development of new, more effective strains.

“This natural detergent could have biotech applications as well, such as for microbial production of key chemical compounds from hydrocarbons,” points out Dörmann, who is a member of the University of Bonn Transdisciplinary Research Area (TRA) “Sustainable Futures.”