PRODUCED BY

The Importance of Adopting a Platform Approach New over Point Solutions Matthew Gardner: Generating More Robustly Infected Cell Lines by Co- Paths Culture Infection in Life Science

Vikrant Minhas: Sickly Sweet — How Utilisation of Dr. : Sugars Afects the Synthetic Biologist, Disease Progression Artist, Advocate, and of Streptococcus Ultimate Puzzle Solver pneumoniae

Dr. Tina Boville: Directing Evolution to Engineer Nature SUMMER 2019

CONTENTS

Dr. Karmella Haynes: Matthew Gardner: Synthetic Biologist, Artist, Generating More Robustly Infected Advocate, and Ultimate Cell Lines by Co-Culture Infection Puzzle Solver

The Only Path Forward The Importance of Adopting a for Biotech Platform Approach over Point Solutions

Dr. Tina Boville: The R&D Data Directing Evolution to Maturity Curve Engineer Nature

Vikrant Minhas: Five Key Takeaways Sickly Sweet — How Utilisation of from Benchtalk West Sugars Afects the Disease Progression of Streptococcus pneumoniae SPOTLIGHT Karmella Haynes Synthetic Biologist, Artist, Advocate, and Ultimate Puzzle Solver

BY LILY HELFRICH

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Dr. Karmella Haynes is an Associate Professor at , where her lab focuses on a novel scientific problem: understanding and creatively modulating epigenetic responses to cancer. Her aptitude for problem DR. KARMELLA solving led her to a career in , but it HAYNES didn’t start with science. She was first an artist, then a LOCATION Atlanta, Georgia scholar, then a teacher and a professor. She is now all CURRENT POSITION of the above, plus a fierce advocate for representation Associate Professor of , in science. Emory University EDUCATIONAL + CAREER HISTORY The Art of Experimentation biology started looking more and • B.S. Biology, Florida A&M • Ph.D. Molecular Karmella Haynes always had a more like a puzzle. , Washington strong leaning toward puzzle solv- University in St. Louis ing and experimentation. In ele- Formative Years • Postdoctoral fellow, mentary school, this came through Karmella’s career as an academic Davidson College in her math classes and, perhaps jump-started during college when • Postdoctoral fellow, Harvard Medical School unexpectedly, her art classes. She she participated in the MIT Summer • Assistant Professor of took of with art projects, morphing Research Program. Karmella Bioengineering, Arizona them beyond their initial scope. She spent two summers working with State University loved asking questions. How could Dr. Mary-Lou Pardue, exploring she put visual elements together telomeres and chromosome PRIMARY AREA OF RESEARCH to convey a message? How could replication in . After Mammalian synthetic she use photorealism to convince finishing her undergraduate degree, biology with a focus on people that they were looking at a she entered the Molecular Genetics cancer research 3D object? Ph.D. program at Washington Through art, Karmella learned to University in Saint Louis, and she RECENT PAPERS 1. The synthetic histone- carry out her first experiments. But joined Dr. ’s lab. She binding regulator protein it wasn’t until late high school that studied Drosophila PcTF activates interferon she developed a clear interest in and the role of chromatin states in genes in breast cancer science. Around that time, Karmel- gene regulation. cells. BMC Syst Biol. 12: 83 la was introduced to genetics in As a graduate student, Karmel- (2018). 2. Design, construction, and her classes—and through Jurassic la developed a strong sense of validation of histone- Park. She got excited about track- confidence in the lab. This confi- binding efectors in vitro ing genetic inheritance with tricky dence—built upon her strengths in and in cells. . but solvable Punnett Squares. She creative thinking, puzzle solving, 57: 31, 4707-4716 (2018). was curious about DNA, a cool and careful experimentation—al- 3. The Impact of Chromatin Dynamics on Cas9- molecular substance that worked lowed her to work productively and Mediated Genome Editing like a code, and what scientists independently. She loved devising in Human Cells. ACS Synth could do with it. To Karmella, testable hypotheses and design- Biol. 6: 3, 428-438 (2017).

05 SPOTLIGHT

MORE ABOUT ing intelligent experiments. “I took started thinking seriously about DR. HAYNES the philosophy very seriously,” pursuing research again; she she says. “And I wasn’t bad at the wanted to apply synthetic biology bench. I had an artist’s skills, had to chromatin biology. ‘the hands’ so-to-speak. I suppose I At the time, there were only was a philosopher and a good tech- a couple of labs working at the nician, which is really what makes a interface of synthetic biology and What’s one word to describe successful Ph.D. student.” eukaryotic molecular biology. The your attitude toward science? Meaningful. leading lab was Dr. Pam Silver’s. The Road to Karmella shortly joined the Silver Synthetic Lab as a postdoc. A few years later, Though she was skilled at the she took her postdoctoral research bench, Karmella was leaning to a faculty position in bioengineer- toward a teaching career at a ing at Arizona State University. What’s your dream liberal arts college. She pursued Karmella now runs a research research project? a postdoc at Davidson College, lab at Emory University whose goal In general, I love inventing where she serendipitously found is, broadly, “to use chromatin as genetic gadgetry that functions in live cells. My dream invention a role as a coach for the Davidson an engineering substrate.” By that, would make discoveries easier iGEM team. Working in synthetic Karmella means that she wants for resource-limited labs. My biology and on bacteria—a system to target engineered regulatory dream cell engineering project is new to Karmella—the iGEM team proteins to histone marks. Because to regulate whole sets of genes made waves when they published histone regulators can modulate in cells in a coordinated fashion to regulate cell behavior and a paper about bacterial computers, the expression of multiple genes, tissue formation. or E. coli engineered to solve a the techniques and bioengineered mathematical puzzle. Karmella proteins developed in the Haynes

Where did you grow up? St. Louis, Missouri Where can people find you outside of the lab or classroom? Jogging through my neighborhood, walking my dog, or enjoying craft beer : MARCO_ALEXIS CHAIRA/ASU. Can you share a fun fact? ) I am the unofcial genealogist for my family. I’ve traced three diferent lineages back to ~1865. This work inspired me to build a collection of antebellum era information to help other descendants of enslaved African-Americans to do their own research: HEADSHOT AND LAB PHOTO www.sankofagenus.com. See Karmella’s Art! karmellahaynes.com/ category/Gallery Karmella shares her infectious energy with her graduate, undergraduate, and

iGEM students. PHOTO CREDIT (

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Lab can be used to study diseas- es in which controlling regulatory “More scientists are needed states is critical. These histone regulators also have the capacity to change 3D genome architecture, when we start talking about so the Haynes Lab is exploring ways to enable CRISPR editing culture and representation.” of previously inaccessible, tight- ly-packaged chromatin. With this —Karmella Haynes research, Karmella aims to improve both the scientific understand- ing and the treatment of various human cancers. me with kiddie gloves. They didn’t the experiences of working with On Representation give me the same kind of coach- trailblazing female professors like in Academia ing they would have if they were Sarah Elgin and Pam Silver, with Looking back on what set the stage comfortable with me.” gratitude. She also identifies the for her successful career, Karmella She fortunately found a program need for similar opportunities else- first credits her education at Florida at Wash U that supported minority where. “More scientists are needed A&M. She received a full scholar- and underrepresented graduate when we start talking about culture ship to Florida A&M, a historically students. Through the Chancellor’s and representation.” black public institution. “A&M Fellows program, students received taught me to be a scholar without a community and resources. Kar- Solving New Puzzles being distracted by being margin- mella remembers, “Ph.D. students Today, Karmella advocates strong- alized. Being marginalized has a like me that didn’t come from Ph.D. ly for representation in science strong impact on a person—on your families tended to be first-genera- and for her students. She balances self-worth. You’re defining your- tion. We lacked the cultural capital several other interests with running self by defending yourself. That’s that many of our peers had. I loved a successful research lab. While just draining.” that program. It really, really en- she works diligently to master grant Karmella did not have the same couraged me to stick it out.” writing and presentation giving, she experience during her first year The program at Wash U and continues excitedly to coach iGEM in graduate school. Though she the environment at A&M didn’t and to teach. Karmella has had to eventually excelled at Wash U, she make Karmella a good scientist, sacrifice painting in recent years, initially found herself distracted, or change how much potential she but fortunately she lives out her lacking moral support and strug- had. Instead, both experiences love of experimentation and puzzle gling with imposter syndrome. “The gave her the confidence to capital- solving through science. And she environment—the opposite of what I ize on that potential, the confidence does take advantage of her artistic try to ofer my students now—didn’t to recognize herself as a schol- side every so often, mostly to make have strong moral support. I feel ar and a philosopher. Karmella intuitive and aesthetically appeal- like some people tried to handle reflects on these experiences, and ing scientific figures.

WHY I think I first heard about Benchling in 2013 at SB 6.0 in London. I was excited to have my whole lab use BENCHLING? Benchling because it’s a revolutionary way to share information about recombinant DNA. In the old days (early 2000s) scientists mailed paper sketches of plasmids and pages of printed-out sequences to each other. As digital media became popular, sharing sequences via NCBI and GenBank format files improved things, but those files are static. With Benchling, your updated, corrected, and amended sequences and maps can be accessible to the public. It’s a great vehicle for transparency. I believe that requiring my trainees to use this platform will improve how science is done in the future. —Karmella Haynes

07 The Stability Problem The first major hurdle in the manipulation of mutant KSHV was cleared in 2012, when robust genetic tools for KSHV were developed.1 The system uses a bacterial artificial chromosome (BAC) that harbors the KSHV genome. This BAC can be propagated in Escherichia coli and manipulated by the Red recombinase system present in the bacteria. There have been some minor improvements to the original protocol by our lab to improve mutagenesis—most notably, we have used gBlocks as RESEARCH the mutational insert. However, a major stumbling block remained: the generation of stably-infected cell lines. Generating a stable infection is a common problem in the study of host-pathogen interactions. The Generating More pathogen of interest often outright kills the target cells, or the target cells detect and inactivate the Robustly Infected Cell pathogen. In the case of KSHV, the virus generally does not have difculty evading the host Lines by Co-Culture response. But, depending on the method of infection, the virus may BY MATTHEW GARDNER act inconsistently. For example, Infection cell lines generated by direct transfection of the purified BAC or erpesviruses are large, double-stranded DNA viruses that have by infection with purified, cell-free evolved over millions of years to become master manipulators virus remain infected, but they lose of cellular machinery. By studying how these viruses—and the ability to express viral genes Hviruses in general—hijack host cell machinery, we can learn a great or to produce new virions over deal not only about strategies of viral pathogenesis, but also about the time. Even when viral production fundamental cellular systems involved. is initiated, it is initiated in an Given the highly-specialized nature of these viruses, it is difcult to attenuated state. When measuring mimic a natural infection in a tissue culture setting. Even when viruses viral genome replication by qPCR, can be cultured and studied, genomic mutants are often difcult to we expected approximately produce or cannot be maintained in the tissue culture system optimized 30-fold DNA replication, but we for the wild-type virus. This was the case for Kaposi’s sarcoma-associat- only observed 5 to 10-fold DNA ed herpesvirus (KSHV), which we study in the Glaunsinger Lab. Finding replication. We also found that a way to stably infect cell lines with mutant KSHV took the entire field very few infectious particles were many years of work. produced.

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Natural Infections purified BAC is then transfected into FIGURE 2. PROGRESSION OF Provide a Solution HEK293T cells, which will serve as KSHV INFECTION DURING DRUG The key to generating a stable cell the producer cell line. HEK293T SELECTION. line turned out to be mimicking a cells are used because they are more natural infection, where cells easily transfected, fast-growing, 24 Hours Post Reactivation are rarely infected with cell-free and sensitive to selection drugs. virus and never by naked viral After 24 hours, the producer cells genomes. Dr. Zsolt Toth (University are checked for infection; infected of Florida) and Dr. Jae Jung cells will constitutively express Uninfected (University of Southern California) GFP, encoded by the viral genome. iSLK Puro found that a more natural route of Producer cells (transfected Cells infection led to a better-behaved HEK293T cells) are next co-cultured Infected HEK293T cell line. In the microenvironment of with target cells (uninfected iSLK Cells a Kaposi’s sarcoma tumor, only 1-2% cells). Both types of cells are of cells are in the virion-producing trypsinized, counted, and mixed lytic phase at any time. The at a 1:1 ratio in a new vessel. majority of cells are in the latent The co-culture vessel should phase, expressing only a subset be large enough to comfortably 1 Week in Drug Selection of the ~90 viral genes. The few accommodate the total number genes that are expressed during of cells that are added, but small latency are required to maintain the enough to maintain them in close Infected tumor microenvironment,2 which contact. Once the cells are mixed, iSLK Puro Cells is densely-packed and highly- viral production is induced by Dying inflammatory. This environment the addition of TPA (PMA) and HEK293T is more closely mimicked by a sodium butyrate (NaBut). After Cells Dying co-culture infection model than four days, the cells should cover the iSLK Puro Cells by a cell-free virus infection entire tissue culture vessel, with iSLK model. In the Glaunsinger Lab, puro cells growing as an even layer we perform co-culture infection on the bottom and the HEK293T according to the protocol outlined cells growing in clumps on top of below, developed with guidance them (Figure 2). from Dr. Toth. Infected target cells are isolated over the next two weeks through How to Perform a the addition of selection drugs, studies. In the Glaunsinger Lab, we Co-Culture Infection which kill the producer cells and generally characterize any new First, a BAC16 clone is produced uninfected target cells. The new cell line by assessing viral gene using a slightly modified version cell line is then expanded and expression, DNA replication, and of the Brulois protocol.1,3 The frozen in small aliquots for future infectious virion production.

FIGURE 1. A METHOD FOR MIMICKING A NATURAL KSHV INFECTION.

Producer Cells Target Cells Induce Viral Select for Infected KSHV Production Target Cells BAC16 TPA + NaBut Puromycin Hygromycin Mix With G418 Target Cells

24 Hours 96 Hours ~2 Weeks

09 RESEARCH

FIGURE 3. CHARACTERIZATION OF THE ORF68-DEFICIENT (ORF68PTC) MUTANT VIRUS.

(A) Diagram depicting the genetic locus of ORF68 and the mutations inserted into the ORF68PTC virus. (B) Western blots showing expression of the early ORF59 protein and the late K8.1 protein in WT, ORF68PTC, and ORF68PTC-MR viruses. Histone H3 served as a loading control. (C) DNA replication was measured by qPCR of the viral genome before and after induction of the lytic cycle. (D) Progeny virion production was assayed by supernatant transfer and flow cytometry of target cells.3

Co-culture infection and characterize ORF68 in vitro. enables the discovery We discovered that it was a DNA- References of KSHV ORF68’s role binding protein associated with 1. Brulois, K. F. et al. 3 Recently, we used this protocol to nuclease activity. Construction and study the role of the KSHV protein Without the cell-based viral char- Manipulation of a New Kaposi’s Sarcoma- ORF68. This protein had not acterization enabled by co-culture Associated Herpesvirus previously been studied, although infection, I doubt we would have Bacterial Artificial homologous proteins in related uncovered this activity. ORF68 is of Chromosome Clone. J. Virol. 86, 9708–9720 (2012). viruses suggested that it would play particular significance because it is 2. Ganem, D. KSHV infection a role in viral DNA packaging. We an essential viral protein, required and the pathogenesis of showed that ORF68 was required for virion production. This study Kaposi’s sarcoma. Annu Rev Pathol 1, 273–296 (2006). for the production of infectious demonstrated how we can use 3. Gardner, M. R. & virions. While the wild-type virus the co-culture infection protocol Glaunsinger, B. A. Kaposi’s could infect new cells, the mutant to study viruses with mutations in sarcoma-associated herpesvirus ORF68 is virus could not, despite replicating essential genes. The only modifica- a DNA binding protein the viral genome. Furthermore, we tion required when working with le- required for viral genome showed that without ORF68, the thal mutations is to use a HEK293T cleavage and packaging. J. Virol. JVI.00840–18–38 viral genome is not cleaved, an cell line that stably expresses the (2018). event integral to the production of gene that you are mutating, which new virions. This lead us to purify in our case was ORF68. Editor’s Note: The featured photo for this article is a TEM image, provided to us by the author. In this image, viral capsids—the dark, geometric shapes—are visible inside a Matthew Gardner is a graduate student in Britt host cell. Glaunsinger’s lab at the University of California, Berkeley.

10 SPRINGSUMMER 2019 2019 VOL VOL 1 1 BENCHTALK BENCHTALK BIOTECH The Only Path Forward for Biotech BY SAJITH WICKRAMASEKARA

iotech is booming, but R&D entirety of biotech investment in pharmaceuticals. The food we is held back by widespread 2013. Industry consensus is that by eat, the crops that make up our inefciencies. If biotech’s 2022, the majority of top 100 drugs agriculture industry, the fuels that Bgoing to industrialize and mature in on the market will be biologics. power our lives, and just about all the same ways as other paradigm- Right now, we’re at the start of everyday materials, from textiles to shifting industries, it needs a new an even broader biotech revolution plastics, will be radically afected approach. comparable to the rise of the and improved by biotech. Six years ago, when I founded computer in the ’70s and ’80s, and But at the same time, the a company to serve scientists even to the industrial revolution pioneering scientists who are pushing the frontiers of biology of the 19th century. Over the actually doing this research are research, large molecule R&D was next 10 to 20 years, biotech will stuck using paper, spreadsheets, by no means a sure thing. In 2012, fundamentally rewrite the way and software built for traditional biologics made up roughly 27% of we live – and this goes beyond small molecule research. These pharmaceutical pipelines, and had researchers routinely spend 30% of been hovering around that level for their time on busy work. Meanwhile, the preceding ten years. The FDA their responsibilities include hadn’t yet approved a single CAR-T not only making a new drug, or gene therapy. CRISPR-Cas9 but figuring out how to make an gene editing hadn’t even been entirely new type of drug. Because invented yet. they can’t easily and accurately Today, of course, biologics report their progress and results, are widely acknowledged as managers and executives end up the drugs of the future. In 2017, having to base pivotal decisions on biologics made up nearly 40% of incomplete data. pharmaceutical pipelines. In the Given the state of things, it’s a first two months of 2018, investment testament to the tenacity of today’s in biotech startups exceeded the scientists that biotech has come

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BIOTECH

this far. But as drugs and other Enable rapid, iterative Accelerate the move to biological products continue to 1 development of new 3 “labless” drug companies get more complex and as R&D therapeutic techniques Externalization and automation are costs continue to rise, biotech’s When someone says, “Large two of the most hyped components only option is to take a diferent molecule R&D,” or even, “Biologics of the future of R&D, and with approach: to industrialize. R&D,” it can mean many diferent good reason. The benefits of 24/7 These impediments – ill- things. From CAR-T immunotherapy, experimentation and geographically suited tools, insufcient record- to genetically engineering new advantageous lab space hardly keeping, and underdeveloped crops, the sheer range of modalities need to be expounded upon. In processes – are the same sorts that biotechs work in today is the context of large molecule R&D, of growing pains that preceded staggering. What’s more, there are going labless means faster iteration the rise of semiconductors, numerous opportunities for these and higher throughput. Biotechs modern manufacturing, and techniques to overlap. For example, need software that can manage even chemistry-based R&D. Over if a company is using CRISPR/Cas9 external partners, obfuscate data time, all of these paradigm shifts to genetically engineer CAR-T cells, when necessary, and surface trended towards standardized, their R&D processes and needs will partners’ data back to them in a structured industrialization. In the difer from a company doing CAR-T digestible manner. If a company context of biotech, this means with lentiviral transfection. Biotechs outsources its early antibody more engineered processes, higher need software that can support not discovery work to a CRO, accessing predictability, higher scalability, only novel therapeutics, but novel the data produced by the CRO and ultimately faster time-to- R&D processes. should be as easy as accessing the market. data that company is producing Compared to many previous Empower faster and internally. Ideally, all of that paradigm shifts, large molecule smarter decision-making upstream data should be accessible R&D is distinguished by the 2In drug discovery, time to market to downstream teams in the same incredible quantity and complexity is key. Especially when you’re system they use to complete and of its data, and of the extent to dealing with iterative workflows record their own work. which numerous teams need to and novel processes, being able Biotechnology will (in some work together. Given that biotech’s to make quick decisions and back cases literally) alter the fabric particular complexity centers them up with comprehensive data of our lives – if the industry can around data and collaboration, is a must. Large molecule R&D in overcome its growing pains. For it makes sense that software will particular involves complex work large molecule R&D, the hurdles have to be the driving force behind from multiple teams. Biotechs are as high as the results are its industrialization. This software need software that can quickly promising. But we can clearly will need to do three central things: synthesize data from across teams delineate the challenges that stand and surface decision-quality in our way. And thankfully, modern results. For example, it shouldn’t software development is more than take days of data collation to up to the task. figure out which parameters during fermentation lead to the highest quality materials after purification.

Sajith Wickramasekara is the Co-Founder & CEO at Benchling.

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BIOTECH The Importance of Adopting an Informatics Platform Over Point Solutions

BY ROGER PELLEGRINI

13 BIOTECH

arge molecule R&D involves and guess parameters for their complex datasets, a broad The Advantages of the calculations. Ultimately, they’ll range of sample types, and Platform Approach produce a subpar yield. The Lintricate crossteam collaboration. platform approach increases When it comes to streamlining scientist usage by giving them a these workflows using third- unified experience and a single party informatics systems, there source of truth within which to are two basic approaches: the Unifed Data access all relevant R&D data. point solution approach, and Architecture Team hand-ofs can happen more the platform approach. In the With all your data readily quickly and be more thorough, more traditional point solution accessible, you can make better since all experimental context is approach, R&D organizations business decisions. Having your gathered in one place. Scientists work with a number of individual data in one place means you can can spend the majority of their tools. For large molecule R&D extract more meaningful learnings, time working together in a in particular, this approach falls faster. For example: Scientists single tool, leading to superior short when dealing with complex can see the locations of all cell data quality and collaboration data types, large datasets, lines that express a given plasmid. throughout the entirety of R&D. and dynamic workflows. Some Group heads can identify the companies try to resolve these conditions behind the fermentation issues by integrating numerous runs that generated the most point solutions, but this does desirable outcomes. Executives little to address the unreliable can track the progress of each data, scattered user experience, individual antibody program in Easy System Administration and burdensome system real-time, from early discovery & Confguration administration unavoidable with through development. With a single central system, point solutions. With the platform you can iterate on your R&D approach, an organization processes faster and more purchases a suite of applications easily. Large molecule R&D built on a common platform workflows are always evolving. to satisfy the majority of the Whether it’s adding a new sample organization’s informatics needs. Heightened type, adjusting a development This approach is favored by large User Adoption process, or testing a new method, molecule R&D organizations due Greater usage leads to superior the changes you make to your to its ability to unify complex data quality and collaboration. organization and to your science and large datasets, empower The inconsistent user experience need to be reflected in your collaboration across teams, and of siloed systems has severe informatics infrastructure. With centralize system administration. impact on data quality and a platform approach, you only productivity. For example, if have to manage a single solution a scientist has to navigate – not endless pieces of niche between multiple tools to design software that regularly break or go a plasmid, register that plasmid out-of-sync. in a completely separate system, and then submit a request via email to a protein purification team, chances are the protein purification team won’t get all the information they need. They’ll have to search through multiple systems for the right sequences

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The Platform Approach Point Solutions

Easily query the entirety of the data your R&D Spend days manually hunting for data across teams are producing. disparate systems.

Quickly identify promising candidates, superior Struggle to answer pivotal R&D questions with development processes, and early indicators of incomplete data. success/failure.

Track R&D in real-time, on one central dashboard. R&D operates in a black box.

Trace lineages from physical lots up to Lose track of the lineages of your digital entities. physical samples. Better Business Decisions Better

Spend months searching through disparate File for IND in days, not months. systems for the right data.

Always question the source and accuracy See the full history of any file, sample, or result. of your data.

Scientists collaborate much more easily with a single, Collaboration is much more difcult with data shared source of truth. scattered across disparate systems.

It isn’t always clear which results line up Link results to samples and experimental conditions. with which conditions.

& Collaboration Scientists search for scattered experimental Give every scientist complete experimental context, context across emails, personal file-sharing folders, Superior Data Quality so team hand-ofs are seamless. and locally-saved files.

Experiments are more reproducible, since all data is Experiment validity is called into question due accurate and interlinked. to incomplete or inaccurate data.

Iterate much more rapidly on your R&D processes, R&D has to wait for their software to catch up. since you only have to reconfigure a single, central Process iteration is continuously held back. informatics system.

If necessary, integrations are much easier, since Each additional integration creates multiple you only have to integrate with the single additional points of failure. central platform.

Manage user permissions from Risk data loss and noncompliant activity due one central location. to inability to keep track of permissions. Faster and More Easily and More Faster Iterate on R&D Processes on Iterate IT can develop novel extensions that Novel IT development is constrained by numerous leverage all R&D data. scattered dependencies.

15 SPOTLIGHT Tina Boville Directing Evolution to Engineer Nature

BY LILY HELFRICH

Dr. Tina Boville has two clear callings: bioengineering and es before graduate school were all sustainability. These callings led her to a postdoc in Frances in industry. Working on a process Arnold’s lab at Caltech, where she is using directed evolution development team at Amgen, Tina learned a rigorous approach to to develop noncanonical amino acids and novel biocatalysts. solving scientific problems and to carrying out scientific techniques. Leveraging this technology, her ultimate goal is to make Though she wasn’t doing discovery chemistry greener. work, her experience at Amgen taught her foundational, valuable skills. “The work I did was very with biology and an excitement Bioengineering Dragons meticulous, and it was a lot like a about its applications stuck with Christina Boville, known as Tina puzzle. In industry, you really have Tina throughout her childhood. to her friends and colleagues, can to find the smartest and most ef- These interests pushed her toward answer the question, “Did you cient way to tackle problems. It was a career in science—specifically always know you wanted to be a good place to learn.” towards a career in protein a scientist?” with more certainty Tina worked at Amgen as an engineering and biochemistry. Now, than most. “Yeah, I wanted to undergraduate intern and as a full- she’s working at the cutting edge of be a scientist since elementary time employee, and she later joined science and, like the Dragonriders school,” she says matter-of-factly. a smaller biotech company that was of Pern, creating things you Tina can even pinpoint an early developing a bioreactor for stem wouldn’t otherwise find in nature. interest in bioengineering. “It cell culture. After a couple of years sounds corny, but I read these in industry, Tina decided to pursue books called Dragonriders of Weaving Industry and Academia a graduate degree. She wanted Pern with genetically engineered Tina pursued a Ph.D. and is now an to be more independent, “to ask dragons. I got excited by the idea academic postdoc, but she took a bigger questions.” But she was also of engineering biology to create somewhat non-traditional path to determined to continue focusing on something new.” A fascination get there: her laboratory experienc- research with practical applications.

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Tina entered the Biochemistry oping novel enzymes for targeted program at University of Colorado biocatalysis of commercially useful Boulder, and she joined Dr. Hubert chemical reactions. Yin’s lab. The Yin Lab was a place Since joining the Arnold Lab, Tina where she could combine her has worked on developing nonca- interests in translational research nonical amino acids (ncAAs). “Non- and basic research. Her goal was to canonical AAs are found in 12% of develop drugs to treat autoimmune the highest-grossing drugs; they’re diseases and related conditions, found in agrochemicals or used TINA such as septic shock. She also stud- as probes for protein studies. With BOVILLE ied how existing drugs interact with more tools, we’ll be able to explore LOCATION the immune system. One project, of biology in new ways and to develop Pasadena, California which is she is most proud, led her new chemistry.” The current meth- to the discovery of novel molecular ods for ncAA development are lim- CURRENT POSITION targets for non-steroidal anti-in- ited, often resulting in prohibitively Resnick Prize Postdoctoral Scholar, Arnold Lab, Caltech flammatory drugs (NSAIDs). She expensive products. However, using found that NSAIDs inhibit caspases, directed evolution as a tool, Tina EDUCATIONAL + proteins known to mediate pro- and the Arnold Lab hope to create CAREER HISTORY grammed cell death—a finding that cheaper, easier ways to produce • B.A. Molecular, Cellular, “could explain some of the negative useful ncAAs. and Developmental Biology & Minor in side efects of these drugs in the Tina’s research, which takes Chemistry, University of human gut.” advantage of directed evolution, Colorado Boulder As she was approaching the end focuses on tryptophan synthase, • Ph.D. Biochemistry, of graduate school, Tina wanted an enzyme that catalyzes the final Yin Lab, University of to pursue an academic postdoc step of tryptophan biosynthesis. Colorado Boulder in which she could explore new The Arnold Lab had engineered the PRIMARY AREA OF and diferent biochemistry. “I have beta subunit of tryptophan synthase RESEARCH always been really interested in to work without its allosteric partner. I evolve enzymes to perform modulating biology to create novel This provided a simpler but more useful chemistry that you efects. In grad school, I did that versatile tool for the synthesis of don’t find in nature. with drugs and the immune system. noncanonical tryptophans. After RECENT PAPERS As a postdoc, I wanted to do that Tina joined the lab, she evolved 1. Engineered Biosynthesis with genetic tools; I wanted to engi- tryptophan synthase further and of β-Alkyl Tryptophan neer nature.” unlocked its potential to produce Analogues. Angewandte new and exciting products. Using Chemie International Edition 57: 45, 14764- From Drug Research to the evolved enzyme, she has syn- 14768 (2018). Directed Evolution thesized β-branched amino acids 2. Improved Synthesis With her sights set on developing and fluorescent ncAAs, including of 4-Cyanotryptophan genetic tools to engineer nature, 4-cyanotryptophan. and Other Tryptophan Tina was drawn to the work of Dr. For Tina, the Arnold Lab has been Analogues in Aqueous Solvent Using Variants Frances Arnold. Dr. Arnold and her a perfect fit. “I enjoy the challenge of TrpB from Thermotoga lab had pioneered work on directed of evolving enzymes to do jobs maritima. J. Org. Chem. 83: evolution, a protein engineering that don’t exist in nature. I also like 14, 7447-7452 (2018). method that mimics natural evo- the mindset that we’ve adopted by 3. Engineering enzymes lutionary processes, for which Dr. mixing biology, engineering, and for noncanonical amino acid synthesis. Chemical Arnold was later awarded the 2018 chemistry. It’s not just that we can Society Reviews 10: (2018). Nobel Prize in Chemistry. Using this make nature do something new, method, the Arnold Lab was devel- but also that we focus on what is

17

SPOTLIGHT

MORE ABOUT DR. BOVILLE “Noncanonical AAs are found in 12% of the highest-grossing drugs; they’re found in agrochemicals or used as probes for

Who has been an influential protein studies. With more tools, we’ll be mentor for you? Frances! She encourages us to be fearless. Just because able to explore biology in new ways and someone thinks your idea is impossible doesn’t mean you to develop new chemistry.” — Dr. Tina Boville shouldn’t do it. You should laugh at them and do it anyway. useful.” The applications of directed Postdoctoral Fellowship. Since then, evolution are nearly endless, but she has been thinking about making the Arnold Lab has focused much her interest in the environment more recent work on pharmaceuticals central to her research and to her What’s your dream and environmentally friendly career. “I’d like to see biocatalysts research project? applications. broadly used to have an impact I’ve been interested in bioleeching because mining is on how we approach sustainable one of the least efcient and Working Towards Green chemistry. There’s a better path most environmentally harmful Bioengineering forward for manufacturing, industries. It would be cool if we Tina has maintained a keen interest pharmaceutical development, could use enzymes to extract in sustainability throughout her and other R&D.” metals instead, but we’re a long way from that at the moment. career—another interest that Tina ultimately hopes to better drew her to the Arnold Lab. At CU both the environment and the Boulder, she was a “Green Labs biotech industry through her Team Lead,” a representative work. To make this happen, she is for an environmental advocacy planning to go back into industry, Where did you grow up? program. Tina helped labs make where she first came to appreciate Parker, Colorado small behavioral changes that smart and efcient science. How do you enjoy spending have a big environmental impact. your time outside of the lab? For example, she encouraged labs I like to do art; mostly painting to turn of and unplug instruments with acrylics, and some colored rather than keep them plugged in, WHY BENCHLING? pencils. I’ve also done some 3D to recycle uncontaminated plastic printing, and I like to play video games. rather than toss it into the autoclave I encouraged the Arnold Lab to use and the trash with contaminated Can you share a fun fact? Benchling because I think that electronic I’m an amateur fighter! I practice plastic, and to set the freezer to notebooks are a better alternative to Muay Thai. People don’t expect -70°C rather than -80°C. For her normal paper notebooks. It’s important it—I’m small and adorable! eforts, Tina was awarded the 2016 to have your information stored in a way Campus Green Labs Award. Tina that is easily accessible from anywhere. believes, “to the extent that they In the Arnold Lab, we constantly use do not compromise the integrity of Benchling to share data with other their science, scientists have a real project members and collaborators. It’s also an easier way to search lab responsibility to keep track of their notebooks and share sequencing consumption and to find ways to be data, plasmids, or protocols. Plus, I’m a more sustainable.” sustainability person; it doesn’t make At Caltech, Tina was awarded sense to use all that paper. a Resnick Sustainability Institute —Dr. Tina Boville

18 SUMMER 2019 VOL 1 BENCHTALK

BIOTECH The R&D Data Maturity Curve BY ROGER PELLEGRINI

esearch and development organizations are only as good as Rtheir data. Compared to traditional small molecule R&D, getting to “good data” in the emerging modalities of large molecule R&D is more challenging. Extracting insights from large molecule R&D data is an even greater challenge.

To measure and improve your competitive position, benchmark yourself with Benchling’s R&D Data Maturity Curve. Here, we outline the five main levels of data maturity, as LEVEL 4 well as concrete next steps to help you to take your data Forecasting to the next level, no matter where you are today. R&D program success and failure. Accelerating programs from LEVEL 1 LEVEL 3 end-to-end. Tracking Optimizing LEVEL 0 complete workfow Unable to experimental efciency for individual INSIGHTS AVAILABLE confdently track histories experimental LEVEL 2 teams outputs Improving individual assay efciency and output quality SOPHISTICATION

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LEVEL 0 LEVEL 1 Unable to confidently track Tracking complete experimental outputs experimental histories How many cell lines is your cell line development team With a modern informatics platform producing? Which antibody lots did those cell lines produce? in place, companies can trust in Which fermentation runs took place yesterday? Questions such the accuracy of the data their as these are difcult to answer using spreadsheets, legacy R&D teams are producing. At software, and point solutions. Many organizations at this level this stage, companies can trace work with data that’s inaccurate, incomplete, or unreliable. Unless the full experimental history of R&D data is centralized and interconnected on a single system, any candidate and view every the accuracy and completeness of your data will always be experiment that contributed to it. questionable. In addition, these organizations can measure the productivity of NEXT STEPS individual R&D teams to ensure the Tracking experimental outputs is the foundation of any R&D overall organization is on track to data strategy. At this stage, certain R&D organizations choose hit milestones. to integrate a number of point solutions with a custom database in an attempt to centralize data. However, this approach creates NEXT STEPS a brittle data infrastructure liable to frequent breakages, and it Tracking experiments is one thing, depends on disparate systems’ data being completely accurate but applying learnings to improve and up-to-date. Most organizations at this stage take the platform assay efciency and output quality approach, in which they purchase a central informatics platform is another. Identify core assays to serve as their single source of truth and power their data which, based on the rate at which strategy for the next levels. they’re producing outputs, seem like they’d be good candidates for improvement. Make sure you’re tracking key metrics for these assays around speed, output quantity, and output quality – and make sure your informatics platform is set up to associate results back to the specific assay runs that produced them.

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LEVEL 2 LEVEL 3 LEVEL 4 Improving individual Optimizing Forecasting R&D assay efficiency and workflow efficiency program success and failure. output quality. for individual teams. Accelerating programs Companies at this stage are able Beyond just improving the from end-to-end. to programmatically evaluate efciency of individual assays, At this stage, companies have the efciency of specific assays companies at this stage are able developed the capacity to by associating assay data and to evaluate and optimize entire accelerate R&D from the granular metadata back to individual runs intra- and inter-team workflows. level of individual assays, to the and analyzing it across runs. These What combination of parameters broader level of the entire program companies regularly and easily leads to the most successful lifecycle. They have also developed answer questions such as, “What fermentation runs? What are the a deeply engrained culture of conditions led to the highest protein biggest bottlenecks in your cell line using data to improve processes yields?” and have established a development workflow? Whenever at all levels of the organization. culture of improving R&D processes a workflow changes, these They not only push their based on data. companies make it a point to have programs along faster than their a framework in place for testing competitors – they also identify NEXT STEPS and optimizing that workflow. failure faster than competitors. Ensure your informatics platform’s With an informatics platform that workflow application is configured NEXT STEPS centralizes data throughout the to support core R&D processes. Structure executive-level organization, integrations that Set up a dashboard to track key dashboards to: Track program extract data from instruments and metrics around workflow speed, progress across teams. Identify automatically associate it with throughput, and results. Think which stages of your pipeline are sample records, and dashboards through which parameters it makes prime bottlenecks. Track candidate/ that track programs across teams most sense to modulate in service product performance relative to against historic benchmarks, of optimizing each particular past successes and failures. these organizations operate at the workflow. For each workflow you forefront of their fields. intend to optimize, integrate all relevant instruments with your informatics platform to automate data extraction.

THE BOTTOM LINE: CULTIVATING A CULTURE OF DATA R&D organizations are only as good as their data, but data is only as good as the people producing and interpreting it. You can purchase all the data management tools in the world, but at the end of the day, if you aren’t internally reinforcing the importance of data - and keeping it in mind as you make hiring decisions - then your organization won’t make the most of its data. Putting in place a concrete data strategy, informed by what you’re getting out of your data today and what you hope to in the future, is critical to cultivating a culture of data- driven decisions throughout your organization. Only with widespread organizational buy-in can you harness the full power of your R&D data.

21 RESEARCH

Sickly Sweet – How Utilisation of Sugars Afects the Disease Progression of Streptococcus pneumoniae BY VIKRANT MINHAS

treptococcus pneumoniae is causing disease.1 mococcal disease can be largely a gram-positive bacterial Of these, individual strains can attributed to the species’ vast ge- pathogen that infects difer greatly in their capacity to netic diversity: at least 98 capsular Smultiple sites of the body, causing cause disease. For example, some serotypes and more than 12,000 diseases such as pneumonia, otitis are only capable of infecting the clonal lineages or sequence types media, bacteraemia and meningitis. middle ear, while others can only (ST). This complexity has made it These diseases result in the death invade into the lungs. Major factors difcult to determine the mecha- of an estimated 1 million children that allow S. pneumoniae to cause nisms that allow certain strains to and in billions of dollars in health disease are known; in particular, we infect specific sites of the body.3 care costs annually.1 Despite this know that the capsule that sur- With ever increasing antibiotic massive mortality and morbidity, rounds the bacteria helps to evade resistance and only partial cover- S. pneumoniae is commonly the host immune system.2 Nonethe- age of current vaccines, we need carried asymptomatically in the less, the mechanisms that dictate to understand the mechanisms of nasopharynx, with a small subset where pneumococcal strains spread pneumococcal disease progression of pneumococcal strains capable of remain poorly understood. to help design optimal vaccines and 4,5 spreading deeper into the body and The poor understanding of pneu- therapeutics. HIGGINS. DAN BY ILLUSTRATED . ) 22883 ID LIBRARY, IMAGE HEALTH PUBLIC ( CDC CREDIT: ILLUSTRATION

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Clonal Comparisons Raffinose Utilisation which encodes an ATP binding to Determine Virulence Dictates Pneumococcal cassette (ABC) transporter and Mechanisms Disease Progression multiple enzymes responsible for This is where the Paton Lab in the Genomic comparisons identified the uptake and metabolism of the University of Adelaide’s Research SNPs in the gene rafR for the sero- trisaccharide sugar rafnose (Figure Centre for Infectious Diseases type 14 ST15 clonal pair, and in the 1). RafR is the regulator of this op- comes into the picture. We are gene rafK for the serotype 3 ST180 eron while rafK acts as the ATPase attempting to understand disease clonal pair. Both of these genes required by the ABC transporter for progression of S. pneumoniae by are part of the rafnose operon, rafnose uptake. focusing on closely related strains within the vast sea of pneumo- coccal genetic diversity. Previous studies from our lab have shown FIGURE 1. RAFFINOSE UPTAKE OPERON. that clinical clonal isolates of S. (A) Genetic loci encoding rafnose uptake and utilization in S. pneumoniae. The numbers pneumoniae, belonging to the below each gene refer to the locus tags in the serotype 14 ST15 947 genome. The same serotype and sequence locations of SNPs in serotype 14 ST15 and serotype 3 ST180 isolates are indicated with type (ST), spread to diferent sites asterisks; horizontal arrows show the locations of promoters. (B) Visual representation of the proteins that make up the ABC transporter of rafnose. in mice; these sites corresponded to their original isolation sites in humans. For example, serotype 3 ST180 and serotype 14 ST15 isolates from the blood of human patients invaded the lungs and/or the blood of intranasal challenged mice. Clones isolated from the ears of patients could not invade the lungs, but they instead spread to the ear and/or brain.6,7 Why can strains from the same clonal lineage stably infect diferent sites of the body? To investigate this, we performed on the blood and ear isolate pairs from the serotype 14 ST15 and serotype 3 ST180 clonal lines.8 Although members of the same serotype and ST type are ge- netically very similar, they have acquired distinct genetic changes such as single nucleotide poly- morphisms (SNPs) or insertions or deletions. We aligned the genomic sequences of each blood and ear isolate pair with the goal of identifying any changes that could be responsible for their varied disease .

23 RESEARCH

10 S. pneumoniae is a strictly fer- remains uncertain. Although FIGURE 2. GROWTH mentative bacteria; it relies solely humans are not readily able to me- AND RAFFINOSE PATHWAY on carbohydrate metabolism for tabolize it, dietary rafnose can be GENE EXPRESSION IN energy, growth and subsequently absorbed by the intestinal epithe- SEROTYPE 14 ST15 BLOOD AND virulence, as sugars provide the lium. This raises the possibility that EAR ISOLATES. simplest and most readily avail- at least small amounts of this sugar able forms of carbon and energy.9 are present on mucosal surfaces.11 Hence, we decided to investigate Another potential explanation for the efects of the SNPs in the the results from this study is that rafnose genes. rafR acts as a gene regulator. It’s Using rafnose as the bacteria’s plausible that rafR acts on other sole sugar source, we performed downstream genes, in turn influ- growth assays and quantitative real encing the disease progression of time RT-PCR assays. These assays these strains. demonstrated that blood isolates utilized rafnose better than their Role of Sugar Metabolism corresponding ear isolates (data in Virulence not shown). We were curious if S. pneumoniae faces diferent en- these diferences impacted disease vironments within the human host, progression. With allelic exchange with each environment providing mutagenesis, I swapped the rafR distinct carbohydrate sources.9 alleles between the blood and Thus, the ability to respond to and ear isolates of serotype 14 ST15. utilize diferent sugars must be These rafR swapped mutants crucial for both pneumococcal sur- showed a switch in their ability to vival and disease progression. The utilize rafnose, suggesting that importance of sugar metabolism is the SNP in rafR was driving the clear: the pneumococcus dedicates diferential rafnose utilisation 30% of all transport mechanisms (Figure 2). Strikingly, in intranasal for carbohydrate import. It possess- mouse challenge models, the rafR es at least 21 phosphotransferase swapped strains also displayed systems (PTS) and up to 8 ABC a switch in their disease profiles. transporters for this purpose.12 Oth- The rafR swapped blood isolate er studies have shown that these spread to the ear and brain, while carbohydrate transporters impact rafR swapped ear isolate instead pneumococcal disease progres- invaded the lungs (Figure 3). These sion. For example, a sucrose PTS (A) Growth of blood isolate, ear isolate and results suggest that the ability to and an ABC transporter system respective rafR swapped mutant in CDM+Raf

utilize rafnose plays a role in dic- of serotype 4 pneumococci each was monitored by OD600 for 12 h. Data are tating tissue tropism and pneumo- play roles in murine colonisation mean OD600 ± SD from triplicate assays. (B&C) coccal disease progression. and pneumonia, respectively. In The indicated strains were grown in CDM+Glc to an OD600 of 0.2, washed and resuspended Rafnose is a plant-derived this same serotype, transporters in CDM+Raf, and then incubated at 37°C for trisaccharide sugar present in many for carbohydrates such as glucose, a further 30 min. RNA was then extracted, staple foods, particularly beans galactose and mannose impacted and levels of aga (B) and rafG (C), mRNA and soy. Its influence on disease invasive pneumococcal disease.12 were analyzed by qRT-PCR using 16S rRNA progression in this study is rather Yet, compared to other factors that as an internal control. The data presented are the means ± SD from three independent confounding, and the precise mech- influence pneumococcal virulence, experiments. * indicates P < 0.05, ** indicates anism by which rafnose utilization carbohydrate metabolism is rela- P < 0.01, and **** indicates P < 0.0001, by determines disease progression tively understudied. unpaired t test.

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References 1. Weiser JN, Ferreira DM, Paton JC. Streptococcus pneumoniae: transmission, colonization and invasion. Nat Rev Microbiol. 2018;16(6):355-367. 2. Kadioglu A, Weiser JN, Paton FIGURE 3. VIRULENCE PHENOTYPE OF RAFR EXCHANGE MUTANTS. JC, Andrew PW. The role of Groups of 16 mice were infected intranasally with 108 CFU of the indicated strain. At Streptococcus pneumoniae virulence factors in host respiratory 24 h, all mice from each group were euthanized and numbers of pneumococci in the colonization and disease. Nat Rev indicated tissues/sites were quantified. Viable counts (total CFU per tissue) are shown Microbiol. 2008;6(4):288-301. for each mouse at each site; horizontal bars indicate the geometric mean (GM) CFU for 3. Enright MC, Spratt BG. A multilocus each group; and the broken line indicates the threshold for detection. Diferences in GM sequence typing scheme for bacterial loads between groups are indicated by asterisks: *, P < 0.05, **, P < 0.01, and ****, Streptococcus pneumoniae: P < 0.0001, by unpaired t test. identification of clones associated with serious invasive disease. Microbiology. 1998;144(11):3049- Nasopharynx Lungs 3060. 4. Lynch J, Zhanel G. Streptococcus pneumoniae : Does Antimicrobial Resistance Matter? Semin Respir Crit Care Med. 2009;30(02):210-238. 5. Katoh S, Suzuki M, Ariyoshi K, Morimoto K. Serotype Replacement in Adult Pneumococcal Pneumonia after the Introduction of Seven- Valent Pneumococcal Conjugate Vaccines for Children in Japan: a Systematic Literature Review and Pooled Data Analysis. Jpn J Infect Dis. 2017;70(5):495-501. 6. Trappetti C, Maten E van der, Amin Z, et al. Site of Isolation Determines Biofilm Formation and Virulence Phenotypes of Streptococcus Ear Brain pneumoniae Serotype 3 Clinical Isolates. Infect Immun. 2013;81(2):505-513. 7. Amin Z, Harvey RM, Wang H, et al. Isolation site influences virulence phenotype of serotype 14 Streptococcus pneumoniae strains belonging to multilocus sequence type 15. Infect Immun. 2015;83(12):4781-4790. 8. Minhas V, Harvey RM, McAllister LJ, et al. Capacity to utilize rafnose dictates pneumococcal disease phenotype. MBio. 2019;10(1). 9. Härtel T, Eylert E, Schulz C, et al. Characterization of Central Carbon Metabolism of Streptococcus pneumoniae by Isotopologue Profiling. J Biol Chem. 2012;287(6):4260-4274. 10. Kumar V, Rani A, Goyal L, et al. S. pneumoniae is a major cause Sucrose and Rafnose Family of pneumonia and otitis media, as Oligosaccharides (RFOs) in Soybean well as a cause of septicemia and Seeds As Influenced by Genotype and Growing Location. J Agric Food meningitis, so this bacteria creates Chem. 2010;58(8):5081-5085. massive disease burdens. With the 11. Lobley RW, Burrows PC, Warwick R, Dawson DJ, Holmes R. Simultaneous shortcomings of current vaccines assessment of intestinal and antibiotics, novel vaccines and permeability and lactose tolerance therapeutics are urgently needed. with orally administered rafnose, lactose and L-arabinose. Clin Sci Future research on the impact of (Lond). 1990;79(2):175-183. sugar metabolism on the disease Vikrant Minhas is a graduate 12. Buckwalter CM, King SJ. Pneumococcal carbohydrate progression of S. pneumoniae will student in James Paton’s lab transport: food for thought. Trends aid in this endeavour. at The University of Adelaide. Microbiol. 2012;20(11):517-522.

25 INDUSTRY Five Key Takeaways from Benchtalk West BY KYRSTIN LULOW

rom developing therapeutics that are sustaining human life, to materials that Fare sustainable for our planet, biotechnology and life science R&D is a mission-in-mind industry made up of individuals and organizations that are striving every day to better the world we live in. At Benchling, we are striving to build a platform that is elevating the way scientists work. This April, Benchling hosted Benchtalk West, our first West Coast user forum, where industry leaders across the life sciences gathered to discuss their groundbreaking work, the challenges they face, and the solutions they are discovering. Speakers included: • Tom Crevier, Director of Life science R&D is evolving faster the way legacy systems like paper Automation, Equipment, and than ever, and despite the wide notebooks and custom LIMS do. Data Management, Juno variety of questions individual orga- Rather, the future of biotechnolo- Therapeutics nizations are racing to answer, they gy calls for software that actively • Deven Dharm, Director of all face similar challenges. Here are supports the lab’s goals as its R&D Software Engineering, Bolt five key takeaways that arose from pipelines progress. Threads the day’s presentations and conver- Members of the Bolt Threads • Patrick Johnson, Systems sations about the new frontiers of team joined Benchtalk West to Analyst, Bolt Threads life sciences R&D. share how they use data to drive in- • Jeannette Grant, Associate novation as they produce nature-in- Director of Project Management, Data needs to actively spired materials and textiles. Patrick Adicet Bio drive insights, not lie idle Johnson, Bolt Threads’ Systems • Kristy Hawkins, Co-Founder and 1Scientists, whether in nascent Analyst, reported that with Bench- CSO, Antheia startups or in seasoned labs, are ling’s applications the Bolt biology • Jackie Papkof, CSO discovering breakthrough tech- team flexibly tracks their fermenta- Microbiome, Assembly nologies. As labs grow, both in tion data, the materials team struc- Biosciences people and process complexity, tures their data and defines their • Hari Jayaram, VP of Technology, they need software solutions that workflows, and all of Bolt’s teams Spotlight Therapeutics aren’t just passively recording data, communicate more readily with one

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another. Now, Bolt has complete are conceived along the way. At Many of the companies represented visibility into their R&D pipelines Bolt, their scientists are discovering at Benchtalk West not only research and can chart the course of their new constructs for their materials and discover novel technologies, research with greater confidence. faster than their paper notebooks they also design, develop, and Benchtalk also featured Jean- could keep up. Not only are they build working versions of those nette Grant from Adicet Bio, a pioneering new technologies, the technologies. company dedicated to immune cell ways in which they discover and CSO and Co-Founder Kristy therapy. Jeannette discussed how develop those technologies are Hawkins and her team at Antheia Adicet uses Benchling’s platform constantly evolving. are developing novel strains and to set standardized guidelines for Spotlight’s VP of Technology, Hari fermentation processes to produce record keeping and data entry that Jayaram, put it this way, plant-based pharmaceuticals. are followed company-wide. Adicet Their goal is to implement these also uses Benchling to compile “At Spotlight we are pioneering a procedures as a platform for drug data for long term analysis. As new class of biologics capable of discovery. To transform their pipe- Adicet grows, both new and veteran editing specific cell populations in line, multiple teams need to be able employees record cell engineering vivo. This breakthrough work re- to track and measure everything experiments, track gamma delta quires fast iteration cycles that are across their many fermentation pro- T-cells, CARs, and TCRs in the closely monitored and centralized. cess iterations, such as the number Registry, and easily analyze their It’s important that we can continu- of strains built and the variety of complex cell engineering data. ously ask ourselves in real time enzymes tested. They also need to – is the process improving?” be able to analyze those iterations Sofware for biotech needs –Hari Jayaram, VP of Technology, to chart improvements. to bend, not break, in the Spotlight Therapeutics 2face of variation and iteration Data centralization Life science R&D companies are In order to manage and monitor 4 is key to ensuring highly individual, with unique life their highly iterative process- regulatory compliance cycles that vary from company es, Spotlight uses Benchling to Regulatory processes, like IND to company and from iteration to track, measure, and standardize filings and patent maintenance, iteration over time within a given their data. require biotech companies to sub- company. The biotechnology indus- mit organized data with detailed try needs software tools that are Platform companies histories. Outdated tools like paper flexible enough to bend when pro- 3 are the new norm and notebooks and other legacy record cesses evolve, rather than breaking biotech R&D needs trackable, keeping systems slow preparation when new methods develop. reproducible, shareable data for these processes and ultimately For many labs, their discoveries Biotech companies have multiple delay approval of revolutionary, are unprecedented – and in some teams, each with their own highly potentially life-saving technologies. cases unpredictable. New iterations specific functions and workflows. When Adicet Bio was operating arise out of innovations, tweaks Yet each team depends on the oth- on paper notebooks and emails, to the process here and there that ers to make one cohesive pipeline. preparing information for these

“We don’t know exactly how the process is going to evolve, so we need a super fexible system, which will allow us to evolve literally every day, every week… Benchling essentially allowed us to handle that – a universal source of truth and a super fexible system that allowed us to evolve rapidly.”

—Deven Dharm, Director of Sofware Engineering, Bolt Threads

27 BIOTECH

processes was incredibly chal- lenging. But once they adopted Benchling, Adicet’s data was cen- tralized and organized in a unified platform. Adicet has 2,500 note- book entries – across 38 projects and 50 authors – and 1,500 unique, registered entities that are all inter- linked within Benchling. With this level of structured data capture, Adicet’s preparation for IND filings is more efcient than ever.

To plan for success, you must also plan 5for attrition along the way Whether you are working on an For Jackie Papkof of Assembly processes. To move forward, indu- emerging biologics project or Biosciences, accounting for unfo- stry leaders need to both recha- working at an emerging biotech reseen setbacks is fundamental to racterize what it means to plan for company, setting yourself up for long term planning. As Assembly success and leverage their data to success can be tricky at the start. sets timelines for isolating and drive decision-making. Decisions about both science and testing novel bacteria, they also Here at Benchling, we are business rely heavily on data- so consider possible attrition. As they humbled by both the opportunity how do you plan months to years progress, they then factor succes- to serve the growing life science ahead when you don’t yet have ses and failures from the previous industry with the Benchling plat- project outcomes or output data? cycle into future planning. form and the possibility to facilitate For the speakers at Benchtalk dialogue between members of West, the key to planning for their What comes next? the life science R&D community. success includes planning for some There was a buzz of excitement Though projects may vary greatly setbacks too. that filled the air at Benchtalk West from lab to lab across academia Kristy Hawkins of Antheia spoke this April after hearing from leaders and industry, a common thread about the field of synthetic biology, and change-makers from across connects the tireless work of life where it seems like no matter how biotech R&D. The future of biologics science professionals: the goal to well you plan, there is always more is bright, promising innovations and impact life for the better. Whether to take into account. Though An- technologies that could radically your work is dedicated to protec- theia’s timelines for developing the- improve the way we live. To get ting human life or life on this planet, ir first molecules didn’t quite meet there, the industry is moving in a we hope to continue to engage the their initial projections, they use this direction that calls for bigger and greater life sciences community outcome as data to forecast for the better data management that can and foster discourse that advances future. handle the rapid evolution of R&D the industry.

“Benchling has allowed us to answer a lot of long-term questions about our data that we wouldn’t have been able to answer before. We have months and months of data on process development that, without Benchling, we wouldn’t be able to compile and analyze.”

—Jeannette Grant, Associate Director of Project Management, Adicet Bio

28 SPRINGSUMMER 2019 2019 VOL VOL 1 1 BENCHTALK BENCHTALK Benchling is the leading Life Sciences R&D Cloud. Scientists using cutting-edge techniques like CRISPR, CAR-T immunotherapy, and genetic engineering depend on Benchling’s suite of cloud applications to design DNA, collaborate on experiments, manage research workfows, and make critical R&D decisions. Over 170,000 scientists use Benchling globally across pharmaceutical corporations, leading biotech companies, and the world’s most renowned academic labs. Our mission is to accelerate the pace of cutting-edge research with cutting-edge sofware.

Benchtalk is Benchling’s quarterly periodical that showcases scientifc leaders in academia and industry, updates readers on Benchling news, and reports on advancements in the life sciences. Benchtalk aims to facilitate discourse among members of the life science community and connect them to revolutionary ideas.

If you or someone you know is interested in being featured in Benchtalk, please email [email protected]. PRODUCED BY