“A scientist in his laboratory is not a mere technician: he is also a child confronting natural phenomena that impress him as though they were fairy tales.” – Marie Curie

“All my life through, the new sights of Nature made me rejoice like a child.” – Marie Curie

Tempo has been publishing interviews with some of today’s experts across science. Today we meet Dr. Ruby Yanru Chen-Tsai, an expert in mammalian embryonic stem cells and transgenic  rodent  models. Having achieved a PhD from Cornell and after two decades leading research at Stanford, Ruby has begun a new adventure in biotech with Applied StemCell (ASC). ASC’s goal is to design, produce and sell an optimized series of cell and animal models for basic research, drug discovery, bioprocessing, bioproduction and preclinical applications. She has authored many highly-cited scientific papers and is the holder of several patents. We caught up with Ruby to hear her story of why she became a scientist, what drives her, what her experiences thus far have taught her and what advice she has for those starting out in biotech. Without further ado, we’re pleased to introduce: Dr. Ruby Chen-Tsai.

Me: Tell us a little about what led you to decide to study science and when you realized it was your passion.

Ruby: I was inspired by Marie Curie when I was young, and wanted to be a scientist ever since.

Me: What made you decide to come to the US? Was there something particular about moving here that appealed to you?

Ruby: I didn’t think about coming to the US… During my last semester in college, I applied for a graduate program at Fudan University in Shanghai and did really well in the entrance exam. I was then selected to participate in an exam for CUSBEA program (China US Biochemistry Examination and Admission). This was a joint program organized by the US and China Ministry of Education. Dr. Ray Wu who was a professor at Cornell University was the founders of the program. Through this exam and subsequent interviews, I was one of thirty students selected from all over China to come to the US. I was accepted into the Biochemistry PhD program at Cornell University.

Me: Tell us about your PhD research. What discoveries did you make? I know a lot of my friends have had very different experiences and each PhD came with its own unique challenges and rewards. What was your experience like? Were there bumps in the road? Did you enjoy being at Cornell and in New York in general?

Ruby: The first year at Cornell was difficult for me both in academic studies due to the language barrier and in terms of adjusting to a new culture. Once I started research rotations in labs, I was more in my comfort zone. After 3 rotations, I chose to stay in a lab focusing on DNA replication studies headed by Dr. Bik Tye. One of the main reasons for choosing this lab was that it used yeast genetics as an approach to dissect the mechanism for DNA replication particularly in replication initiation. At the time genetic tools and methods were well established in yeast compared to other organisms.

My project was to study the function of several MCM (minichromosome maintenance) proteins in DNA replication initiation. The discoveries I made through the study include (1) The flux of a basic pathway glycolysis affects MCM protein activity in initiation of DNA replication; (2) A cell cycle protein CDC46/MCM5 is involved in DNA replication. I spent 6 years completing my PhD, which was a bit longer than what I had anticipated. I had also hoped for a more “earthshaking” story to publish. But at the end, I think everything worked out okay and I was able to build a solid foundation for furthering my career later. Cornell in Ithaca, upstate New York is a beautiful place with many state parks, waterfalls, and endless hiking trails, although the winters are long and cold.

Me: After your PhD, you came to Stanford University in California and received a post-doc fellowship. What were some of the exciting questions you got to explore as part of this experience?

Ruby: I had a chance to attend a conference in San Francisco when I was doing my PhD at Cornell. I just fell in love with the Bay Area and wanted to find a post-doc position here. I was lucky to join Dr. Barsh’s lab in the Department of Genetics at the Howard Hughes Medical Institute (HHMI) at Stanford University. I was sure that I wanted to do research on mammalian genetics, a logical transition from yeast genetics. Dr. Barsh was one of the first investigators at Stanford who utilized mouse genetics to study some of the fundamental questions, one of which is gene regulation. My project was to study gene regulation in the “Agouti” gene, a coat color gene in mice. Agouti gene expression is quite complex and fascinating with varying coat color depending on the particular alleles present. My study uncovered a model for molecular evolution of the agouti locus in which homologous recombination produces a reversible switch in allelic identity. I was also involved in a study on agouti related protein, “Agrp”, whose function is related to obesity. Through my post-doc training, I mastered the technique of manipulating the mouse embryos, working with embryonic stem cells, and the generation of transgenic mouse models. This work has had a significant impact on my career path.

Me:  After your post-doc, you became the Director of Stanford’s Transgenic Research Center and then as the Director at Stanford’s Cancer Institute Core Technology Facilities. Tell us about each position: how did they compare?

Ruby: When I was still a postdoc, genetic tools for modifying the mouse genome became available. These tools included gene targeting in embryonic stem cells and gene modification in mouse embryos through pronuclear microinjection. These procedures were very technically demanding so it was more cost-effective to establish a centralized resource to handle these procedures. Because of my post-doc training in mouse genetics and gene modification, I became the founding director of the Stanford Transgenic Research Center and served as the director for the next 16 years. This position was highly rewarding. The Center generated genetically modified mouse models including both transgenic and gene targeted models for Stanford and non-Stanford investigators. On average, we were generating about 100 animal models per year. I was one of the very first center directors who made a significant contribution to standardize the procedures and charge-back systems for this very important resource. Some researchers who I made the animal models for about 15 years ago are now customers of Applied StemCell.

Me: What would you say is your greatest accomplishment from this period, something there something you’re most proud of?

Ruby: As an Associate Director of Stanford Cancer Institute, I oversaw nine technology core facilities including genomics, proteomics, microscopy imaging, flow cytometry, tissue bank, animal tumor models, and immune monitoring cores to ensure cancer center programs and members’ research needs are well supported. I effectively developed and managed multi-million dollar budget to support all cancer center shared resources through the NCI’s CCSG grant (cancer center support grant). One thing I am proud of doing at this role is leading and implementing a university-wide, central management system that facilitates the workflow of over 30 university core labs.

A major scientific contribution I made on developing the integrase system as well as applying other gene editing technologies for site-specific gene modification in both cells and animal models. I had the chance to collaborate with some of the top scientists in the world and contributed to the genome editing field. I worked with Dr. Michele Calos of Stanford University on using the phiC31 integrase in the production of transgenic mice (Hollis et al. 2003), and with Dr. Yitao Zeng of Shanghai Jiao-Tong University in the production of transgenic bovine cells (Ma et al. 2006). I collaborated with Dr. Matthew Porteus of Stanford on using zinc finger nucleases and Tal effector nucleases (TALENs) on gene editing in mouse embryos. Additionally, I collaborated with Dr. Liqun Luo of Stanford on using the phiC31 integrase/attP system for generating transgenic mice with site-specific DNA integration. This study has resulted in a patent (US9,125,385 B2) and two publications (Tasic et al. 2011; Tasic et al. 2012). Prior to joining ASC, my research at Stanford focused on using TARGATTTM to genetically modify Parkinson patient specific iPSCs with the goal of optimizing neuronal differentiation. This work was funded by CIRM (California Institute of Regenerative Medicine) and generated a peer-reviewed publication with me as a co-corresponding author (Zhu et al. 2014).

Me: What made you decide it was time to move on from Stanford? How did you know it was time for a new adventure?

Ruby: I cofounded Applied StemCell, Inc. in 2008 right after the discovery of induced pluripotent stem cells (iPSCs) by Yamanaka. I was always interested in new adventures. At the beginning, the company was only a couple of people. I was able to do my full time job at Stanford and consulted for the company. Over time, the company grew and in turn they needed my efforts more and more. To avoid conflict of interest and also to devote my full attention to the company, I decided to work for ASC full-time about 3 and a half years ago.

Me: You’re now a co-founder and Chief Scientific Officer of Applied StemCells Inc. Tell us about your company. How did you make the transition from a prestigious academic position to a start-up adventure?

Ruby: Applied StemCell Inc. (ASC) is a fast growing biotechnology company headquartered in Milpitas, California. Our goal is to advance genome editing and stem cell innovation for biomedical research and the biotechnology industry. After years of research and development, we offer an optimized series of tools for research. We are currently focusing on three areas: (1) cell line generation for bio-production and bioassays (2) patient-relevant cell models for personalized medicine and (3) physiologically predictive animal models of human diseases. We have recently closed a new round of funding that is to support our internal stem cell based gene therapy programs.

The main difference between my academic position and my role at ASC is the scale of responsibilities and urgency. Even though I was supervising a lot more people at Stanford with multiple responsibilities, the responsibilities and urgency at ASC are at a much higher level. We have to constantly think about how to get ahead in a rapidly-growing and very competitive market. We also have to worry about balancing our budget so that we can “live” for another few months. I never had to worry about these things while I was at Stanford. But the upside of working at a company is the impact one can make and contribute to the growth of the company, and ultimately to the society. It is very rewarding.

Me: How did you meet your fellow co-founder and investors?

Ruby: The other co-founder was my college classmate at Fudan University. We have known each other for many years. It was the right time to start a company together. Our initial angel investors were all friends and families who had faith in us.

Me: A common challenge among scientist is burning out. What advice would you give to scientists just starting out on how from becoming frustrated or jaded? What motivates you each day?

Ruby: Science can be frustrating. Most of the time research doesn’t work the way you anticipated. I try to focus on a bigger picture and try to solve problems one at a time. I have a to-do list everyday and what motivates me is to cross out each task.

Me: Do you have advice for female biotech entrepreneurs getting started?

Ruby: I don’t see too many differences between female versus male entrepreneurs. As any entrepreneur, he/she needs support from his/her family. There is no doubt some of the family time is going to be compromised and sacrifice needs to be made, but it can all be worked out as a family. Professionally, there are as many successful female entrepreneurs as male entrepreneurs. My 2 cent advice is to set a clear goal and execute you plan to reach it.

Me: What are your thoughts on current stem cell research? Do you think stem cells will soon be used routinely in clinics? Do you feel they’re the future for treating neurodegenerative disease like Alzheimer’s Disease?

Ruby: Stem cell research is currently at its most exciting time ever, especially combined with genome editing technologies. It is difficult to predict how soon stem cells will be used routinely in clinics but if I had to speculate, I would say in 5-10 years. Among the disease indications that are being researched, I believe treating neurodegenerative disease such as Alzheimer’s Disease will be one of the first attempts.

Me: What’s next for you? Do you have any future plans or dreams?

Ruby: My next goal is to build a stem cell based gene therapy program at ASC and take it to the clinic in the next 2-3 years.

Me: What do you like to do outside of work (hobbies, interests, etc.)?

Ruby: I try to exercise at least 3 times a week. I like zumba, Ujam, yoga and running.

Me: Tell us something surprising about yourself!

Ruby: I used to sing and perform. I was trained by a famous opera singer in China and was almost going to pursue a professional singing career. But I’m glad I chose science and got to come to the US. I also met President Reagan when I was in China. I was the student representative to meet Reagan when he visited China back in 1984. There were pictures of me presenting flowers to Reagan on major newspaper and TV in China.

From the team here at Tempo, thank you for interviewing with us, Ruby!

Interview by Olwen Reina. Contact Olwen at olwen@tempobioscience.com.
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