Gerhard Bauer

Learning life lessons in the lab

/ Kevin McCormack / Leave a comment
Rohan Upadhyay, CIRM SPARK student 2021

One of the most amazing parts of an amazing job is getting to know the students who take part in CIRM’s SPARK (Summer Program to Accelerate Regenerative Medicine Knowledge) program. It’s an internship giving high school students, that reflect the diversity of California, a chance to work in a world-class stem cell research facility.

This year because of the pandemic I didn’t get a chance to meet them in person but reading the blogs they wrote about their experiences I feel as if I know them anyway.

The blogs were fun, creative, engaging and dealt with many issues, as well as stem cell and gene therapy research.

A common theme was how hard the students, many of whom knew little about stem cells before they started, had to work just to understand all the scientific jargon.

Areana Ramirez, who did her internship at UC Davis summed it up nicely when she wrote:

“Despite the struggles of taking over an hour to read a scientific article and researching what every other word meant, it was rewarding to know that all of the strain I had put on my brain was going toward a larger understanding of what it means to help others. I may not know everything about osteogenic differentiation or the polyamine pathway, but I do know the adversities that patients with Snyder-Robinson are facing and the work that is being done to help them. I do know how hard each one of our mentors are working to find new cures and are coming up with innovating ideas that will only help humankind.”

Lauren Ginn at City of Hope had the same experience, but said it taught her a valuable lesson:

“Make no mistake, searching for answers through research can sometimes feel like shooting arrows at a bulls-eye out of sight. Nonetheless, what CIRM SPARK has taught me is the potential for exploration that lies in the unknown. This internship showed me that there is so much more to science than the facts printed in textbooks.”

Rohan Upadhyay at UC Davis discovered that even when something doesn’t work out, you can still learn a lot:

“I asked my mentor (Gerhard Bauer) about what he thought had occurred. But unlike the textbooks there was no obvious answer. My mentor and I could only speculate what had occurred. It was at this point that I realized the true nature of research: every research project leads to more questions that need to be answered. As a result there is no endpoint to research. Instead there are only new beginnings.”

Melanie Nguyen, also at UC Davis, wrote her blog as a poem. But she saved the best part for the prose at the end:

“Like a hematopoietic stem cell, I have learned that I am able to pursue my different interests, to be multi-potential. One can indulge in the joys of biology while simultaneously live out their dreams of being an amateur poet. I choose it all. Similarly, a bone marrow stem cell can become whatever it may please—red, white, platelet. It’s ability to divide and differentiate is the source of its ingenuity. I view myself in the same light. Whether I can influence others with research, words, or stories, I know that with each route I will be able to make change in personalized ways.”

For Lizbeth Bonilla, at Stanford, her experiences transcended the personal and took on an even bigger significance:

“As a first-generation Mexican American, my family was thrilled about this internship and opportunity especially knowing it came from a prestigious institution. Unfortunately there is very little to no representation in our community in regards to the S.T.E.M. field. Our dreams of education and prosperity for the future have to be compromised because of the lack of support and resources. To maintain pride in our culture, we focus on work ethics and family, hoping it will be the next generations’ time to bring successful opportunities home. However, while this is a hope widely shared the effort to have it realized is often limited to men. A Latina woman’s success and interest in education are still celebrated, but not expected. As a first-generation Latina, I want to prove that I can have a career and hopefully contribute to raising the next leading generation, not with the hope that dreams are possible but to be living proof that they are.”

Reading the blogs it was sometimes easy to forget these are 16 and 17 year old students. They write with creativity, humor, thoughtfulness and maturity. They learned a lot about stem cell research over the summer. But I think they also learned a lot more about who they are as individuals and what they can achieve.

SPARKing the genius of the next generation of scientists

/ Kevin McCormack / 4 Comments
Dr. Kelly Shepard, SPARK program director

After almost 18 months – and counting – that have put us all to the test, made us wear masks, work from home, limit contact with all but the closest of family and friends it’s a wonderful thing to be able to get a glimpse of the future and feel that we are in good hands.

That’s how it felt this week when we held our SPARK conference. SPARK stands for Summer Program to Accelerate Regenerative Medicine Knowledge. The program helps high school students, that reflect the diversity of California, to take part in summer research at various institutions with a stem cell, gene therapy, or regenerative medicine focus. 

We hope the experience will inspire these students to become the next generation of scientists. Many of the students are first generation Americans, many also come from families with limited resources and without our help might not be able to afford an internship like this.

As part of the program we ask the students to not only do stem cell research and prepare a poster of their work, we also ask them to blog about it. And the blogs they write are things of beauty.

It’s hard to pick winners from so many fine writers, but in the end a team of CIRMites managed to identify a few we thought really stood out. First was Hassan Samiullah who spent his internship at Cedars-Sinai. Hassan wrote three blogs charting his journey at the research facility, working with mice and a deadly brain cancer. This is part of one of his entries.

“When many of us think of scientists, we think of crazy people performing crazy procedures in a lab. While I won’t try refuting the first part, the crazy procedures can actually be very consequential to society at large. What is now common knowledge was once found in the discussion section of a research paper. The therapies we will use to treat cancer tomorrow are being tested in labs today, even if they’re being injected into mice brains.” 

We liked his writing because he explained complex science clearly, with humor and obvious delight that he got to work in a research facility with “real” scientists. Crazy or otherwise. Here is his final blog which, I think, reflects the skill and creativity he brought to the task.

I’m almost at the end of my 7.5-week internship at Cedars-Sinai through the CIRM SPARK program. Looking back at the whole experience, I don’t think I’ve ever been through anything that’s required as much critical thinking.

I remember seeing pX330-dual-U6-Pten-Cdkn2a-Ex2-chimeric-BB-CBh-espCas9, and not having the slightest idea of what any of it meant. Sure, I understood the basics of what I was told: it’s a plasmid that can be transfected into mice brains to model glioblastoma tumors. But what do any of those strings of letters and numbers have to do with that? Well, I saw “Pten” and read it aloud: “P-t-e-n.” After I spelled it out like a kindergartener, I finally made a realization. p10 is a gene—specifically a tumor suppressor gene. I figured that the two jumbles of letters and numbers to the right must also be genes. Sure enough, the plasmid contains three mutated genes that get incorporated into a mouse’s genome, eventually leading to cancer. We didn’t actually end up using this model, however. Part of being in science is procedures not working out as expected.

Resilience is key.

When I found out that the image analysis software I was supposed to use didn’t support the type of data collection I needed to perform, I had to burn a little midnight oil to count the cells of interest manually. It proved to be well worth the effort: we found that mice tumors treated with radiation saw increased interactions between immune cells and endogenous (brain-resident) stem cells, even though they had fewer cells from the original tumor (difference wasn’t statistically significant due to an outlier in the control group). This is an important finding because it may explain the common narrative of glioblastoma: many patients see their tumors recede but suffer an aggressive relapse. This relapse may be due to immune cells’ interacting with stem cells to make them resistant to future treatments.

Understanding stem cells are so critical to cancer research, just as they are to many other fields of research. It is critical for everyone involved in science, medicine, healthcare, and policymaking to recognize and act on the potential of the regenerative medicine field to dramatically improve the quality of life for so many people.

This is just the beginning of my journey in science! I really look forward to seeing what’s next.

We look forward to it too Hassan.

Hassan wasn’t the only one we singled out for praise. Sheila Teker spent her summer at Children’s Hospital Oakland Research Institute. She says her internship didn’t get off to a very encouraging start.

“When the CHORI security guard implied that “kids aren’t allowed” on my first day–likely assuming I was a 10-year-old smuggling myself into a highly professional laboratory – I’d also personally doubted my presence there. Being 16, I wasn’t sure I’d fit in with others in such an intimidating environment; and never did I think, applying for this program, that I could be working with stem cells. I’d heard about stem cells in the news, science classes, and the like, but even doing any cell culturing at all seemed inaccessible to me. At my age, I’d become accustomed to and discouraged by rejection since I was perceived as “too young” for anything.”

Over the course of the summer Sheila showed that while you might question her age, no one should ever question her talent and determination.  

Finally, we thought Alvin Cheng of Stanford also deserved recognition for his fine writing, starting with a really fun way to introduce his research into lower back pain.

“Perhaps a corpse would be reanimated”, Mary Shelley wrote her in 1831 edition of “Frankenstein”. Decades prior, Luigi Galvani discovered with his wife how a dead frog’s leg could twitch when an electric spark was induced. ‘Galvanism’ became the scientific basis behind the infamous novel and bioelectricity.”

While many of the students had to do their research remotely this year, that did not stop them doing amazing work. And working remotely might actually be good training for the future. CIRM’s Dr. Kelly Shepard, the Associate Director of Discovery and Translation and who runs the SPARK program, pointed out to the students that scientists now do research on the international space station from their labs here on earth, so the skills these SPARK students learned this past summer might prove invaluable in years to come.

Regardless of where they work, we see great things in the futures of these young scientists.

The Journey of a Homegrown Stem Cell Research All-Star

/ Todd Dubnicoff / Leave a comment

Nothing makes a professional sports team prouder than its homegrown talent. Training and mentoring a promising, hard-working athlete who eventually helps carry the team to a championship can lift the spirits of an entire city.

Gerhard and Brian 1

Brian Fury

Here at CIRM, we hold a similar sense of pride in Brian Fury, one of our own homegrown all-stars. Nearly a decade ago, Brian was accepted into the inaugural class of CIRM’s Bridges program which provides paid stem cell research internships to students at California universities and colleges that don’t have major stem cell research programs. The aim of the program, which has trained over 1200 students to date, is to build the stem cell work force here in California to accelerate stem cell treatments to patients with unmet medical needs.

A CIRM full circle
Today, Brian is doing just that as manager of manufacturing at the UC Davis Institute for Regenerative Cures (IRC) where he leads the preparation of stem cell therapy products for clinical trials in patients. It was at UC Davis that he did his CIRM Bridges internship as a Sacramento State masters student back in 2009. So, he’s really come full circle, especially considering he currently works in a CIRM-funded facility and manufactures stem cell therapy products for CIRM-funded clinical trials.

gerhardbauer

Gerhard Bauer

“Many of the technicians we have in the [cell manufacturing] facility are actually from the Bridges program CIRM has funded, and were educated by us,” Gerhard Bauer, Brian’s boss and director of the facility, explained to me. “Brian, in particular, has made me incredibly proud. To witness that the skills and knowledge I imparted onto my student would make him such an integral part of our program and would lead to so many novel products to be administered to people, helping with so many devastating diseases is a very special experience. I treasure it every day.”

“It sustains me”
Brian’s career path wasn’t always headed toward stem cell science. In a previous life, he was an undergrad in computer management information systems. It was a required biology class at the time that first sparked his interest in the subject. He was fascinated by the course and was inspired by his professor, Cathy Bradshaw. He still recalls a conversation he had with her to better understand her enthusiasm for biology:

“I asked her, ‘what is it about biology that really made you decide this is what you wanted to do?’ And she just said, ‘It sustains me. It is air in my lungs.’ It was what she lived and breathed. That really stuck with me early on.“

Still, Brian went on to earn his computer degree and worked as a computer professional for several years after college. But when the dot com boom went bust in the early 2000’s, Brian saw it as a sign to re-invent himself. Remembering that course with Professor Bradshaw, he went back to school to pursue a biology degree at Sacramento State University.

On a path before there was a path
Not content with just his textbooks and lectures at Sac State, Brian offered to volunteer in any lab he could find, looking for opportunities to get hands-on experience:

Sac State 1

Brian at work during his Sacramento State days.

“I was really hungry to get involved and I really wanted to not just be in class and learning about all these amazing things in biology but I also wanted to start putting them to work. And so, I looked for any opportunity that I could to become actively involved in actually seeing how biology really works and not just the theory.”

This drive to learn led to several volunteer stints in labs on campus as well as a lab manager job. But it was an opportunity he pursued as he was finishing up his degree that really set in motion his current career path. Gerhard Bauer happened to be giving a guest lecture at Sac State about UC Davis’ efforts to develop a stem cell-based treatment for HIV. Hearing that talk was an epiphany for Brian. “That’s really what hooked me in and helped determine that this is definitely the field that I want to enter into. It was my stepping off point.”

GerhardBrianJan

Brian Fury (center) flanked by mentors Gerhard Bauer (left) and Jan Nolta (right)

Inspired, Brian secured a volunteering gig on that project at UC Davis – along with all his other commitments at Sac State – working under Bauer and Dr. Jan Nolta, the director of the UC Davis Stem Cell Program.

That was 2008 and this little path Brian was creating by himself was just about to get some serious pavement. The next year, Sacramento State was one of sixteen California schools that was awarded the CIRM Bridges to Stem Cell Research grant. Their five-year, $3 million award (the total CIRM investment for all the schools was over $55 million) helped support a full-blown, stem cell research-focused master’s program which included 12-month, CIRM-funded internships. One of the host researchers for the internships was, you guessed it, Jan Nolta at UC Davis.

Good Manufacturing Practice (GMP) was a good move
Applying to this new program was a no brainer for Brian and, sure enough, he was one of ten students selected for the first-year class. His volunteer HIV project in the Nolta lab seamlessly dovetailed into his Bridges internship project. He was placed under the mentorship of Dr. Joseph Anderson, a researcher in the Nolta lab at the time, and gained many important skills in stem cell research. Brian’s project focused on a stem cell and gene therapy approach to making HIV-resistant immune cells with the long-term goal of eradicating the virus in patients. In fact, follow on studies by the Anderson lab have helped lead to a CIRM-funded clinical trial, now underway at UC Davis, that’s testing a stem cell-based treatment for HIV/AIDs patients.

After his Bridges internship came to a close, Brian worked on a few short-term research projects at UC Davis but then found himself in a similar spot: needing to strike out on a career path that wasn’t necessarily clearly paved. He reached out to Nolta and Bauer and basically cut to the chase in an email asking, “do you know anybody?”. Bauer reply immediately, “yeah, me!”. It was late 2011 and UC Davis had built a Good Manufacturing Practice (GMP) facility with the help of a CIRM Major Facility grant. Bauer only had one technician at the time and work was starting to pick up.

gmp_facility

The Good Manufacturing Practice (GMP) facility in UC Davis’ Institute for Regenerative Cures.

A GMP facility is a specialized laboratory where clinical-grade cell products are prepared for use in people. To ensure the cells are not contaminated, the entire lab is sealed off from the outside environment and researchers must don full-body lab suits. We produced the video below about the GMP facility just before it opened.

Bauer knew Brian would be perfect at their GMP facility:

“Brian was a student in the first cohort of CIRM Bridges trainees and took my class Bio225 – stem cell biology and manufacturing practices. He excelled in this class, and I also could observe his lab skills in the GMP training part incorporated in this class. I was very lucky to be able to hire Brian then, since I knew what excellent abilities he had in GMP manufacturing.”

CIRM-supported student now supporting CIRM-funded clinical trials

brianingmp

Brian Fury suited up in GMP facility

Since then, Brian has worked his way up to managing the entire GMP facility and its production of cell therapy products. At last count, he and the five people he supervises are juggling sixteen cell manufacturing projects. One of his current clients is Angiocrine which has a CIRM-funded clinical trial testing a cell therapy aimed to improve the availability and engraftment of blood stem cell transplants. This treatment is geared for cancer patients who have had their cancerous bone marrow removed by chemotherapy.

When a company like Angiocrine approaches Brian at the GMP facility, they already have a well-defined method for generating their cell product. Brian’s challenge is figuring out how to scale up that process to make enough cells for all the patients participating in the clinical trial. And on top of that, he must design the procedures for the clean room environment of the GMP facility, where every element of making the cells must be written down and tracked to demonstrate safety to the Food and Drug Administration (FDA).

The right time, the right place…and a whole bunch of determination and passion
It’s extremely precise and challenging work but that’s what makes it so exciting for Brian. He tells me he’s never bored and always wakes up looking forward to what each day’s challenges will bring and figuring out how he and his team are going get these products into the clinic. It’s a responsibility he takes very seriously because he realizes what it means for his clients:

“I invest as much energy and passion and commitment into these projects as I would my own family. This is extremely important to me and I feel so incredibly fortunate to have the opportunity to work on things like this. The reality is, in the GMP, people are bringing their life’s work to us in the hopes we can help people on the other end. They share all their years of development, knowledge and experience and put it in our hands and hope we can scale this up to make it meaningful for patients in need of these treatments.”

Despite all his impressive accomplishments, Brian is a very modest guy using phrases like “I was just in the right place at the right time,” during our conversation. But I was glad to hear him add “and I was the right candidate”. Because it’s clear to me that his determination and passion are the reasons for his success and is the epitome of the type of researcher CIRM had hoped its investment in the Bridges program and our SPARK high school internship program would produce for the stem cell research field.

That’s why we’ll be brimming over with an extra dose of pride on the day that one of Brian’s CIRM-funded stem cell therapy products reaches the goal line with an FDA approval.

Cell mate: the man who makes stem cells for clinical trials

/ Kevin McCormack / Leave a comment

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.