SPARKing the genius of the next generation of scientists

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.

Overcoming obstacles in blood stem cell therapies

Photo Credit: OHSU Knight Cancer Institute

Today, we here at CIRM wanted to provide an update on the fascinating world of hematopoietic (blood) stem cell-based therapies.  What is the current status of this promising field and what are some of the challenges that need to be overcome? Dr. Kelly Shepard, Associate Director of Discovery and Translation here at CIRM, answers these questions and many more in the blog entry below.

There have been a number of exciting advances in regenerative medicine over the past few years, especially in the use of gene therapy and hematopoietic (blood) stem cell transplantation to treat and even cure various diseases of the blood and immune system. These studies built off groundbreaking research by Till and McCulloch in the 1950-60’s, who identified a rare and special stem cell in the bone marrow of mice that gives rise to all cells of the blood and immune system for the lifetime of the animal, the “hematopoietic stem cell”, or HSC. It wasn’t long before scientists and doctors realized the therapeutic implications of this discovery, and the journey to identify the human counterpart began. Fast forward to the present, and HSC transplantation (HSCT) has become a standard medical procedure for treating various cancers and genetic disorders of the blood. The basic premise is this: a patient with a diseased or defective blood/immune system receives an infusion of healthy HSCs, which are typically procured from donated bone marrow or umbilical cords, but in certain situations, might come from the patient him/herself. Once established in the recipient, these healthy cells will divide and regenerate a new blood and immune system over the course of the patient’s lifetime.

For HSCT to be successful, the donor cells must “engraft”, or take up permanent residence in their new environment. This usually necessitates “conditioning” the recipient with some form of chemotherapy or radiation, which eliminates some of the patient’s own cells to create room for the new arrivals. Unfortunately, conditioning creates a situation where the patient is extremely vulnerable to infections and other complications during the period of recovery, as it will take weeks for his/her blood and immune systems to be reestablished. These inherent risks mean HSC transplants can only be offered to patients with life threatening diseases such as leukemia, or to those with significant blood/immune disorders who are sufficiently healthy to tolerate the toxic conditioning regimen and to weather the extended period of recovery.

A second major issue preventing a more widespread use of HSCT is the shortage of healthy donor HSCs that are available for transplant, which must be immune matched to the recipient to prevent rejection. Immune matching is also critical to avoid a dangerous complication called graft vs. host disease, where the transplanted cells or their progeny launch an immune attack against the recipient’s organs, often leading to chronic disease and sometimes, death. Unfortunately, there are many people who have no compatible donors and for whom the risk of even a partially matched transplant is unacceptable.

Scientists and clinicians have long sought means to overcome the technical challenges of HSCT in order to “unleash” its true potential to cure and treat a wider variety of diseases, and to  make it feasible (and affordable) for a much larger number of patients. CIRM has endeavored to support novel approaches that could hopefully produce game changing advances for the field. Some of these approaches were recently highlighted in a Perspective article, published in Stem Cells Translational Medicine in early 2020, along with a discussion of other important advances in related areas, listed below. More information can be found in that article or referring to our website to learn more about the individual projects.

Approaches that could increase the availability of healthy HSCs for transplant include development of non-toxic conditioning regimens to facilitate a patient’s acceptance and recovery from the transplant procedure; novel technologies for expanding HSCs for transplant; and gene modification technologies to correct inherited mutations in HSCs.
Illustration Credit: Dr. Kelly Shepard, CIRM

Developing New Sources of Healthy and Immune Compatible HSCs for transplant

  • Exploring ways to produce HSCs from pluripotent stem cells in the lab
  • Expanding populations of HSCs that are already present in donated tissues such as cord blood
  • Using genetic engineering to “repair” defects in the DNA of HSCs from patients with inherited blood and/or immune disorders
  • Using genetic engineering to create “immune invisible” or “universal donor” HSCs that will not be rejected after transplantation

Developing Safer and More Tolerable Conditioning Regimens

  • Exploring reduced intensity forms of conditioning with drugs or radiation
  • Using antibodies rather than chemicals to free up space in the bone marrow for incoming, donor HSCs
  • Using dietary methods to free up space in the bone marrow for incoming, donor HSCs

Accelerating Reovery of Immune Function Lost Through Conditioning

  • Adding back key populations of immune cells to protect the host during regeneration of their immune system
  • Discovering new drugs and treatments to accelerate the pace of regeneration after transplant, or to prevent the death of HSCs that survived conditioning

Overcoming these scientific and technical challenges could create a paradigm shift in the way HSCT is applied and used and consequently, reduce the costs and risks associated with the procedure. In this way, the true potential of HSCT could be unleashed for the greatest good.